Epidermal growth factor-related peptides and their receptors in human malignancies

Prostate cancer has the highest prevalence of any nonskin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating androgens will develop microscopic prostate cancer if they live long enough. This review is a contemporary and comprehensive, literature-based analysis of the putative risk factors for human prostate cancer, and the results were presented at a multidisciplinary consensus conference held in Crystal City, Virginia, in the fall of 2002. The objectives were to evaluate known environmental factors and mechanisms of prostatic carcinogenesis and to identify existing data gaps and future research needs. The review is divided into four sections, including 1) epidemiology (endogenous factors [family history, hormones, race, aging and oxidative stress] and exogenous factors [diet, environmental agents, occupation and other factors, including lifestyle factors]); 2) animal and cell culture models for prediction of human risk (rodent models, transgenic models, mouse reconstitution models, severe combined immunodeficiency syndrome mouse models, canine models, xenograft models, and cell culture models); 3) biomarkers in prostate cancer, most of which have been tested only as predictive factors for patient outcome after treatment rather than as risk factors; and 4) genotoxic and nongenotoxic mechanisms of carcinogenesis. The authors conclude that most of the data regarding risk relies, of necessity, on epidemiologic studies, but animal and cell culture models offer promise in confirming some important findings. The current understanding of biomarkers of disease and risk factors is limited. An understanding of the risk factors for prostate cancer has practical importance for public health research and policy, genetic and nutritional education and chemoprevention, and prevention strategies.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.20408

Human prostate cancer risk factors.

Purpose: The transforming growth factor α-epidermal growth factor receptor (EGFR) autocrine pathway has been implicated in prostate cancer cell growth. Amplification and/or overexpression of c-erbB-2, a receptor closely related to the EGFR, has been recently involved in prostate cancer progression. We investigated EGFR and c-erbB-2 expression in primary androgen-dependent and in advanced androgen-independent prostate cancer and their potential role as markers of disease progression. Experimental Design: EGFR and c-erbB-2 expression were evaluated by immunohistochemistry in a consecutive series of 74 prostate cancer patients with the following characteristics: 29 patients (group 1) treated with radical prostatectomy; 29 patients (group 2) treated with luteinizing hormone-releasing hormone analogues and antiandrogen therapy followed by radical prostatectomy; and 16 patients with hormone-refractory metastatic disease. In all patients we evaluated: association between EGFR and/or c-erbB-2 expression and clinicopathological parameters; and disease-free survival according to EGFR and c-erbB-2 expression in univariate analysis (Kaplan-Meier product-limit method) and in multivariate analysis (Cox proportional hazards regression model). Results: EGFR expression was found in 12 of 29 (41.4%) group 1 patients, in 22 of 29 (75.9%) group 2 patients (P Conclusions: EGFR expression increases during the natural history of prostate cancer. Correlation with disease progression and hormone-refractory disease suggests that EGFR-targeted drugs could be of therapeutic relevance in prostate cancer.

http://clincancerres.aacrjournals.org/content/clincanres/8/11/3438.full.pdf

Expression of Epidermal Growth Factor Receptor Correlates with Disease Relapse and Progression to Androgen-independence in Human Prostate Cancer

We have explored the therapeutic effects of anti-epidermal growth factor receptor monoclonal antibodies (MAbs) 225 and 528 on well established A431 epidermoid carcinoma xenografts, approximately 400 mm 3 (1 cm in diameter) at the start of treatment. In previous reports we demonstrated that MAbs 225 and 528 prevented the growth of A431 cell xenografts in nude mice when treatment was begun on the day of tumor cell inoculation. Since anti-epidermal growth factor receptor MAb therapy of well established tumors was unable to retard growth, we explored combination therapy with MAb plus the chemotherapeutic agent c/s-diamminedichloroplatinum (c/s-DDP). Additive and concentration-dependent growth-inhibitory effects of MAb with c/s-DDP were observed in cultures of A431 cells. Neither intensive treatment with 225 MAb (1 mg/ mouse, i.p. on day 8 after tumor inoculation, and twice weekly for 4 weeks) nor a maximally tolerated single dose of c/s-DDP [150 pg/25 g (6 mg/kg) mouse weight, i.p. on day 8] had significant effects on tumor growth. However, the two treatments in combination resulted in substantial xenograft growth inhibition, compared with both an untreated control group and animals treated with a single modality. When a second dose of cis-DDP (150/zg/25 g) was added after 10 days, combination therapy with 225 MAb produced striking antitumor effects. At the end of 1 month tumor xenografts had disappeared in all but one mouse, and no tumor relapses occurred during 6 months of observation. Identical results were obtained with anti-epidermal growth factor receptor MAb 528 in combination with c/s-DDP. The results of these studies provide a novel approach to the treatment of well established tumor xenografts, which may have application in the therapy of human malignancies.

