Specimens of benign prostatic hypertrophy (BPH) and prostate carcinoma and prostate cells in culture were assessed for their capacity to bind androgens, radioiodinated EGF, and IGF-I, and to express certain cellular protooncogenes.
These data suggested that TGFbeta1, uPA, and IGF-I mediate at least in part cell-cell interactions and GR function in PA-III prostate cancer and UMR 106 osteosarcoma cells.
Although differences in circulating IGF-1 do not seem to account for the greater prostate cancer risk among African-American men, their absolute lower levels of IGFBP-3 may be contributory.
Elevated levels of IGF-IR are observed in a variety of human tumour types, whereas epidemiological studies implicate the IGF-1 axis as a predisposing factor in the pathogenesis of human breast and prostate cancer.
These mice offer an animal model for prostate cancer that will allow study of the stepwise development of this disease and the mechanism(s) whereby IGF-1 mediates this process.
These findings suggest that up-regulation of IGFBP-5 after castration serves to enhance IGF bioactivity and raise the possibility that the response of prostate cancer to androgen withdrawal can be enhanced by strategies, such as antisense IGFBP-5 ODN therapy, that target IGF signal transduction.
One of the principal regulators of IGF-IR gene expression, the WT1 tumor suppressor, is expressed in prostate cancer and in prostate cancer cell lines.
To further investigate the relationship between the plasma levels of insulin-like growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), insulin-like growth factor binding protein-3 (IGFBP-3), growth hormone, testosterone, and demographic factors, particularly race, within a group of men at increased risk of prostate cancer development.
In vivo progression of LAPC-9 and LNCaP prostate cancer models to androgen independence is associated with increased expression of insulin-like growth factor I (IGF-I) and IGF-I receptor (IGF-IR).
In this study, we investigated the effects of NaB on the expression of IGF binding protein (IGFBP)-3, a known growth regulator, in two human prostate cancer cell lines (PC-3 and LNCaP).
This is the first study that suggests inactivation of IGFBP-rP1 is through CpG methylation, and tumor-suppressive activity of IGFBP-rP1 is through induction of apoptosis in an IGF-I independent manner in prostate cancer.
The adjusted odds ratios for having prostate cancer for patients with the GST-T1 and IGF-I variant alleles were 1.64 (95% confidence interval, 1.1-2.4; P = 0.01) and 1.70 (95% confidence interval, 1.1-2.7; P = 0.02), respectively.
We have postulated that tumor secreted IGF-I in conjunction with endogenous IGF-I contributes to the osteoblastic phenotype characteristic of metastatic PC.
The risk of prostate cancer increased across quartiles of IGF-I (highest vs. lowest quartile, OR = 2.34; 95% CI = 1.26-4.34; p(trend) = 0.02) and IGF-II (OR = 1.78; 95% CI = 0.94-3.15; p(trend) = 0.09).
These results indicate an important role for IGF-IR and IGFBP-3 in the homeostasis of prostate carcinoma cells and provide a further basis for targeting IGF-IR or IGFBP-3 gene expression in order to improve understanding of the IGF-IR-activated signalling pathways and as a potential treatment for prostate cancer.
The present observations strongly suggest that AR activation may stimulate prostate cancer progression through the altered IGF-IR expression and IGF action.
Of these 14 genes only 6 (Cip1, IGF-1, NK4, CXCL 12, ILGF2R, RHOE) have already been associated with PCa, whereas the other 8 genes (FSTL-1, SOCS-2, Midkine, Thrombospondin 1, Secretory leukocyte protease inhibitor, Desmoglein 2, MLT 1, PTPRF) had not been previously related to PCa.
Recent research has outlined the association of circulating IGF-1 and prostate cancer risk, and studies have elucidated the implication of the IGF network in the early stages of prostate carcinogenesis.
To investigate the role of the GH-IGF-I axis on in vivo prostate carcinogenesis and neoplastic progression, we generated mice genetically predisposed to prostate cancer (the TRAMP model) to be homozygous for lit, a mutation that inactivates the GHRH receptor (GHRH-R) and reduces circulating levels of GH and IGF-I.
Using small interfering RNA oligonucleotides to down-regulate beta1A, we show that beta1A expression is required for IGF-IR-mediated prostate cancer cell proliferation and anchorage-independent growth.