Malignant Prostatic Growth Research Articles

New generation biomarkers for the detection of prostate cancer

Malignant growth is the most dangerous illness with the most elevated mortality rate. Early identification of malignant growth can be fundamental in effective treatment. One of the most promising early symptomatic tools for tracking infection spread and subsequent disease treatment is biomarker-based malignant growth screening. Prostate cancer (PCa) is the most widely recognized reason for death in men and is the following driving reason for death from the disease worldwide. Prostate-specific antigen (PSA) is a fundamental biomarker for diagnosing PCa. Despite signs against its utilization in massive populace tests, PSA concentrates most on PCa biomarkers. This biomarker does remain an essential determinant in the therapy of prostate malignant growth due to its different structures and its inclusion in rehashed plans with other biomarkers. This paper depicts the most recent advances in electrochemical biosensors intended to identify different malignant growth biomarkers utilizing further sign transmission and biological detection strategies. In treating malignant prostate growth, disclosing its specific structures and inclusion in revised schemes with other biomarkers are crucial indicators.

BAG1L: a promising therapeutic target for androgen receptor-dependent prostate cancer.

Androgens are important determinants of normal and malignant prostate growth. They function by binding to the C-terminal ligand-binding domain (LBD) of the androgen receptor (AR). All clinically approved AR-targeting antiandrogens for prostate cancer therapy function by competing with endogenous androgens. Despite initial robust responses to androgen deprivation therapy, nearly all patients with advanced prostate cancer relapse with lethal castration-resistant prostate cancer (CRPC). Progression to CRPC is associated with ongoing AR signaling, which in part, is due to the expression of constitutively active AR splice variants that contain the N-terminus of the receptor but lack the C-terminus. Currently, there are no approved therapies specifically targeting the AR N-terminus. Current pharmacologic targeting strategies for inhibiting the AR N-terminal region have proven difficult, due to its intrinsically unstructured nature and lack of enzymatic activity. An alternative approach is to target key molecules such as the cochaperone BAG1L that bind to and enhance the activity of the AR AF1. Here, we review recent literature that suggest Bag-1L is a promising target for AR-positive prostate cancer.

Abstract 864: Androgen receptor stability in prostate cancer is regulated by the cochaperone Bag-1L

Abstract The androgen receptor (AR) is an important determinant of normal and malignant prostate growth and its function is usually regulated by circulating levels of androgens, which act by binding to the ligand-binding domain (LBD) of the receptor. Currently available therapeutic intervention in prostate cancer concentrates on reducing the androgen-mediated activation of the receptor by either blocking the production of androgens or by competing with endogenous androgens for the ligand-binding pocket. However, these treatments are often palliative as almost all patients eventually develop castration-resistant prostate cancer (CRPC). Therefore a great need exists to discover alternative modes of AR inhibition, outside of targeting the LBD. Factors that control AR stability and receptor turnover may constitute new regulatory targets for inhibiting AR action. Bag-1L is a nuclear-resident cochaperone with the ability to control AR transactivation function by directly interacting with the receptor. Here we show that a conserved domain (BAG) within the C-terminus of Bag-1L induces significant structural changes within the intrinsically disordered N-terminal domain of the AR upon binding the receptor. A consequence of this may be increased accessibility of either domain for additional protein interactions. Using a mass spectrometry approach involving the combination of tandem affinity purification (TAP) and rapid immunoprecipitation mass spectrometry of endogenous proteins (RIME) we could show that Bag-1L, besides its ability to interact with AR, forms a complex involving the E3 ubiquitin-protein ligase CHIP and its known interaction partner Hsp70/Hsc70. Both proteins are involved in the folding and proteolytic turnover of AR, implying a role of Bag-1L in both processes. To further test this, we investigated the function of Bag-1L in human patient samples and in prostate cancer cell lines. We observed that nuclear Bag-1 protein levels are increased from hormone naïve to CRPC status in prostate cancer patients and this correlates with an increase in AR protein level. TALEN-mediated loss of Bag-1L in a CRPC cell line model leads to a stabilization of the AR protein, yet a drastic reduction in genome-wide AR binding and about a 50% decrease in AR-regulated target genes critical for cell proliferation and migration. Correspondingly, we observed a significant reduction in prostate cancer growth, which could be rescued when Bag-1L was re-expressed. Combined these results demonstrate the importance of Bag-1L for AR stability and function, and the potential of this protein for the therapeutic intervention in prostate cancer. Citation Format: Laura Cato, Antje Neeb, Adam Sharp, Scott Ficarro, Victor Buzon, Xavier Salvatella, Jarrod A. Marto, Johann S. de Bono, Andrew C. Cato, Myles Brown. Androgen receptor stability in prostate cancer is regulated by the cochaperone Bag-1L. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 864.

