In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
In this issue of European Urology, Rane et al [1] report on measurement of telomerase (hTERT) expression, TERC RNA expression, telomere length, and telomerase activity to define for the first time the differentiation status of the epithelium in benign prostatic hyperplasia (BPH) samples from patients. Classically, keratin, p63, prostate-specific antigen, androgen receptor, and NKX3.1 markers are used to define basal and luminal epithelial-cell populations in tissue. A key finding from this study is that there is no measurable telomerase activity in luminal epithelial cells; however, luminal cells have longer telomeres than committed basal cells. On the basis of these observations, the authors suggest that luminal epithelial cells cannot arise from a population of basal cells, which have shorter telomeres. The authors propose that a progenitor cell can give rise to both committed basal and luminal cell types through independent differentiation pathways.
Hypothetically, a progenitor cell is characterised by long telomeres and telomerase activity, these are features of both stem and transit amplifying cell types [2]. Lineage tracking has revealed that it most likely that luminal cells are the cell of origin for prostate cancer [3], [4], and [5], and luminal progenitor cells are now also identified as a key contributor to epithelial hyperplasia in BPH. Luminal progenitor cells have been identified in human prostate cancers and have been implicated as the resistant cell population surviving androgen deprivation therapy [6]. The study found that BPH epithelium consists of varied proportions of luminal and basal cells [1]. As both cell types arise from progenitor cells with high telomerase activity, the authors propose the use of telomerase inhibitors to treat BPH rather than drugs targeting hormonal signalling (eg, anti-androgens and α1 blockers). Small-molecule inhibitors of telomerase have failed to reach clinical trials, although oligonucleotide inhibitors such as GRN163L are currently being evaluated [7] and have shown efficacy in prostate cancer in preclinical studies targeting a putative stem-like tumour-initiating cell population [8]. Alternative strategies for targeting hTERT activity include inhibitors of HSP90, a chaperone required for hTERT maturation and activation and for stabilisation of the non–ligand-bound androgen receptor. Rane et al suggest that telomerase inhibitors would be faster-acting and more effective debulking agents than drugs, particularly anti-androgens, since it is predicted that the latter have their most potent impact on luminal epithelial cells, in which the androgen receptor is highly expressed.
This is an interesting hypothesis; however, the therapeutic efficacy is not unimodal and requires some degree of tissue-type or disease-based specificity to ensure an acceptable therapeutic index. The further that we move towards drugging the biology of primordial or progenitor-like cells, the greater are the challenges in delivering a targeted or condition-specific impact for the patient. This is the very essence of the challenge facing the field in treating not only BPH but also cancer. Most therapies essentially involve an attempt to debulk; in a cancer context, this is also the basis for the impact of radiotherapy or chemotherapy on tumours. While there are clear conceptual overlaps, a direct link between BPH and the emergence of prostate cancer remains to be proven, even though the conditions often coexist in patients [9]. From a therapeutic perspective, it will be interesting to debate a bimodal approach to therapy given that both telomerase inhibition and anti-androgen therapy have limitations because of their impact on different components of the lineage development tree in the prostate gland. If the overall goal in treating BPH is to achieve an optimal or normal distribution balance for the size of these subpopulations, then this indicates that phasic or alternating administration of telomerase inhibitors and anti-androgens is warranted if telomerase inhibition can restrict a progenitor population and anti-androgens can affect a more differentiated epithelial population of cells. One example of this phasic approach in a clinical trial setting is the bipolar androgen therapy trial, which alternates androgen deprivation therapy with super-high doses of testosterone [10]. The goal is perhaps to inhibit telomerase activity to push the balance of cell types towards a differentiated luminal androgen-dependent cell pool in one treatment phase, and then to deplete that pool using anti-androgens in a subsequent treatment phase.
For implementation of this approach with telomerase inhibitors and anti-androgens, a huge number of open questions prompted by the work of Rane et al need to be addressed. First, does telomerase inhibition change the cell type distribution in tissue towards an expanded pool of differentiated cells and, if so, over what timeframe. Second, does administration of drugs targeting androgen signalling deplete these differentiated cells and, if so, over what timeframe. Most importantly, how do we assess these effects in vivo or via sampling of biological fluids.
In conclusion, this study has two key elements. First, it defines some properties of a cell subpopulation in prostate tissue that may contribute to the emergence of BPH. Second, it identifies a potential avenue for therapeutic intervention to treat BPH. Translation of these findings will require intensive study, but the work provides an invaluable new focus in the field.
I.G.M. is a reader at Queen's University Belfast and funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research. He is a group leader within the Centre for Molecular Medicine (Norway), an adjunct member of the Department of Molecular Oncology, Oslo University Hospitals, and a visiting scientist and honorary senior visiting research fellow at Cambridge University. His research is funded in Norway by the Norwegian Cancer Society, Helse Sor-Ost, the Norwegian Research Council and the Movember Foundation. A.P. is a postdoctoral researcher at Queen's University Belfast and is funded through the PCUK/Movember Centre of Excellence for Prostate Cancer Research.
