| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Clinical Physiopathology, Andrology Unit, University of Florence, 50139 Firenze, Italy
Address all correspondence and requests for reprints to: E. Baldi, Department of Clinical Physiopathology, Andrology Unit, University of Florence, viale Pieraccini 6, 50139 Firenze, Italy. E-mail: e.baldi{at}dfc.unifi.it.
Prostate cancer (PC) is the most frequently diagnosed male malignancy and the second leading cause of death in men of western countries. Because in these countries populations continue to age and the mortality from other diseases decreases, PC is likely to achieve an increasing importance. Early PC can be treated and cured either by radical prostatectomy or radiotherapy, whereas advanced metastatic PC can be treated only by surgical or pharmacological castration often coupled with the peripheral blockage of androgen action. However, withdrawal of androgens only leads to a transient regression of PC that is followed approximately 18–36 months later by relapse and progression to androgen-independent PC. Several mechanisms have been hypothesized to account for transition to androgen independence (1), which, however, remains poorly understood. Clonal selection of cells able to grow in an androgen-deprived environment and overexpression of the androgen receptor (AR) appear to be the most plausible hypothesis. One of the questions that arise from clinical evidence of androgen-refractory PC concerns the reasons of its higher invasive potential. Understanding how androgen regulates the molecules involved in promoting or suppressing invasion and metastasis is thus critically important for defining the role of the steroid and its receptor in this process.
Studies performed using available PC cell lines show that androgen-responsive ones, such as LNCaP, are less tumorigenic when injected in nude mice compared with androgen-insensitive DU145 and PC3 and to cells expressing low levels of AR such as ARCaP (2, 3). In addition, expression by transfection of the AR in androgen-independent PC cell lines or overexpression in ARCaP cells leads to a decrease of invasion and adhesion properties in vitro (4, 5, 6). Overall, these results suggest that maintaining the expression of a functional AR keeps a more differentiated and less invasive phenotype of the cells. During the last few years, evidence has emerged that these effects may be due to regulation of expression of molecules involved in these processes.
NEP, a neutral endopeptidase whose expression is positively regulated by androgens (7), is lost in androgen-independent PC (8). Its expression by transfection in androgen-independent PC cells leads to inhibition of PC cell invasion by blocking focal adhesion kinase-phosphatidylinositol 3-kinase interaction (9). Dolichol-phosphate-mannose-3 (DPM3)/prostin-1 is another protein negatively associated with PC invasion, whose expression is induced by androgens (10). Interestingly, exogenous expression of NEP in androgen-independent PC cell lines (11) and of DPM3/prostin-1 in COS cells (10) leads to apoptosis, suggesting a possible role of these molecules as tumor suppressors. Another protein whose exogenous expression in PC cells inhibits cell growth and invasion in vitro is Hepsin (HPS) (12). HPS gene promoter contains a sterol regulatory element (13), and the protein is found in the androgen-sensitive cell line LNCaP but not in the androgen-insensitive PC3 and DU145 (12). Of interest, HPS expression, which is high in prostatic intraepithelial neoplasia and progressively decreases in advanced stages of PC, is negatively correlated with clinical outcome (14). Concerning adhesion and antiadhesion molecules, androgens have been shown to negatively regulate expression of some integrins, the main cell adhesion molecules that regulate cell-to-cell adhesion and cell-extracellular matrix interaction. In particular, androgens have been shown to down-regulate 
6ß4 and 3ß1 integrins (4, 6), whereas they up-regulate the expression of the antiadhesion molecule antiadhesion protein mucin-1 (6). It must be considered, as also suggested by Evangelou et al. (6), that a decrease of adhesion of tumor cells may be a starting point for development of metastasis. However, at least in vitro, detached PC cells after androgen treatment undergo apoptosis and there is a general consensus that stable expression of AR leads to a retardation of growth of PC cells in vitro (4, 5, 15, 16). In addition, the integrin 6ß4 is a key molecule in carcinoma cell invasion process, as it mediates traction forces on extracellular matrix (17), whereas 3ß1 is required for completeness of the metastasis process in PC cells because it mediates adhesion to bone matrix (18). Recently, a possible role for endothelin-1 (ET-1) in the metastatic progression of PC to bone has been suggested. In PC3 and DU145 cells, ET-1 gene expression and secretion was reported to be up-regulated by factors involved in tumor progression such as TGFß-1, epidermal growth factor, and IL-1 (19). In PC3 cells transfected with a full-length AR, the treatment with androgens reduced gene expression and secretion of ET-1 (19). The clinical relevance of these findings was recently confirmed by a controlled clinical trial in which 288 patients with metastatic cancer were randomized to treatment with an ET receptor A antagonist. In comparison to placebo, treatment with the ET receptor antagonist induced a significant suppression of markers of bone remodeling and an improvement of bone scans (20).