Abstract 4677: Control of androgen receptor function by the genomic action of the cochaperone Bag-1L

Abstract The androgen receptor (AR) is an important determinant of normal and malignant prostate growth and its function is regulated by many factors, including molecular chaperones, cochaperones and coregulators. One such factor is the nuclear-resident cochaperone Bag-1L. Overexpression of Bag-1L and the amplification of its gene have been reported in the hormone-refractory and metastatic stages of prostate cancer and in androgen-independent prostate cancer cells. However the exact mechanism of Bag-1L-mediated regulation of AR action in prostate cancer remains unclear. Here we show that Bag-1L and AR directly interact with one another through two distinct domains in both proteins. While the N-terminus of Bag-1L binds to the AR BF-3 domain via a conserved GARRPR motif, the C-terminal Hsp70/Hsc70-binding domain (BAG) of Bag-1L binds to the tau5 region in the intrinsically disordered AR AF1. The latter interaction is of particular significance as tau5 is a region crucial for the ligand-independent transcriptional activity of the receptor. Understanding the details of this interaction will therefore provide new opportunities of controlling AR action for therapeutic purposes outside of targeting the LBD. We have identified the exact amino acids (K231, K232 and K279) in the BAG domain that are required for the interaction with AR. Amino acid substitution of these residues destroy the interaction of Bag-1L and AR but do not affect the binding to Hsp70/Hsc70. We also observed significant reduction in androgen-dependent cell growth when the BAG-domain mutant is overexpressed in prostate cancer cells in culture and in xenograft mouse models. We further tested the consequence of the BAG-domain mutation on AR transactivation by microarray analysis. We observed repressed expression of multiple genes, including the AR coactivator NCoA2. Correspondingly, we observed multiple changes in the Bag-1L interactome when comparing the wild-type with the BAG mutant; this includes the loss of interaction with the heat shock protein Hsp27 for the mutant Bag-1L protein. Combined these results demonstrate the importance of Bag-1L for AR function and the potential of this protein for therapeutic intervention in prostate cancer. Citation Format: Laura Cato, Antje Neeb, Guillaume Adelmant, Scott Ficarro, Thomas Westerling, Jarrod A. Marto, Andrew C. Cato, Myles Brown. Control of androgen receptor function by the genomic action of the cochaperone Bag-1L. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4677. doi:10.1158/1538-7445.AM2015-4677

Caveolin-1 overexpression enhances androgen-dependent growth and proliferation in the mouse prostate

Prostate cancer (PCa) continues to be one of the leading causes of cancer-related deaths among American men. The prostate relies upon the androgen receptor (AR) to mediate the effects of androgens on normal growth, a reliance that is maintained during malignant prostate growth. Caveolin-1 (Cav-1), the main structural component of caveolae, has been shown to promote the malignant growth and invasion of prostate tumors. In vitro work has shown that Cav-1 can act as an AR coactivator by enhancing its transciptional activity. However, it is unknown how Cav-1 affects androgen-dependent growth and signaling in vivo. To explore this role, a novel mouse model of Cav-1 overexpression was developed with a hormone-insensitive promoter. Cav-1 transgenic (Tg) mice subjected to castration and androgen stimulation display enlarged prostate weights and increased DNA synthesis. Through gene transcript and proteomic profiling, we demonstrate that Cav-1 overexpression favors androgen-regulated responses and enhances processes involved in transcription, cell cycle progression and protein synthesis. Interestingly, Cav-1 overexpression was associated with an increase in the phosphorylation of AR on serine 210, a post-translational modification linked to its activity under androgen-stimulated conditions. In addition, these mice exhibited an increase in the phosphorylation of ribosomal S6 protein on serine 235/236 (pS6), a marker of protein synthesis and a downstream component of the mTOR pathway. Thus, Cav-1 Tg mice could serve as a novel model for studying AR-regulated pathways involved in prostate growth and proliferation.

