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Prostate cancer: New therapies in the pipeline?
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Dispatch
Prostate cancer: New therapies in the pipeline? Adam Hurlstone and Donald M. Black
Cancer of the prostate gland is the highest unavoidable cause of cancer mortality in men. The recent identification and characterisation of genes specifically expressed in prostate cancer helps us to understand its molecular basis and should offer new therapeutic avenues to combat this disease. Address: Beatson Institute for Cancer Research, CRC Beatson Laboratories, Switchback Road, Bearsden, Glasgow G61 1BD, UK. E-mail: [email protected] Current Biology 1998, 8:R428–R430 http://biomednet.com/elecref/09609822008R0428 © Current Biology Ltd ISSN 0960-9822
Prostate cancer (prostatic adenocarcinoma) is the most frequently diagnosed malignancy in men in many of the world’s developed countries, and accounts for 10% of cancer-related deaths in men. An increase in the histological incidence of prostate cancer has been reported recently in many countries in the western world. The greatest proportion of this increase is due to more sensitive and earlier detection of the disease, largely attributable to the introduction of testing for the presence of a prostate cancerassociated protein in serum. However, a more alarming upward trend in age-adjusted mortality rates from prostate cancer reveals a genuine increase in the incidence of aggressive cancers [1]. The majority of prostate cancer is diagnosed incidentally as benign prostatic hyperplasia, which affects approximately 80% of males by the age of 80 years. It has been estimated that about one in six prostate glands resected to alleviate this condition contains areas of carcinoma. Additionally, post-mortem examinations indicate that 10–30% of all men older than 50 years harbour a ‘silent’ microscopic form of prostate cancer. The majority of latent carcinomas follow an indolent course, but a small proportion become aggressive and these often prove fatal [2]. Localised prostate cancer is potentially curable by radical prostatectomy or radiotherapy. However, the majority of prostate cancer patients present with disseminated disease. Ablation of male hormones — androgens —is the key form of treatment for these individuals, as the cancer cells initially depend on hormone supply for growth. This measure is largely palliative, though, and most patients show disease progression between 12 and 18 months after this treatment begins, as the prostate tumour cells progress to androgen-independent growth. Regrettably, there is no effective remedy for hormone-resistant disease, and survival time is typically 2–3 years from the time of diagnosis of metastatic disease [3].
The increased incidence of prostate cancer and a burgeoning older population make it imperative that reliable prognostic indicators become available to clinicians to allow the early detection of that subset of latent tumours that is likely to become aggressive. In turn, this requires that the cellular and molecular events underlying tumour progression and recurrence be fully understood. Markers of prostate cancer
A number of markers associated with the prostate gland have been identified to date including prostate-specific antigen (PSA) [4], prostate carcinoma-associated glycoprotein complex (PAC) [5], prostatic acid phosphatase (PAP), prostate mucin antigen (PMA) [6], and prostate-specific membrane antigen (PSM) [7]; only a subset of these markers are elevated in or specifically associated with prostate cancer, however. A number of studies have focused on PSA, a serine protease that liquefies seminal coagulum. PSA is secreted by luminal epithelial cells of prostate glands and can be detected in the bloodstream. Expression of PSA is higher in normal than in malignant prostate cells, and even falls in recurrent hormone-resistant disease. However, the vast increase in the number of PSA-producing cells due to the cancer-induced enlargement of the prostate gland results in the elevation of PSA protein levels in the serum of prostate cancer patients. Measurements of serum levels of PSA are therefore used clinically to provide an indication of tumour burden, metastatic involvement, and response to surgery, radiotherapy and androgen ablation. PSA levels fail to discriminate accurately, however, between indolent and aggressive cancers, benign prostatic hyperplasia, prostatitis and other non-malignant disorders; thus, PSA measurements alone cannot be used diagnostically or prognostically. By analysing PSA or PSM messenger RNA (mRNA) expression by the highly sensitive reverse-transcriptioncoupled polymerase chain reaction (RT–PCR) approach, it is possible to detect the presence of a single prostate cancer cell among a million non-prostatic cells [9]. PCR analysis can therefore be used to detect prostate cancer micrometastases distributed by the bloodstream [8], thus providing an early indication of prostate cancer progression. PSM may be a more accurate and sensitive indicator of the metastatic progression of prostate cancer than PSA, because expression of this marker is elevated in tumour cells, hormone-resistant cancer cells, and bony metastases [10], unlike PSA. Two recent papers herald important advances in our ability to detect and possibly intervene in the progress of
Dispatch
prostate cancer. In a paper from Owen Witte’s laboratory, Reiter et al. [11] document the discovery of a prostate cancer-associated cell surface antigen, prostate stem cell antigen (PSCA), which was overexpressed in about 90% of the prostate cancer specimens they examined. In the other paper, Paul Fisher’s group have continued their analysis of the prostate cancer tumour-inducing gene 1 (PTI-1), demonstrating the dominant transforming potential of the gene and showing that expression of antisense PTI-1 RNA reverses the tumorigenicity of an experimentally transformed cell line, while inhibiting the growth of a number of carcinoma-derived cell lines [12].
