Transgenic mice expressing human insulin-like growth factor 1 (IGF-1) in basal epithelial cells of prostate have been characterized. Transgene expression led to activation of the IGF-1 receptor and spontaneous tumorigenesis in prostate epithelium. Hyperplasia was evident in these mice by 2-3 months of age. Atypical hyperplasias and prostatic intraepithelial neoplasia were evident by 6 -7 months of age. Well differentiated adenocarcinomas appeared in mice 6 months or older. Less differentiated tumors, diagnosed as small cell carcinomas, were also observed in two of the older mice. Both lobes of the mouse prostate gland (dorsolateral and ventral) presented preneoplastic and neoplastic changes. The incidence of tumors in mice >6 months of age (38 mice total) was 50%. The development of neoplasia in these transgenic mice appeared to follow a stepwise progression through early preneoplastic changes that ultimately culminated in frank neoplasia. 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. P rostate cancer is the most commonly diagnosed cancer in men in the United States (1). Progress in prostate disease research has been impaired by the lack of adequate animal models that reproduce the human disease. There are several established rat models of prostate cancer that are either hormonally and͞or chemically induced, such as the Lobund Wistar or Nobel rat models (2-5). In these models, the time frame to adenocarcinoma is 12-24 months. Spontaneous adenocarcinomas develop in the Dunning model (R-3327 system), which is carried as both cell lines and transplantable tumors in syngeneic Copenhagen rats (4). All of these model systems have certain limitations that have hampered their utility. Recently, several laboratories have created transgenic models in which prostate adenocarcinomas develop with high frequency (6-10). All of these models are based on expression of SV40-T antigen in prostate epithelium. Thus, a potential limitation of these models is the use of a transgene not directly involved in human prostate cancer. In some of these models, tumors develop rapidly (in some cases by 10-12 weeks), are poorly differentiated or undifferentiated, and progress rapidly to metastatic disease (6-8, 10).Recently, Chan et al. (11) reported a strong positive association between serum insulin-like growth factor 1 (IGF-1) levels and prostate cancer risk. The importance of IGF-1 receptor (IGF-1r) signaling in neoplastic transformation is clearly evident from a variety of studies (reviewed in refs. 12-16). Several transgenic models have been developed to explore the role of IGF-1r signaling in cellular growth and neoplasia (17)(18)(19)(20). However, with the exception of transgenic mice in which IGF-2 expression was driven by the major urinary protein promoter (MUP), none developed spontaneous tumors in any tissue. The MUP͞IGF-2 transgenic mice developed a variety of tumors, primarily hepatocellular carcinoma...
A series of both genetic and epigenetic factors have been implicated in the genesis and progression of prostate cancer. Recent evidence revealed that protein kinase C (PKC) isozymes play a crucial role in the control of cell proliferation and apoptosis in prostate cancer models, as well as in the transition from an androgen-dependent to an androgen-independent status. Indeed, PKCalpha and PKCdelta promote apoptosis in androgen-dependent prostate cancer cells. Due to the relevance of PKC isozymes in the control of cell cycle, both in G1/S and G2/M, the elucidation of such complex intracellular networks using cellular and animal models has become of outmost importance. In this review, we present the current knowledge on the regulation of apoptosis and tumorigenicity by PKC isozymes and the functional roles of cell cycle regulators in prostate carcinogenesis. The development of animal models where overexpression of discrete PKCs or cell cycle regulators is targeted to the prostate will greatly contribute to the understanding of the molecular basis of the disease, and more importantly, it will have profound implications for the development of novel strategies for prostate cancer therapy.
Major adhesion routes between lymphoid cells involve the receptor/ligand pairs LFA-l/ICAM-1 and CD2/LFA-3, in addition to VLA or CD44 molecules. In this study we evaluated the role of these adhesion receptors in the proliferative response of lymphoid cells to interleukin-2 (IL-2). Blocking studies were performed with a panel of monoclonal antibodies (mAb) directed against these adhesion molecules. Selective inhibition of recombinant (r)IL-2-induced cell proliferation was observed with mAb directed against the a or ¡3 subunit of LFA-1 or to its ligand ICAM-1. Interestingly, rIL-2-induced proliferation was also inhibited by NKI-L16, an anti-la antibody known to enhance cell-cell interac tion. Resting lymphocytes were preferentially susceptible to the inhibition, particularly in an early phase of culture and when stimulated with a relatively low dose of rIL-2. By using mAb that specifically could block distinct rIL-2 activation pathways, LFA-l/ICAM-1 interaction was found to be required for p55 IL-2 receptor (IL-2R)-mediated interaction of rIL-2 with its high-affinity receptor, but not for p75 IL-2R-rnediated responses. Furthermore, it was shown that the rIL-2 response of T lymphocytes, but not of natural killer cells, was dependent on LFA-l/ICAM-1 interaction. This suggests that LFA-l/ICAM-1 interaction is required for an optimal iiL-2 response of cells capable of IL-2 secretion. Our data provide evidence for the hypothesis that adhesion receptor-directed release of IL-2 may result in a locally high concentration of IL-2 that triggers high-affinity IL-2R signaling and up-regulates p55 IL-2R to enhance cytokine responsive ness.
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