Abstract 1247: Transcriptional regulation of VEGF by WT1 and AR in prostate cancer

Abstract Identifying molecular mechanisms that influence prostate cancer progression is central to understanding how this disease develops. Angiogenesis is key for cancer development and growth as tumors require new blood vessels for nutrients and oxygen. Vascular endothelial growth factor (VEGF) is the most important signaling protein involved in angiogenesis and is up-regulated by oncogene expression among other things. Previous studies have shown that the zinc finger transcription factor WT1 (Wilms tumor 1) transcriptionally regulated VEGF in multiple cell lines. Additionally, WT1 activation of VEGF required an intact zinc finger domain and was mediated by DNA binding. Potential WT1 binding sites were identified in the VEGF promoter using in silico approaches and shown to bind WT1 protein using electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays. Luciferase reporter assays showed increased activation of the VEGF promoter by over-expression of WT1. Additional factors known to induce VEGF expression are growth factors, hypoxia and hormones. How androgen regulates VEGF transcription is unknown, but we have identified two potential androgen receptor (AR) binding sites within 2kb of the transcriptional start site and demonstrated reporter activation by R1881 treatment of transfected LNCaP cells. This study examined the effect of mutating selected WT1 and AR binding sites in the VEGF promoter to determine whether they were responsible for activation of VEGF transcription. Mutating these binding sites by site-directed mutagenesis significantly decreased activation of the VEGF promoter by WT1 and the androgen analog R1881 in LNCaP cells. As predicted, treatment with the anti-androgen casodex similarly eliminated hormone response of the VEGF promoter, suggesting that androgens are functioning via androgen signaling. This was confirmed in vivo by both western blot analysis of VEGF protein and quantitative real-time PCR measurement of VEGF mRNA in cells treated with casodex. This is important because androgen signaling is vital to normal prostate development and malignant prostate growth. Overall these results show that both WT1 and AR transcriptionally regulate VEGF expression in prostate cancer cells and these factors directly bind and activate the promoter in vivo. Understanding how angiogenesis is regulated will lead to improved therapy and prevention of prostate cancer progression. This work was supported by NIHR15CA11360 (GF), Sigma Xi GIAR220034 (KE), and GSSKSU (KE) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1247.

A comparative study of serum protein-bound sialic acid in benign and malignant prostatic growth: possible role of oxidative stress in sialic acid homeostasis

Benign and malignant prostatic growths are associated with an increase in sialoconjugates (e.g. prostate-specific antigen (PSA)) in blood. Oxidative stress plays a crucial role in pathogenesis of various malignancies. The objective of this study was to evaluate oxidative stress parameters and protein-bound sialic acid level in sera of prostatic tumor cases and to asses for any association between them. Sera samples were collected and estimated for carbonylation of proteins, lipid peroxidation products, PSA and protein-bound sialic acid from 10 patients in each group with prostatic carcinoma (Ca prostate) and benign prostatic hyperplasia (BPH) along with 10 healthy male subjects of similar age group as control. In carcinoma prostate cases, lipid peroxides, protein carbonyls, protein-bound sialic acid and PSA were significantly increased compared to BPH and controls. There was significant association between oxidative stress parameters (lipid peroxide and protein carbonyl) and sialoconjugates (PSA and protein-bound sialic acid). In BPH cases, serum lipid peroxides and protein-bound sialic acid were significantly higher in comparison to controls and protein carbonyls were correlated with protein-bound sialic acid. ROC curve for sialic acid showed that it can be used as a marker to differentiate carcinoma prostate from benign growth of prostate at a cutoff level of 11.38 mug/mg protein with a sensitivity of 100% and specificity of 80%. We conclude that oxidative stress might be associated with the degree of sialylation of protein and graded changes in these parameters possibly unveil the pathogenic demarcation from benign to malignant condition of prostate.