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of prostate cancer. If coupled to radioisotopes or cytotoxic agents, antibodies specific to these markers could even selectively kill cancer cells. Identification of the natural ligands for both PSM and PSCA might allow small peptides to be designed that could selectively bind cancer cells, substituting for antibody-mediated therapies and avoiding associated problems with immunological attenuation. Finally, the restricted expression of PSCA to prostate cancer tissue and its expression on the surface of cells advance its candidacy as a possible prostate cancer immunogen for anti-cancer vaccination therapy. Prostate cancer tumour-inducing gene, PTI-1
Prostate stem cell antigen, PSCA
PSCA is a previously unidentified molecule related to stem cell antigen 2 (Sca-2), a member of the Thy-1/Ly-6 superfamily of glycosylphosphatidylinositol (GPI)anchored cell surface antigens [11]. The authors demonstrated, using mRNA in situ hybridisation, that the gene encoding PSCA was overexpressed in 90% of prostate cancers. These included high-grade intraepithelial neoplasia and hormone-resistant cancers. Overexpression of PSCA may result from gene amplification because the PSCA gene maps to chromosomal region 8q24.2, which has been reported to be a region of allelic gain and amplification in a majority of advanced and recurrent prostate cancers. Reiter et al. [11] confirm that PSCA is GPIanchored at the cell surface, and also show that PSCA is expressed only in a subset of basal epithelial cells in normal prostate gland. The authors conclude that this finding supports other data suggesting that prostate cancers arise from the transformation of basal cells, which are believed to be the progenitors of the terminally differentiated secretory cells in the prostate gland. Finally, although no data are available as yet to support this, by analogy with Sca-2, the authors propose that PSCA may play a role in the survival or self-renewal of the basal epithelial cells. The association between elevated PSCA expression and prostate tumorigenesis, coupled with sustained expression of this molecule even in recurrent hormone-resistant disease, promotes the use of this marker in disease detection, and possibly in prognosis and treatment. Serum detection of PSCA protein may be possible if, like other GPI-anchored proteins, a fraction of the PSCA molecules are secreted. Alternatively, RT–PCR detection of PSCA expression could be used, as with PSM, to detect disease spread by the bloodstream. Also, the cell surface expression of PSCA or PSM could allow for the immunological detection of metastases using specific antibodies raised against these proteins. In fact, a clinical study using an antibody raised against PSM is currently under way [13]. If these studies prove successful, detection of prostatecancer-associated molecules in the blood of patients would clearly be of immense benefit for the clinical management
Expression of the PTI-1 gene appears to be even more restricted to prostate cancer cells than that of either PMS or PSCA: again, RT–PCR was used to detect the expression of the PTI-1 gene in the blood of prostate cancer patients [14]. The PTI-1 gene was cloned by a complex experimental strategy. This involved transferring DNA from a metastatic prostate carcinoma-derived cell line into rat embryo fibroblasts, followed by the injection of these cells into ‘nude’ mice — mice that lack T cells and therefore cannot elicit an immune response — thereby generating tumours. RNA from the tumours was then characterised using differential display, a PCR-based technique for comparing RNA profiles between different cell populations, in order to identify genes that had increased expression in the tumours, one of which was PTI-1 [15]. The