Disregulation of growth factor signal transduction in prostate cancer - Research Canadian Health&Care Mall

The MAPK signalling pathway links signal transduction of growth factors and the AR in
carcinoma of the prostate. Besides activating MAPK, these peptides act through other
signalling pathways, for example the pathway of phosphatidylinositol 3-kinase. There is
evidence for overexpression of some growth factors in carcinoma of the prostate.

Epidermal growth factor (EGF) and transforming growth factor-α (TGF-α), both of which
bind to the EGFR, are differentially expressed in benign and malignant prostate tissue46.
In benign prostate tissue, there is predominant expression of EGF, whereas prostate
cancer metastases stain predominantly for TGF-α. There is ongoing controversy whether
EGF-related molecule HER-2/neu expression is elevated in prostate cancer. HER-2 is an
important activator of the AR, and its overexpression is frequently associated with
malignant transformation.

TGF-β is a pleiotropic regulator of prostate growth that exhibits different effects on
cell growth in vitro and in vivo. It is considered an important growth-inhibitory factor for
prostate cells in culture, where it antagonizes stimulatory effects of EGF. Inhibitory
action, however, depends on duration of treatment and percentage of serum in individual
experiments. Prostate cancer cells PC-3 and DU-145 respond to TGF-β by reducing their
proliferation, whereas growth of LNCaP cells cannot be retarded by the growth factor.

In earlier studies, it was suggested that this is due to absence of the TGF-β receptor type I. However, studies carried out by others have revealed that there is missing expression of  restoration of TGF-β responsiveness. In clinical specimens, either receptor could be lost in advanced carcinoma of the prostate. In addition, TGF-β intermediary effectors
caspase-1 and caspase-3 also decrease in human prostate cancer51. In vivo, TGF-β
influences angiogenesis and suppresses immune response. Therefore, it is not surprising
that prostate cancer cells stably transfected with TGF-β cDNA confer a growth advantage
in vivo. Elevated levels of TGF-β were measured in some studies in sera from prostate
cancer patients.

Similar elevation of growth factor serum levels have been reported for basic fibroblast
growth factor (bFGF, FGF-2), which is involved in promotion of metastasis by regulation
of matrix metalloproteinases and angiogenesis. bFGF is expressed in prostate cancer cell lines PC-3 and DU-145 but not in LNCaP cells, and is capable of down-regulating
AR expression.

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It is mainly contained in the extracellular matrix, and only a very small percentage is secreted. The presence of bFGF in prostate tissues was initially reported in stromal cells. In more recent publications, it was recognized that some tumor cells also show bFGF immunoreactivity.

Keratinocyte growth factor (KGF), which belongs to the same family of peptides, is implicated in mediation of androgenic effects between the stromal and epithelial compartments of the prostate, as evidenced in studies with coculture of prostatic cells. However, in vivo experiments did not confirm that role of KGF. KGF binds to the variant IIIb isoform of the FGF receptor-2, whereas bFGF binds to the isoform IIIc, whose expression is up-regulated in prostate cancer.

Therapeutic approaches to down-regulate bFGF in cancer may be based on an
antagonistic effect of interferons-α and -β. Transfection of cells with a recombinant
adenovirus expressing dominant-negative FGF receptor-1 led to G2 growth arrest. Little is known about signalling pathways by which FGF enhances growth of prostate cancer cells and down-regulates AR expression.

Recent studies have focused on the other member of the FGF family of growth factors,
FGF-8, which is expressed in high-grade prostate intraepithelial neoplasia lesions and in
prostate cancer; administration of neutralizing anti-FGF-8 antibodies abolished the
effect of androgens on cell growth. LNCaP cells generated to overexpress FGF-8b
proliferated at a high rate and increased invasive potential.

Insulin-like growth factor-I (IGF-I) has been suggested to be associated with increased
prostate cancer risk. IGF-I action is determined by its association with several binding
proteins, and the growth factor is implicated in regulation of apoptosis, mitogenic
responses and AR activity.

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