Alpha2 macroglobulin, a PSA binding protein, is expressed in human prostate stroma

Benign prostatic hyperplasia (BPH) is characterized as a stromal process. The stroma smooth muscle (SM) may alter its phenotype during the progression of BPH. We have identified gene transcripts that may be differentially expressed in BPH using a differential display method. Among the fragments isolated, alpha(2) macroglobulin (alpha(2)-M) is one of the most interesting. alpha(2)-M is a binding protein of a variety of proteinases, including prostatic specific antigen (PSA). It also plays roles in molecular trapping and targeting. In this study, we characterized alpha(2)-M expression in the human prostate. Differential display was used to identify and isolate the differentially expressed transcripts between normal prostate and BPH tissues. RT-PCR, Western blot, in situ hybridization, and immunohistochemistry were utilized to confirm and characterize alpha(2)-M expression in the prostate. Real-time RT-PCR results revealed that a 3.2-fold increase in alpha(2)-M mRNA expression is observed in BPH compared with normal prostate tissue. A 1.9-fold increase at protein level was also observed. In situ hybridization and immunohistochemistry showed that alpha(2)-M expression is primarily localized to the stromal compartment. Cultured primary stroma cells maintained alpha(2)-M expression, while prostate epithelial cells had a significantly lower level of alpha(2)-M expression. Furthermore, stromal cells in culture produce and secrete alpha(2)-M in the medium. We identified alpha(2)-M expression in the human prostate. An increased alpha(2)-M expression appears to be associated with BPH. Considering the unique features of its protein binding and targeting properties, alpha(2)-M expressed in the prostate may play an important role in regulating benign and malignant prostatic growth.

The Janus-faced nature of prostasomes: their pluripotency favours the normal reproductive process and malignant prostate growth.

Prostasomes are submicron secretory granules synthesized, stored and secreted by the epithelial cells of the human prostate gland. They are membrane-surrounded also in their extracellular appearance and the membrane architecture is composite. They are believed to be life-giving and act as protectors of the spermatozoa in the lower and upper female genital tract on their way to the ovum. Hence, the prostasomes are immunosuppressive and inhibitory of complement activation. Further, they promote sperm's forward motility and have antioxidant and antibacterial capacities. The prostasomes with their many composite abilities seem to turn against the host cell after the age of 50 y being conducive to the transition of the normal prostate epithelial cell into a neoplastic cell and therewith lay the foundations of the very high prevalence of prostate cancer of men of more than 50 y of age.

Apoptotic impact of alpha1-blockers on prostate cancer growth: a myth or an inviting reality?

