Cellular growth factors as prospective therapeutic targets for combination therapy in androgen independent prostate cancer (AIPC)

Abstract Prostate cancer invariably recurs after androgen deprivation therapy. Growth of this recurrent/androgen-independent form of prostate cancer may be due to increased androgen receptor (AR) transcriptional activity in the absence of androgen. This ligand-independent AR activation is promoted by some growth factors but the mechanism is not well understood. Vav3, a Rho guanosine triphosphatase guanine nucleotide exchange factor, which is activated by growth factors, is up-regulated in human prostate cancer. We show here that Vav3 levels increase during in vivo progression of prostate cancer to androgen independence. Vav3 strikingly enhanced growth factor activation of AR in the absence of androgen. Because Vav3 may be chronically activated in prostate cancer by growth factor receptors, we examined the effects of a constitutively active (Ca) form of Vav3 on AR transcriptional activity. Ca Vav3 caused nuclear localization and ligand-independent activation of AR via the Rho guanosine triphosphatase, Rac1. Ca Rac1 activation of AR occurred, in part, through MAPK/ERK signaling. Expression of active Rac1 conferred androgen-independent growth of prostate cancer cells in culture, soft agar, and mice. These findings suggest that Vav3/Rac 1 signaling is an important modulator of ligand-independent AR transcriptional activity in prostate cancer progression.

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433. Combination Therapy of Androgen-Independent Prostate Cancer Using a Prostate Restricted Replicative Adenovirus and a Replication-Defective Adenovirus Encoding Human Endostatin-Angiostatin Fusion Gene

Molecular Therapy ◽

10.1016/j.ymthe.2006.08.499 ◽

2006 ◽

Vol 13 ◽

pp. S167

Author(s):

Xiong Li ◽

Sudhanshu P. Raikwar ◽

You-Hong Liu ◽

Sang-Jin Lee ◽

Yan-Ping Zhang ◽

...

Keyword(s):

Prostate Cancer ◽

Combination Therapy ◽

Fusion Gene ◽

Replication Defective Adenovirus ◽

Androgen Independent

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Growth factor involvement in progression of prostate cancer

Clinical Chemistry ◽

10.1093/clinchem/44.4.705 ◽

1998 ◽

Vol 44 (4) ◽

pp. 705-723 ◽

Cited By ~ 42

Author(s):

Pamela J Russell ◽

Suzanne Bennett ◽

Phillip Stricker

Keyword(s):

Prostate Cancer ◽

Growth Factors ◽

Growth Factor ◽

Cancer Progression ◽

Stromal Cells ◽

Transforming Growth Factor ◽

Normal Prostate ◽

Independent State ◽

Transforming Growth Factor Α ◽

Androgen Independent

Abstract Understanding how the regulation of growth factor pathways alters during prostate cancer (PC) progression may enable researchers to develop targeted therapeutic strategies for advanced disease. PC progression involves the shifting of cells from androgen-dependent growth to an androgen-independent state, sometimes with the loss or mutation of the androgen receptors in PC cells. Both autocrine and paracrine pathways are up-regulated in androgen-independent tumors and may replace androgens as primary growth stimulatory factors in cancer progression. Our discussion focuses on growth factor families that maintain homeostasis between epithelial and stromal cells in the normal prostate and that undergo changes as PC progresses, often making stromal cells redundant. These growth factors include fibroblast growth factor, insulin-like growth factors, epidermal growth factor, transforming growth factor α, retinoic acid, vitamin D3, and the transforming growth factor β families. We review their role in normal prostate development and in cancer progression, using evidence from clinical specimens and models of PC cell growth.

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Expression profiling of androgen-dependent and -independent LNCaP cells: EGF versus androgen signalling

Endocrine Related Cancer ◽

10.1677/erc.1.00897 ◽

2005 ◽

Vol 12 (1) ◽

pp. 135-148 ◽

Cited By ~ 16

Author(s):

Josien K Oosterhoff ◽

J Anton Grootegoed ◽

Leen J Blok

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Growth Factors ◽

Expression Profiling ◽

Egf Receptor ◽

Cancer Cell Line ◽

Prostate Cancer Cell Line ◽

Prostate Cancer Development ◽

Epidermal Growth ◽

Androgen Independent

Prostate cancer development often includes a shift from androgen-dependent to androgen-independent growth. It is hypothesized that, during this transition, growth factors like the epidermal growth factor (EGF) gain importance as activators of tumour cell proliferation. To study this, androgen- and EGF-regulation of growth and gene-expression was analysed in the androgen-dependent human prostate cancer cell line LNCaP-FGC (FGC) and its androgen-independent derivative line LNCaP-LNO (LNO). It was observed that androgen-dependent FGC cells require exposure to either androgens or EGF to proliferate. This is in contrast to androgen-independent LNO cells that showed significant proliferation in medium depleted of androgens and growth factors. Gene expression data were obtained for the androgen-dependent FGC and androgen-independent LNO cells cultured in the presence or absence of androgens (synthetic R1881) or EGF for different time periods. Expression profiling showed that many cell cycle genes, including a number of androgen- and EGF-regulated genes, are constitutively activated in androgen-independent LNO cells. Furthermore, the overlap between changes in gene expression activated by androgen and EGF receptor signalling pathways was found to be very high (75%). These results partly explain why androgen-independent LNO cells can proliferate in the absence of androgenic stimulation. However, possibly other, so far unknown, signal transduction pathways that induce and maintain proliferation, have also been activated.

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