Antitumor Effect of Anti-Epidermal Growth Factor Receptor Monoclonal Antibodies plus cis-Diamminedichloroplatinum on Well Established

Both EGF and insulin, or IGF, stimulate the growth of many cell types by activating receptors that contain tyrosine kinase activities A monoclonal antibody (mAb 225) against the EGF receptor produced in this laboratory has been shown to competitively inhibit EGF binding and block activation of receptor tyrosine kinase Here we report that a human colorectal carcinoma cell line, DiFi, which expresses high levels of EGF receptors on plasma membranes, can be induced to undergo G1 cell cycle arrest and programmed cell death (apoptosis) when cultured with mAb 225 at concentrations that saturate EGF receptors Addition of IGF-1 or high concentrations of insulin can delay apoptosis induced by mAb 225, while the G1 arrest cannot be reversed by either IGF-1 or insulin Insulin/IGF-1 cannot activate EGF receptor tyrosine kinase that has been inhibited by mAb 225 Moreover, an mAb against the IGF-1 receptor, which has little direct effect on DiFi cell growth, can block the capacity of insulin/IGF-1 to delay apoptosis induced by mAb 225, suggesting that the insulin/IGF-1-mediated delay of apoptosis is acting through the IGF-1 receptor In contrast, insulin/IGF-1 cannot delay the apoptosis caused by the DNA damaging agent, cisplatin The results indicate that EGF receptor activation is required both for cell cycle progression and for prevention of apoptosis in DiFi cells, and that a signal transduction pathway shared by receptors for insulin/IGF-1 and EGF may be involved in regulating apoptosis triggered by blockade of the EGF receptor

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Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin.

The androgen-independent prostatic carcinoma cell line PC3 is known to exhibit autonomous growth in vitro and in vivo. The purpose of the present study was to investigate the role of transforming growth factor alpha (TGF-alpha) and its receptor, the epidermal growth factor (EGF) receptor, in the regulation of PC3 cell proliferation. Results showed that PC3 cells secrete factors into conditioned medium that are mitogenic for the less aggressive prostatic carcinoma lines DU145 and LNCaP. Gel filtration chromatography of PC3-conditioned medium revealed a major peak of mitogenic activity at a molecular weight of 5,000 to 10,000 which was inhibited by the addition of antibody to TGF-alpha. The synthesis and secretion of TGF-alpha by PC3 cells were further demonstrated by immunoblotting and radioimmunoassay. Radioreceptor analysis showed a single class (Kd 5.3 nM) of EGF receptors on PC3 cells. The presence of Mr 170,000 EGF receptors on PC3 cells was further demonstrated by immunoprecipitation of metabolically labeled proteins. TGF-alpha was effective in stimulating the growth of low-density, but not high-density, PC3 cultures. In addition, the proliferation of PC3 cells under serum-free defined conditions was inhibited by antibodies to TGF-alpha and/or the EGF receptor. These data indicate that TGF-alpha/EGF receptor interactions are partially responsible for autonomous growth of the PC3 cell line and may explain one mechanism of escape from androgen-dependent growth in human prostatic carcinoma.

https://cancerres.aacrjournals.org/content/canres/51/11/2780.full.pdf

Warren D. Bromberg

Papers

Autonomous growth of androgen-independent human prostatic carcinoma cells: role of transforming growth factor alpha.

Pkostate-type Gland in the Epididymis

Isolated Pulmonary Metastases from Carcinoma of the Prostate: A Case Report and Deoxyribonucleic Acid Analysis Using Flow Cytometry