Pharmacological manipulation or genetic targeting of the major apoptosis regulators, such as bcl-2, caspases, and inhibitors of apoptosis (IAPs), represent clinically attractive avenues towards effective therapeutic strategies for advanced prostate cancer. A wealth of evidence established the alpha(1)-adrenoceptor antagonists to be clinically effective in relieving the symptoms associated with benign prostatic hyperplasia (BPH) by relaxing prostatic smooth muscle tone. This action alone however does not fully account for the long-term clinical response to these drugs in BPH patients. Experimental and retrospective clinical studies provided new evidence supporting a differential growth-suppressing function of two alpha(1)-adrenoceptor antagonists against prostate cancer, independent of an alpha(1)-adrenoceptor mechanism. The quinazoline-based antagonists, doxazosin and terazosin, induce apoptosis, inhibit cell adhesion to the extracellular matrix (by activating anoikis), and prevent cell invasion and migration of prostate tumor epithelial cells and vascular endothelial cells. Tamsulosin, a sulphonamide-based, clinically effective alpha(1)-adrenoceptor antagonist for BPH treatment, fails to exert a similar apoptotic action against prostate cells. Furthermore, at pharmacologically relevant doses, doxazosin suppresses benign and malignant prostate growth in in vivo experimental models. The effect is characterized by three intriguing features: (a) it is mediated by an alpha(1)-adrenoceptor-independent action, (possibly related to the quinazoline nucleus); (b) it is targeted at the apoptotic process without affecting cell proliferation; and (c) the elevated apoptotic index correlated with symptom score improvement in BPH patients. This evidence challenges conventional knowledge of the mechanism of action of alpha(1)-adrenoceptor antagonists, and points to a new therapeutic value for these drugs by providing a differential molecular basis for their anti-tumor efficacy. The present review focuses on the characterization of the apoptotic/anti-angiogenic effect of quinazoline-based alpha(1)-adrenoceptor antagonists against prostate cancer cells and discusses the clinical significance of this action in the prevention and treatment of prostate cancer.

Role of the stromal microenvironment in carcinogenesis of the prostate.

The topic of this review is the role of stromal-epithelial interactions in normal and malignant prostatic growth. Because cell-cell interactions and androgens play such key roles in the prostate, the goal of this review will be to apply endocrinologic and developmental concepts to the understanding of normal and malignant prostatic growth. Prostatic development is induced by androgens, which act via androgen receptors. Androgens elicit prostatic epithelial growth during fetal and prepubertal periods, and in adulthood androgens act via reciprocal homeostatic stromal-epithelial interactions to maintain functional differentiation and growth quiescence. During carcinogenesis, these reciprocal homeostatic stromal-epithelial interactions are disrupted. In this review, 2 models of prostatic carcinogenesis will be reviewed, both of which emphasize the role of the stromal microenvironment in the carcinogenic process. Hormonal carcinogenesis of the prostate can be elicited by treatment of rats and mice with testosterone plus estradiol (T+E2). Using an immortalized but nontumorigenic human prostatic epithelial cell line (BPH-1), tissue recombinant studies were employed to explore the cellular mechanisms of prostatic carcinogenesis. Accordingly, human BPH-1 prostatic epithelial cells were combined with rat UGM, and the resultant UGM+BPH-1 recombinants were grown in adult male nude mouse hosts. In untreated mouse hosts, UGM+BPH-1 recombinants produced solid branched epithelial cords and ductal structures exhibiting benign growth. In T+E2-treated hosts, UGM+BPH-1 recombinants formed invasive carcinomas. Since BPH-1 cells lack androgen and estrogen receptors, whereas rat UGM expresses both of these receptors, it is proposed that hormonal carcinogenesis is elicited by T+E2 via paracrine mechanisms mediated by the stromal microenvironment. During prostatic carcinogenesis in rats and humans, the periepithelial stroma undergoes progressive loss in smooth muscle with the appearance of carcinoma-associated fibroblasts (CAFs). This abnormal stroma was shown to promote carcinogenesis in genetically abnormal but nontumorigenic epithelial cells. CAF+BPH-1 tissue recombinants grown in male hosts formed carcinomas, whereas benign growth and orderly tissue architecture developed in recombinants composed of normal prostatic stroma+BPH-1. Malignant transformation triggered by CAF was associated with additional genetic alterations and changes in gene expression in the BPH-1 cells. Thus, the stromal microenvironment is a critical determinant of benign versus malignant growth.

