Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice

Abstract

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...

Antixenograft tumor activity of a humanized anti-insulin-like growth factor-I receptor monoclonal antibody is associated with decreased AKT activation and glucose uptake

“…High serum IGF-I concentrations correlate with increased risk for breast, prostate, and colon cancers in humans (6). Gain-of-function studies show that the IGF system can drive tumorigenesis in animal models (7,8), whereas IGF-IR deficiency conversely inhibits cellular transformation (9). Taken together, these data provide a strong scientific rationale for developing targeted therapies to inhibit this pathway in human cancer.…”

Androgen receptor targets NFκB and TSP1 to suppress prostate tumor growth in vivo

“…60 Only three genes have been found critical for prostate carcinogenesis in mice: an oncogenic IGF-1 and cMyc, and a tumor suppressor PTEN. 61,62 Surprisingly, AR failed as prostate-specific oncogene in transgenic models, its overexpression yields PIN but no invasive carcinoma. 63 In another study, wild-type and promiscuous AR mutant T857A (T877A analogue) fail to induce PIN in young animals suggesting that ligand driven AR activation does not induce epithelial hyperproliferation in the whole prostate.…”

Prostate targeting: PSP94 gene promoter/enhancer region directed prostate tissue-specific expression in a transgenic mouse prostate cancer model

“…In this regard, several purported (nonprostate) tissue-specific promoters/enhancers have been tested for targeting the prostate in transgenic mouse experiments. These include the mouse mammary tumor virus (MMTV) long terminal repeat (LTR), 2 mouse cryptdin-2 (CR-2) gene, 3 human fatal G␥-globin, 4 bovine keratin 5 promoter 5 and gp91-phox 6 (for review see Refs 7 and 8). However none of these promoter/enhancers have been found to be adequate for targeted specifically to the prostate (for reviews see .…”