PTI-1 mRNA has a most peculiar structure. It comprises a 630 bp 5′-untranslated region, with very high similarity (about 90% identity) to the Mycoplasma hyopneumoniae 23S ribosomal RNA, fused to a sequence which encodes a mutated and truncated version of human translation elongation factor-1α (EF-1α). It appears therefore that the PTI-1 gene arose by fusion between these two genes, followed by subsequent divergence from the ancestral sequences. It is not clear if the PTI-1 gene is present in the human genome as a single genetic locus, or if it is a fusion product specifically generated in cancer cells by chromosomal translocation, deletion or insertion. The region of PTI-1 that is homologous to the prokaryotic 23S ribosomal RNA has been confirmed to be present in humans by PCR analysis of genomic DNA [14]: direct confirmation by Southern hybridisation analysis of genomic DNA using this region of the PTI-1 gene as a probe and by cloning and chromosomally mapping the PTI-1 locus would help eradicate any suspicions that this gene might be in some way artefactual. This information would also enable us to determine whether the PTI-1 locus is linked to familial prostate cancer, which is believed to be responsible for about 10% of the cases of the disease. The PTI-1 mRNA has been detected only in carcinoma cell lines (not exclusively prostatic, but also breast and colon cancer cell lines), and in about 90% of prostate cancers. Importantly,
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Current Biology, Vol 8 No 12
the PTI-1 gene is not expressed in normal prostate glands or in benign prostatic hyperplasia [15].
these genes could potentially even be used to tackle recurrent disease, the Gordian knot waiting to be cut.
In their recent paper [12], the Fisher group provide further cogent evidence for the dominant transforming ability of PTI-1, thus substantiating it as one of very few oncogenes identified to date — including c-ERBB-2/NEU/HER-2, c-Ki-RAS, c-MET, and c-MYC — that are implicated in prostate tumorigenesis. From studies largely of EF-1α homologues in bacteria and yeast, EF-1α is believed to ensure proper codon–anticodon binding interactions between mRNAs and transfer RNAs (tRNAs) at the tRNA acceptor site of the ribosome [16]. Mutations in EF-1α would be likely to affect its proofreading ability and could therefore promote the synthesis of mutant proteins, which themselves may possess transforming ability. This theory for the oncogenic potential of EF-1α has been termed the ‘translational infidelity hypothesis’ [15].
References
Altered protein translation has previously been associated with cellular transformation. Enhanced expression of EF1α has been demonstrated in tumours of the pancreas, colon, breast, lung, and stomach when compared with that in adjacent normal tissues [17]. Overexpression of the wild-type form of the eukaryotic translation initiation factor eIF-4E, the mRNA cap-binding subunit of eIF-4F, or a constitutively active form of the eIF-2α initiation factor promotes fibroblast transformation. The work of the Fisher laboratory on PTI-1 further strengthens the proposed link between translation and transformation. The ability of antisense PTI-1 RNA to revert the malignant phenotype of PTI-1-transformed cells highlights the potential for this mode of oncogene inactivation as an antitumour gene therapy, should mechanisms of cell targeting and gene transfer become practicable. Alternatively, it may be possible to engineer small antisense oligonucleotides to inhibit PTI-1 expression. These could be delivered systemically and would diffuse throughout tissue spaces finding their way even to metastases. Alternatively, it might be possible to exploit the tissue-specific expression of molecules such as PMS, PSA, PSCA and PTI-1 in