Body Size And Serum Levels of Insulin and Leptin in Relation to the Risk of Benign Prostatic Hyperplasia

Obesity has been implicated in the etiology of benign and malignant prostatic growth due to its influence on metabolic and endocrine changes. Because obesity is an important determinant of serum levels of insulin and leptin (the product of the obesity gene Ob), we investigated the role of obesity and serum levels of insulin and leptin in benign prostatic hyperplasia (BPH) etiology. Fasting serum levels of insulin and leptin as well as the body mass index, a measure of overall obesity, and waist-to-hip ratio, an indicator of abdominal obesity, were determined in 200 men newly diagnosed with BPH who were hospitalized for surgery and in 302 randomly selected healthy male subjects from the population in Shanghai, China. A higher waist-to-hip ratio and higher serum insulin were significantly associated with an increased risk of BPH. Relative to men in the lowest waist-to-hip ratio quartile (less than 0.856) those in the highest quartile (greater than 0.923) were at 2.4-fold risk (odds ratio 2.42, 95% confidence interval [CI] 1.34 to 4.37, test for trend p = 0.01). Similarly relative to men in the lowest quartile of insulin (less than 5.87 microU. per ml.) those in the highest quartile (greater than 9.76 microU. per ml.) were at significantly increased risk (odds ratio 2.47, 95% CI 1.35 to 4.54, test for trend p = 0.009). The effect of insulin on BPH risk was more pronounced in men in low and middle tertiles of the waist-to-hip ratio (odds ratios comparing high to low insulin tertiles 2.8 and 2.7, respectively), while among men in the highest waist-to-hip ratio tertile insulin was not significantly associated with BPH risk. In contrast, we found no significant odds ratio comparing the highest to lowest quartiles of leptin (odds ratio 0.62, 95% CI 0.33 to 1.17) or body mass index (odds ratio 1.64, 95% CI 0.96 to 2.81). Our results suggest that abdominal obesity and increasing serum insulin, and possibly overall obesity but not serum leptin are associated with a higher risk of BPH. Further prospective and laboratory studies are needed to confirm these results and elucidate the underlying mechanisms.

Evidence for the differential expression of a variant EGF receptor protein in human prostate cancer.

Earlier studies have demonstrated an unexplained depletion of the epidermal growth factor receptor (EGFR) protein expression in prostatic cancer. We now attribute this phenomenon to the presence of a variant EGFR (EGFRvIII) that is highly expressed in malignant prostatic neoplasms. In a retrospective study, normal, benign hyperplastic and malignant prostatic tissues were examined at the mRNA and protein levels for the presence of this mutant receptor. The results demonstrated that whilst EGFRvIII was not present in normal prostatic glands, the level of expression of this variant protein increased progressively with the gradual transformation of the tissues to the malignant phenotype. The selective association of high EGFRvIII levels with the cancer phenotype underlines the role that this mutant receptor may maintain in the initiation and progression of malignant prostatic growth, and opens the way for new approaches in the management of this disease including gene therapy. © 2000 Cancer Research Campaign

Variations in activin receptor, inhibin/activin subunit and follistatin mRNAs in human prostate tumour tissues.

The possible role of activin in the regulation of malignant prostatic growth was studied using RNAase protection assays of activin receptors, inhibin/activin subunits and follistatin mRNAs in the human prostatic carcinoma cell lines LNCaP-FGC, -R and -LNO, in human prostatic carcinoma xenografts and in human prostatic tissue. Activin receptor types IA (ActRIA), IB (ActRIB), IIA (ActRIIA) and IIB (ActRIIB) mRNAs were generally expressed in prostate pithelial cells, with significantly lower levels of ActRIB mRNA in prostate tumour aterial when compared to non-malignant tissue (P< 0.05; Mann–Whitney U -test). Inhibin/activin βA- and βB-subunit mRNA expression was also found in prostate tissue. Androgen-independent xenografts expressed significantly lower amounts of βB-subunit mRNA when compared to androgen-dependent xenografts (P< 0.05). While βB-subunit mRNA was expressed by LNCaP-FGC and -LNO cells, virtually no expression was found in the androgen-independent LNCaP-R line. Inhibin α-subunit mRNA levels were low or undetectable in all samples investigated. Follistatin mRNA was undetectable in LNCaP-sublines, while low levels were found in prostatic tissues. In androgen-independent LNCaP-R cells, activin inhibited cell growth in a dose-dependent manner. These results suggest that prostate tumour progression is accompanied by a decrease of the inhibitory effect of locally produced activin by either a decrease in the expression of activin βB-subunit mRNA or by a decrease of ActRIB mRNA levels. © 2000 Cancer Research Campaign

Cellular interactions in prostate cancer.

