The insulin-like growth factor-I receptor and apoptosis

Roith, Derek Le; Parrizas, Marcelina; Blakesley, Vicky A.

doi:10.1007/bf02778074

Cited by 31 publications

(13 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Several studies were performed to initially address this question. Because IGF-1 can have both mitogenic and anti-apoptotic actions (14,16), we examined these parameters in intact and castrated BK5.IGF-1 transgenic mice. Surprisingly, there were no clear differences in cell proliferation rates or apoptotic rates in the intact transgenic mice compared with nontransgenic littermates under the conditions of our experiments.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

DiGiovanni

Kiguchi

Frijhoff

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

243

133

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

“…The importance of IGF-1 receptor (IGF-1r) signaling in neoplastic transformation is clearly evident from a variety of studies (reviewed in refs. [12][13][14][15][16]. Several transgenic models have been developed to explore the role of IGF-1r signaling in cellular growth and neoplasia (17)(18)(19)(20).…”

mentioning

confidence: 99%

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

DiGiovanni

Kiguchi

Frijhoff

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

243

133

View full text Add to dashboard Cite

show abstract

“…Defining mediators that favor cell growth or limit apoptosis in the normal colonic mucosa is important in the prevention of colorectal cancer. Insulin and insulin-like growth factors (IGF) have been observed to have growth-promoting effects and antiapoptotic actions in vitro (1) and in animal models (2)(3)(4)(5).…”

Section: Introductionmentioning

confidence: 99%

“…Insulin has high affinity for the insulin receptor, which mediates its metabolic actions. At high concentrations, insulin can bind to IGF-I receptors or the hybrid insulin-IGF receptor to activate signal transduction cascades leading to proliferation and apoptosis (2,(5)(6)(7)(8). Insulin can also act directly to promote IGF-I biosynthesis, enhancing IGF-I bioavailability and inhibiting the production of IGF-binding protein (IGFBP)-1, IGFBP-2, and IGFBP-3 (6,(9)(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

“…IGFBP-3 limits the bioavailability of circulating IGFs for interactions with the IGF-I receptor (15,18,19). IGFBP-3 also has independent growth-inhibitory effects through the induction of apoptosis (2,5,20). IGFBP-3 has been reported to mediate p53-dependent apoptosis of colon cancer cell lines following g-radiation-induced DNA damage (21) and to reduce the growth of experimental colon tumors (22).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Insulin Resistance, Apoptosis, and Colorectal Adenoma Risk

Keku

Lund²,

Galanko

et al. 2005

Cancer Epidemiology, Biomarkers &Amp; Prevention

109

View full text Add to dashboard Cite

Compelling evidence from epidemiologic studies indicates that elevated circulating insulin-like growth factor (IGF)-I, insulin resistance, and associated complications, such as elevated fasting plasma insulin, glucose and free fatty acids, glucose intolerance, increased body mass index, and visceral adiposity, are linked with increased risk of colorectal cancer. However, the role of insulin and markers of glucose control in the development of adenomas, precursors to colorectal cancer, has not been fully explored. We evaluated the relationship between plasma insulin, glucose, IGF-I, IGF-II, IGF-binding protein-3 (IGFBP-3), apoptosis, and colorectal adenomas in a case-control study. Participants were drawn from consenting patients undergoing colonoscopy at the University of North Carolina hospitals (Chapel Hill, NC). Participants were classified as cases or controls based on whether they had one or more colorectal adenomatous polyps. Fasting plasma insulin, IGF-I, IGF-II, and IGFBP-3 levels were assessed by ELISA. Glucose was measured by glucose hexokinase assay. Apoptosis was assessed by morphology on H&E-stained sections. Dietary and lifestyle information were obtained by telephone interview. Logistic regression was used to examine the association between adenoma status and insulin-IGF markers. Adenoma cases (n = 239) and adenoma-free controls (n = 517) provided rectal biopsies and/or blood samples and interview data. Consistent with prior findings, cases were more likely to be males, older, have higher waist-to-hip ratio, lower calcium intake, lower apoptosis, and less likely to report nonsteroidal anti-inflammatory drug use. Those in the highest quartile of insulin (adjusted odds ratio, 2.2; 95% confidence interval, 1.1-4.2) and glucose (adjusted odds ratio, 1.8; 95% confidence interval, 0.9-3.6) were more likely to have an adenoma compared with the lowest quartile. Similarly, subjects in the highest two quartiles of insulin were more likely to be in the lowest two quartiles of apoptosis. Overall, there were no significant differences between mean circulating levels of glucose, IGF-I, IGF-II, and IGFBP-3 among cases and controls and no association between these variables and apoptosis. The results provide novel evidence that elevated insulin and glucose are associated with increased adenoma risk and decreased apoptosis in normal rectal mucosa. These findings suggest that insulin may act early in the adenoma-carcinoma sequence to promote the development of colorectal adenoma by decreasing apoptosis in the normal mucosa. (Cancer Epidemiol Biomarkers Prev 2005;14(9):2076 -81)

show abstract

Enhancement of susceptibility to diverse skin tumor promoters by activation of the insulin-like growth factor-1 receptor in the epidermis of transgenic mice

et al. 1999

View full text Add to dashboard Cite

Insulin-like growth factor-1 (IGF-1) and its receptor are believed to play an important role in mitogenesis and neoplastic transformation. The purpose of this study was to further examine the role of IGF-1 during tumor promotion in mouse skin. HK1.IGF1 transgenic mice, which overexpress IGF-1 in epidermis via the human keratin 1 promoter, were previously shown to be hypersensitive to skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). We examined these mice for their sensitivity to diverse classes of tumor-promoting agents. HK1.IGF-1 transgenic mice initiated with 7,12-dimethylbenz[a]anthracene were more sensitive to treatment with a wide variety of tumor promoters, including chrysarobin, okadaic acid, and benzoyl peroxide, which resulted in more rapid development of tumors and a dramatic increase in the number of tumors per mouse compared with corresponding non-transgenic mice treated with the same compounds. Histological analyses of skin from HK1.IGF-1 mice treated with various tumor promoters revealed that these mice were also more sensitive to the induction of epidermal hyperplasia and cell proliferation. Analysis of the IGF-1 receptor (IGF-1r) and epidermal growth factor (EGFr) in the epidermis of TPA-treated HK1.IGF-1 transgenic and non-transgenic mice revealed that both receptors were activated (hyperphosphorylated on tyrosine residues), and the level of activation was higher in transgenic mice. The mechanism for the increased sensitivity of HK1.IGF-1 mice to tumor promoters may involve cooperation between the IGF-1r and EGFr signaling pathways. Our data suggest that IGF-1r signaling may play an important role in the process of tumor promotion by diverse classes of tumor promoters.

show abstract

The insulin-like growth factor-I receptor and apoptosis

Cited by 31 publications

References 16 publications

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

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

Insulin Resistance, Apoptosis, and Colorectal Adenoma Risk

Enhancement of susceptibility to diverse skin tumor promoters by activation of the insulin-like growth factor-1 receptor in the epidermis of transgenic mice

Contact Info

Product

Resources

About