antiprostate cancer gene therapy approaches: promoters of the genes encoding these products could be used to drive the expression of suicide genes (such as the thymidine kinase gene of herpes simplex virus) specifically within prostate cancer cells. In fact, as you read this, you can be quite sure that these promoters have already been inserted into someone’s favourite ‘gene therapy vector’, and that pilot studies are currently under way in a ‘pet’ model system to determine the efficacy of such an approach. The demonstration that the PMS, PSCA and PTI-1 genes are expressed in androgen-insensitive cells, unlike PSA which is expressed in an androgen-dependent manner, suggests that therapies intervening with the function of
1. Whittemore AS: Trends in prostate cancer incidence and mortality. In Cancer Surveys 19-20. Edited by Doll R, Fraumeni JF Jr, Muir CS. Cold Spring Harbor New York: Cold Spring Harbor Laboratory Press; 1994:309-322. 2. Coffey DS: Prostate cancer. An overview of an increasing dilemma. Cancer 1993, 71(3 Suppl):880-886. 3. Crawford ED: Hormonal therapy of prostatic carcinoma. Defining the challenge. Cancer 1990, 66(5 Suppl):1035-1038. 4. Lundwall A, Lilja H: Molecular cloning of human prostate specific antigen cDNA. FEBS Lett 1987 214:317-322. 5. Wright GL Jr, Beckett ML, Lipford GB, Haley CL, Schellhammer PF: A novel prostate carcinoma-associated glycoprotein complex (PAC) recognised by monoclonal antibody TURP-27. Int J Cancer 1991, 47:717-725. 6. Beckett ML, Wright GL Jr: Characterization of a prostate carcinoma mucin-like antigen (PMA). Int J Cancer 1995, 62:703-710. 7. Israeli RS, Powell CT, Fair WR, Heston WD: Molecular cloning of a prostate-specific membrane antigen. Cancer Res 1993, 53:227-230. 8. Moreno JG, Croce CM, Fischer R, Monne M, Vihko P, Mulholland SG, Gomella LG: Detection of hematogenous micrometastasis in patients with prostate cancer. Cancer Res 1992, 52:6110-6112. 9. Israeli RS, Miller WH Jr, Su SL, Powell CT, Fair WR, Samadi DS, Huryk RF, DeBlasio A, Edwards ET, Wise GJ, et al.: Sensitive nested reverse transcription polymerase chain reaction detection of circulating prostatic tumor cells:comparison of prostate-specific membrane antigen and prostate-specific antigen-based assays. Cancer Res 1994, 54:6306-6310. 10. Israeli RS, Powell CT, Corr JG, Fair WR, Heston WD: Expression of the prostate-specific membrane antigen. Cancer Res 1994, 54:1807-1811. 11. Reiter RE, Gu Z, Watabe T, Thomas G, Szigeti K, Davis E, Wahl M, Nisitani S, Yamashiro J, Le Beau MM, Loda M, Witte ON: Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc Natl Acad Sci USA 1998, 95:1735-1740. 12. Su Z-Z, Goldstein NI, Fisher PB: Antisense inhibition of the PTI-1 oncogene reverses cancer phenotypes. Proc Natl Acad Sci USA 1998, 95:1764-1769. 13. Sodee DB, Conant R, Chalfant M, Miron S, Klein E, Bahnson R, Spirnak JP, Carlin B, Bellon EM, Rogers B: Preliminary imaging results using In-111 labelled CYT-356 (Prostascint) in the detection of recurrent prostate cancer. Clin Nucl Med 1996, 21:759-767. 14. Sun Y, Lin J, Katz AE, Fisher PB: Human prostatic carcinoma oncogene PTI-1 is expressed in human tumor cell lines and prostate carcinoma patient blood samples. Cancer Res 1997, 57:18-23. 15. Shen R, Su Z-Z, Olsson CA, Fisher PB: Identification of the human prostatic carcinoma oncogene PTI-1 by rapid expression cloning and differential RNA display. Proc Natl Acad Sci USA 1995, 92:6778-6782. 16. Merrick WC: Mechanism and regulation of eukaryotic protein synthesis. Microbiol Rev 1992, 56:291-315. 17. Grant AG, Flomen RM, Tizard MLV, Grant DAW: Differential screening of a human pancreatic adenocarcinoma lambda gt11 expression library has identified increased transcription of elongation factor EF-1 alpha in tumour cells. Int J Cancer 1992, 51:740-745.