This article will review the different modes of action of soluble growth factors in the growth of benign and malignant prostatic cells. Cellular proliferation, growth arrest or even apoptosis requires the participation of appropriate growth factors [1]. Proliferative activities of prostatic epithelial cells, like other cells, are governed by the action of a variety of growth factors. Prostatic growth is traditionally considered to be regulated by androgen, as the prostate is an androgen-sensitive organ, in that the growth and maintenance of the structure and functional integrity are dependent upon the presence of circulating androgen [2,3]. A depletion of this androgenic support, e.g. by bilateral orchidectomy in the host, results in massive apoptosis in prostatic epithelial cells, leading to a rapid rate of tissue involution [4]. Subsequent androgen replacement therapy reactivates prostatic growth. Therefore, androgen is the most potent mitogen to the prostate. It is now apparent that this mitogenic effect of androgen on the prostate is mediated through the action of various growth factors as a consequence of an intricate cell-to-cell interaction, a characteristic feature of benign prostatic growth [5,6]. On the other hand, malignant prostatic growth is characterized by additional mechanisms of cellular proliferation that provide a distinct growth advantage over that of their benign counterparts. Cancer develops as a result of a series of genetic mutations [7]. Prostatic cancer is no exception; however, its progression seems to follow a relatively predictable course, from an androgen-sensitive state to an autonomous state [8]. Sensitivity to androgen in prostatic cancer is mainly due to the presence of androgen receptors in malignant cells, which retain some properties of the benign prostatic cells. However, the manner in which androgen interacts with prostatic cancer cells can be drastically different from that in which it reacts with benign cells. Despite androgen playing an important role in the progression of prostatic cancer, eventually these cancer cells are able to convert from an androgen-responsive growth mode to an androgen-independent mode. Often, a conversion from one state to another is associated with a poorer prognosis and is preceded by the acquisition of new growth advantages within the cancer cells. Again, soluble growth factors are the underlying mechanisms of androgen-sensitive and androgen-insensitive malignant growth. The abnormal growth behaviour in prostatic cancer cells can be manifested by an over-expression of growth-stimulating factor(s) and/or a loss of expression (or function) of growth-suppressive factor(s). The production and action of growth factors in the context of benign and malignant growth of prostatic cells will be the focus of the present discussion.

Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease.

Prostate specific antigen (PSA) is an insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) protease found in seminal plasma and produced by prostatic epithelial cells (PC-E) in vivo. We examined the effects of PSA-proteolysis of IGFBP-3 on the affinity of IGFBP-3 fragments for IGFs and on the mitogenic action of IGFs on PC-E. Recombinant human IGFBP-3 was cleaved by PSA, then incubated with 125I-IGF-I or -II in the presence of varying concentrations of unlabelled peptides, and then cross-linking electrophoresis and densitometric analysis were performed. While the affinity of IGF-II for the PSA-generated IGFBP-3 fragments fell slightly compared to intact IGFBP-3, the affinity of the PSA-generated IGFBP-3 fragments for IGF-I fell by ten fold. The addition of IGF-I or -II to PC-E in serum-free culture conditions resulted in a two-fold stimulation of cell number compared to control. The presence of IGFBP-3 in the media blocked the IGF-induced stimulation, but had no independent effect in the absence of IGFs. When PSA was added to PC-E cultures to which both IGF-I or -II and IGFBP-3 were added, the inhibitory effects of IGFBP-3 on IGF mitogenesis were reversed. We conclude that PSA decreases the affinity of IGFBP-3 for IGF and can potentiate IGF action in the presence of inhibitory IGFBP-3. This phenomenon may contribute to normal and malignant prostate growth.