Nevertheless, in the report by Li’s laboratory (published in this issue, Ref. 21), it is clearly shown that the treatment of androgen-sensitive LNCaP and LAPC-4 cells with the synthetic androgen R1881 leads to functional expression of pro-MMP-2, the precursor of matrix metalloproteinase (MMP)-2, a protein of the MMP family strongly involved in development of metastasis and cancer progression (22). In this article, Liao et al. demonstrate that expression of the protein is low or undetectable in serum starving cells and increases dose-dependently after treatment with R1881, pointing out that androgens may generate an invasive behavior of PC cells. Indeed LNCaP cells, which are normally unable to migrate, migrate in response to androgen stimulation (21), suggesting that increased expression of pro-MMP-2 promotes invasion of these cells. It must be noted that, through interaction with Ets protein, the AR has been shown to down-regulate gene expression of other metalloproteinases such as MMP1, MMP3, and MMP7 (23), indicating that androgens may have different effects on expression of this family of proteins. A clear-cut scenario on the effect of androgens on this family of protein and their function, however, will be possible only when information on effects of androgens on all its components as well as on endogenous MMP inhibitors, such as tissue inhibitor of metalloproteinase and reversion-inducing cysteine-rich protein, will be available in more than one model of androgen-dependent cell lines. The decrease of the ratio MMP-7/tissue inhibitor of metalloproteinase 1 mRNA levels in PC patients with high prostate-specific antigen levels following hormonal therapy (24) points out a possible role of MMP inhibitors in the progression of the disease.
From these studies, it emerges that androgens may have diverse effects on molecules involved in the processes of invasion and metastasis that may lead to good (up-regulation of NEP, HSP, DPM3/prostin-1, down-modulation of 6ß4 and 3ß1 integrins, MMP1, MMP3, MMP7, and ET-1 secretion) and to bad (up-regulation of pro-MMP-2) effects on PC cell invasion. If loss of androgen dependence following endocrine therapy for PC may thus result in selection of cells with higher invasive potential due to loss of androgen regulation of some genes important for progression, the results shown by Liao et al. (21) demonstrate that PC cells may also initiate the invasion process in androgen-dependent stage of the disease under androgen stimulation. On the other hand, the invasive behavior of PC cells may be generated by alterations of the microenvironment, mutations of activator/repressors genes and coactivators of AR and overexpression of growth factors and their receptors, leading to selections of cells with higher aggressive potential. If such alterations occur at early stages of the disease, invasion and metastasis may develop even in the presence of a low tumor mass.
Lessons from other hormone-sensitive carcinomas, such as breast and endometrial cancer, indicate that loss of expression of functional steroid receptors is often associated to development of less differentiated tumors with a consequent poor prognosis. Studies in vitro and in vivo in nude mice demonstrate that invasion is generally inhibited by expression of functional steroid receptors in cell lines derived from these tumors. Indeed, expression of estrogen receptor (25, 26) in breast cancer cells decreases invasive and metastatic potential of these cells, whereas progesterone inhibits invasion of endometrial cancer cells through down-regulation of several adhesion molecules, including integrins and cadherin 6 (27).
 |
Acknowledgments |
|---|
|
Footnotes |
|---|
Received February 20, 2003.
Accepted for publication February 25, 2003.
|
References |
|---|
 Top References |
|---|
6ß4 integrin-mediated invasive phenotype. Endocrinology 141:3172–3182
regulated gene negatively associated with prostate tumor invasion. Oncogene 20:2781–2790[CrossRef][Medline]
6ß4 integrin: implications for basement membrane organization and tumor invasion. Mol Biol Cell 12:4030–40432ß1 integrin. Clin Exp Metastasis 14:19–26[CrossRef][Medline]
This article has been cited by other articles:
 |
|
 |
|
  K. Ishii, T. Imamura, K. Iguchi, S. Arase, Y. Yoshio, K. Arima, K. Hirano, and Y. Sugimura Evidence that androgen-independent stromal growth factor signals promote androgen-insensitive prostate cancer cell growth in vivo Endocr. Relat. Cancer, June 1, 2009; 16(2): 415 - 428. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Wang, Y. Li, X. Zhu, Y. Wang, F. Diao, and J. Lu Signal regulatory protein {alpha}1 is involved in the inhibitory effect of glucocorticoid receptor on the proliferation of murine macrophage RAW264.7 cell and mouse peritoneal macrophage J. Mol. Endocrinol., November 1, 2008; 41(5): 393 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Hara, H. Miyazaki, A. Lee, C. P. Tran, and R. E. Reiter Androgen Receptor and Invasion in Prostate Cancer Cancer Res., February 15, 2008; 68(4): 1128 - 1135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Bonaccorsi, D. Nosi, M. Muratori, L. Formigli, G. Forti, and E. Baldi Altered endocytosis of epidermal growth factor receptor in androgen receptor positive prostate cancer cell lines J. Mol. Endocrinol., January 1, 2007; 38(1): 51 - 66. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. S. Shah, J. Arlotti, R. Dhir, S. Lu, G. Pirozzi, K. Prakash, and R. H. Getzenberg Androgen Regulation of JM-27 Is Associated With the Diseased Prostate J Androl, July 1, 2004; 25(4): 618 - 624. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