Dispatch
Prostate cancer: New therapies in the pipeline? Adam Hurlstone and Donald M. Black
Cancer of the prostate gland is the highest unavoidable cause of cancer mortality in men. The recent identification and characterisation of genes specifically expressed in prostate cancer helps us to understand its molecular basis and should offer new therapeutic avenues to combat this disease. Address: Beatson Institute for Cancer Research, CRC Beatson Laboratories, Switchback Road, Bearsden, Glasgow G61 1BD, UK. E-mail: [email protected] Current Biology 1998, 8:R428–R430 http://biomednet.com/elecref/09609822008R0428 © Current Biology Ltd ISSN 0960-9822
Prostate cancer (prostatic adenocarcinoma) is the most frequently diagnosed malignancy in men in many of the world’s developed countries, and accounts for 10% of cancer-related deaths in men. An increase in the histological incidence of prostate cancer has been reported recently in many countries in the western world. The greatest proportion of this increase is due to more sensitive and earlier detection of the disease, largely attributable to the introduction of testing for the presence of a prostate cancerassociated protein in serum. However, a more alarming upward trend in age-adjusted mortality rates from prostate cancer reveals a genuine increase in the incidence of aggressive cancers [1]. The majority of prostate cancer is diagnosed incidentally as benign prostatic hyperplasia, which affects approximately 80% of males by the age of 80 years. It has been estimated that about one in six prostate glands resected to alleviate this condition contains areas of carcinoma. Additionally, post-mortem examinations indicate that 10–30% of all men older than 50 years harbour a ‘silent’ microscopic form of prostate cancer. The majority of latent carcinomas follow an indolent course, but a small proportion become aggressive and these often prove fatal [2]. Localised prostate cancer is potentially curable by radical prostatectomy or radiotherapy. However, the majority of prostate cancer patients present with disseminated disease. Ablation of male hormones — androgens —is the key form of treatment for these individuals, as the cancer cells initially depend on hormone supply for growth. This measure is largely palliative, though, and most patients show disease progression between 12 and 18 months after this treatment begins, as the prostate tumour cells progress to androgen-independent growth. Regrettably, there is no effective remedy for hormone-resistant disease, and survival time is typically 2–3 years from the time of diagnosis of metastatic disease [3].
The increased incidence of prostate cancer and a burgeoning older population make it imperative that reliable prognostic indicators become available to clinicians to allow the early detection of that subset of latent tumours that is likely to become aggressive. In turn, this requires that the cellular and molecular events underlying tumour progression and recurrence be fully understood. Markers of prostate cancer
A number of markers associated with the prostate gland have been identified to date including prostate-specific antigen (PSA) [4], prostate carcinoma-associated glycoprotein complex (PAC) [5], prostatic acid phosphatase (PAP), prostate mucin antigen (PMA) [6], and prostate-specific membrane antigen (PSM) [7]; only a subset of these markers are elevated in or specifically associated with prostate cancer, however. A number of studies have focused on PSA, a serine protease that liquefies seminal coagulum. PSA is secreted by luminal epithelial cells of prostate glands and can be detected in the bloodstream. Expression of PSA is higher in normal than in malignant prostate cells, and even falls in recurrent hormone-resistant disease. However, the vast increase in the number of PSA-producing cells due to the cancer-induced enlargement of the prostate gland results in the elevation of PSA protein levels in the serum of prostate cancer patients. Measurements of serum levels of PSA are therefore used clinically to provide an indication of tumour burden, metastatic involvement, and response to surgery, radiotherapy and androgen ablation. PSA levels fail to discriminate accurately, however, between indolent and aggressive cancers, benign prostatic hyperplasia, prostatitis and other non-malignant disorders; thus, PSA measurements alone cannot be used diagnostically or prognostically. By analysing PSA or PSM messenger RNA (mRNA) expression by the highly sensitive reverse-transcriptioncoupled polymerase chain reaction (RT–PCR) approach, it is possible to detect the presence of a single prostate cancer cell among a million non-prostatic cells [9]. PCR analysis can therefore be used to detect prostate cancer micrometastases distributed by the bloodstream [8], thus providing an early indication of prostate cancer progression. PSM may be a more accurate and sensitive indicator of the metastatic progression of prostate cancer than PSA, because expression of this marker is elevated in tumour cells, hormone-resistant cancer cells, and bony metastases [10], unlike PSA. Two recent papers herald important advances in our ability to detect and possibly intervene in the progress of
Dispatch
prostate cancer. In a paper from Owen Witte’s laboratory, Reiter et al. [11] document the discovery of a prostate cancer-associated cell surface antigen, prostate stem cell antigen (PSCA), which was overexpressed in about 90% of the prostate cancer specimens they examined. In the other paper, Paul Fisher’s group have continued their analysis of the prostate cancer tumour-inducing gene 1 (PTI-1), demonstrating the dominant transforming potential of the gene and showing that expression of antisense PTI-1 RNA reverses the tumorigenicity of an experimentally transformed cell line, while inhibiting the growth of a number of carcinoma-derived cell lines [12].
R429
of prostate cancer. If coupled to radioisotopes or cytotoxic agents, antibodies specific to these markers could even selectively kill cancer cells. Identification of the natural ligands for both PSM and PSCA might allow small peptides to be designed that could selectively bind cancer cells, substituting for antibody-mediated therapies and avoiding associated problems with immunological attenuation. Finally, the restricted expression of PSCA to prostate cancer tissue and its expression on the surface of cells advance its candidacy as a possible prostate cancer immunogen for anti-cancer vaccination therapy. Prostate cancer tumour-inducing gene, PTI-1
Prostate stem cell antigen, PSCA
PSCA is a previously unidentified molecule related to stem cell antigen 2 (Sca-2), a member of the Thy-1/Ly-6 superfamily of glycosylphosphatidylinositol (GPI)anchored cell surface antigens [11]. The authors demonstrated, using mRNA in situ hybridisation, that the gene encoding PSCA was overexpressed in 90% of prostate cancers. These included high-grade intraepithelial neoplasia and hormone-resistant cancers. Overexpression of PSCA may result from gene amplification because the PSCA gene maps to chromosomal region 8q24.2, which has been reported to be a region of allelic gain and amplification in a majority of advanced and recurrent prostate cancers. Reiter et al. [11] confirm that PSCA is GPIanchored at the cell surface, and also show that PSCA is expressed only in a subset of basal epithelial cells in normal prostate gland. The authors conclude that this finding supports other data suggesting that prostate cancers arise from the transformation of basal cells, which are believed to be the progenitors of the terminally differentiated secretory cells in the prostate gland. Finally, although no data are available as yet to support this, by analogy with Sca-2, the authors propose that PSCA may play a role in the survival or self-renewal of the basal epithelial cells. The association between elevated PSCA expression and prostate tumorigenesis, coupled with sustained expression of this molecule even in recurrent hormone-resistant disease, promotes the use of this marker in disease detection, and possibly in prognosis and treatment. Serum detection of PSCA protein may be possible if, like other GPI-anchored proteins, a fraction of the PSCA molecules are secreted. Alternatively, RT–PCR detection of PSCA expression could be used, as with PSM, to detect disease spread by the bloodstream. Also, the cell surface expression of PSCA or PSM could allow for the immunological detection of metastases using specific antibodies raised against these proteins. In fact, a clinical study using an antibody raised against PSM is currently under way [13]. If these studies prove successful, detection of prostatecancer-associated molecules in the blood of patients would clearly be of immense benefit for the clinical management
Expression of the PTI-1 gene appears to be even more restricted to prostate cancer cells than that of either PMS or PSCA: again, RT–PCR was used to detect the expression of the PTI-1 gene in the blood of prostate cancer patients [14]. The PTI-1 gene was cloned by a complex experimental strategy. This involved transferring DNA from a metastatic prostate carcinoma-derived cell line into rat embryo fibroblasts, followed by the injection of these cells into ‘nude’ mice — mice that lack T cells and therefore cannot elicit an immune response — thereby generating tumours. RNA from the tumours was then characterised using differential display, a PCR-based technique for comparing RNA profiles between different cell populations, in order to identify genes that had increased expression in the tumours, one of which was PTI-1 [15]. The PTI-1 mRNA has a most peculiar structure. It comprises a 630 bp 5′-untranslated region, with very high similarity (about 90% identity) to the Mycoplasma hyopneumoniae 23S ribosomal RNA, fused to a sequence which encodes a mutated and truncated version of human translation elongation factor-1α (EF-1α). It appears therefore that the PTI-1 gene arose by fusion between these two genes, followed by subsequent divergence from the ancestral sequences. It is not clear if the PTI-1 gene is present in the human genome as a single genetic locus, or if it is a fusion product specifically generated in cancer cells by chromosomal translocation, deletion or insertion. The region of PTI-1 that is homologous to the prokaryotic 23S ribosomal RNA has been confirmed to be present in humans by PCR analysis of genomic DNA [14]: direct confirmation by Southern hybridisation analysis of genomic DNA using this region of the PTI-1 gene as a probe and by cloning and chromosomally mapping the PTI-1 locus would help eradicate any suspicions that this gene might be in some way artefactual. This information would also enable us to determine whether the PTI-1 locus is linked to familial prostate cancer, which is believed to be responsible for about 10% of the cases of the disease. The PTI-1 mRNA has been detected only in carcinoma cell lines (not exclusively prostatic, but also breast and colon cancer cell lines), and in about 90% of prostate cancers. Importantly,
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Current Biology, Vol 8 No 12
the PTI-1 gene is not expressed in normal prostate glands or in benign prostatic hyperplasia [15].
these genes could potentially even be used to tackle recurrent disease, the Gordian knot waiting to be cut.
In their recent paper [12], the Fisher group provide further cogent evidence for the dominant transforming ability of PTI-1, thus substantiating it as one of very few oncogenes identified to date — including c-ERBB-2/NEU/HER-2, c-Ki-RAS, c-MET, and c-MYC — that are implicated in prostate tumorigenesis. From studies largely of EF-1α homologues in bacteria and yeast, EF-1α is believed to ensure proper codon–anticodon binding interactions between mRNAs and transfer RNAs (tRNAs) at the tRNA acceptor site of the ribosome [16]. Mutations in EF-1α would be likely to affect its proofreading ability and could therefore promote the synthesis of mutant proteins, which themselves may possess transforming ability. This theory for the oncogenic potential of EF-1α has been termed the ‘translational infidelity hypothesis’ [15].
References
Altered protein translation has previously been associated with cellular transformation. Enhanced expression of EF1α has been demonstrated in tumours of the pancreas, colon, breast, lung, and stomach when compared with that in adjacent normal tissues [17]. Overexpression of the wild-type form of the eukaryotic translation initiation factor eIF-4E, the mRNA cap-binding subunit of eIF-4F, or a constitutively active form of the eIF-2α initiation factor promotes fibroblast transformation. The work of the Fisher laboratory on PTI-1 further strengthens the proposed link between translation and transformation. The ability of antisense PTI-1 RNA to revert the malignant phenotype of PTI-1-transformed cells highlights the potential for this mode of oncogene inactivation as an antitumour gene therapy, should mechanisms of cell targeting and gene transfer become practicable. Alternatively, it may be possible to engineer small antisense oligonucleotides to inhibit PTI-1 expression. These could be delivered systemically and would diffuse throughout tissue spaces finding their way even to metastases. Alternatively, it might be possible to exploit the tissue-specific expression of molecules such as PMS, PSA, PSCA and PTI-1 in antiprostate cancer gene therapy approaches: promoters of the genes encoding these products could be used to drive the expression of suicide genes (such as the thymidine kinase gene of herpes simplex virus) specifically within prostate cancer cells. In fact, as you read this, you can be quite sure that these promoters have already been inserted into someone’s favourite ‘gene therapy vector’, and that pilot studies are currently under way in a ‘pet’ model system to determine the efficacy of such an approach. The demonstration that the PMS, PSCA and PTI-1 genes are expressed in androgen-insensitive cells, unlike PSA which is expressed in an androgen-dependent manner, suggests that therapies intervening with the function of
1. Whittemore AS: Trends in prostate cancer incidence and mortality. In Cancer Surveys 19-20. Edited by Doll R, Fraumeni JF Jr, Muir CS. Cold Spring Harbor New York: Cold Spring Harbor Laboratory Press; 1994:309-322. 2. Coffey DS: Prostate cancer. An overview of an increasing dilemma. Cancer 1993, 71(3 Suppl):880-886. 3. Crawford ED: Hormonal therapy of prostatic carcinoma. Defining the challenge. Cancer 1990, 66(5 Suppl):1035-1038. 4. Lundwall A, Lilja H: Molecular cloning of human prostate specific antigen cDNA. FEBS Lett 1987 214:317-322. 5. Wright GL Jr, Beckett ML, Lipford GB, Haley CL, Schellhammer PF: A novel prostate carcinoma-associated glycoprotein complex (PAC) recognised by monoclonal antibody TURP-27. Int J Cancer 1991, 47:717-725. 6. Beckett ML, Wright GL Jr: Characterization of a prostate carcinoma mucin-like antigen (PMA). Int J Cancer 1995, 62:703-710. 7. Israeli RS, Powell CT, Fair WR, Heston WD: Molecular cloning of a prostate-specific membrane antigen. Cancer Res 1993, 53:227-230. 8. Moreno JG, Croce CM, Fischer R, Monne M, Vihko P, Mulholland SG, Gomella LG: Detection of hematogenous micrometastasis in patients with prostate cancer. Cancer Res 1992, 52:6110-6112. 9. Israeli RS, Miller WH Jr, Su SL, Powell CT, Fair WR, Samadi DS, Huryk RF, DeBlasio A, Edwards ET, Wise GJ, et al.: Sensitive nested reverse transcription polymerase chain reaction detection of circulating prostatic tumor cells:comparison of prostate-specific membrane antigen and prostate-specific antigen-based assays. Cancer Res 1994, 54:6306-6310. 10. Israeli RS, Powell CT, Corr JG, Fair WR, Heston WD: Expression of the prostate-specific membrane antigen. Cancer Res 1994, 54:1807-1811. 11. Reiter RE, Gu Z, Watabe T, Thomas G, Szigeti K, Davis E, Wahl M, Nisitani S, Yamashiro J, Le Beau MM, Loda M, Witte ON: Prostate stem cell antigen: a cell surface marker overexpressed in prostate cancer. Proc Natl Acad Sci USA 1998, 95:1735-1740. 12. Su Z-Z, Goldstein NI, Fisher PB: Antisense inhibition of the PTI-1 oncogene reverses cancer phenotypes. Proc Natl Acad Sci USA 1998, 95:1764-1769. 13. Sodee DB, Conant R, Chalfant M, Miron S, Klein E, Bahnson R, Spirnak JP, Carlin B, Bellon EM, Rogers B: Preliminary imaging results using In-111 labelled CYT-356 (Prostascint) in the detection of recurrent prostate cancer. Clin Nucl Med 1996, 21:759-767. 14. Sun Y, Lin J, Katz AE, Fisher PB: Human prostatic carcinoma oncogene PTI-1 is expressed in human tumor cell lines and prostate carcinoma patient blood samples. Cancer Res 1997, 57:18-23. 15. Shen R, Su Z-Z, Olsson CA, Fisher PB: Identification of the human prostatic carcinoma oncogene PTI-1 by rapid expression cloning and differential RNA display. Proc Natl Acad Sci USA 1995, 92:6778-6782. 16. Merrick WC: Mechanism and regulation of eukaryotic protein synthesis. Microbiol Rev 1992, 56:291-315. 17. Grant AG, Flomen RM, Tizard MLV, Grant DAW: Differential screening of a human pancreatic adenocarcinoma lambda gt11 expression library has identified increased transcription of elongation factor EF-1 alpha in tumour cells. Int J Cancer 1992, 51:740-745.