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Insulin-like growth factor I stimulate angiogenesis and the production of vascular endothelial growth factor
Growfh Hormone & IGF Research 2000, Supplement
A, S41-S42
Insulin-like growth factor I .stimulates angiogenesis and the production of vascular endothelial growth factor Sandra E. Dunn Laboratory of Molecular Carolina. USA
Carcinogenesis.
National
institute
of Environmental
Health Sciences,
Clinical studies show that tumour angiogenesis correlates with a high incidence of metastases and a poor prognosis for cancers of the breast, bladder, prostate and skin. As a result of these studies, intense research efforts are under way to elucidate how the process of angiogenesis is regulated. The recent finding that insulin-like growth factor I (IGF-I) stimulates an angiogenesis factor known as vascular endothelial growth factor (VEGF) in human colon cancer cell lines is therefore timely’. This finding is very interesting in light of epidemiological data showing that elevated serum IGF-I levels impose an increased risk for developing lung*, colorecta13, prostate4 and breast5 cancers. Given these data, we embarked on testing the theory that IGF-I facilitates cancer progression by stimulating angiogenesis. This idea is supported by some of our previous work, which demonstrated that lowering IGF-I by dietary restriction decreased the progression of bladder cancefl. In a separate study, we showed that inhibition of the IGF-I receptor significantly suppressed breast cancer metastases to the lymph nodes, lung and lymph’. It is therefore possible that disruption of the IGF-I-IGF-I receptor interaction will slow cancer progression, in part by decreasing angiogenesis. To test this hypothesis, neovascularization was measured in our bladder cancer model. Heterozygous p53deficient mice received a bladder carcinogen, p-cresidine, to induce pre-neoplasia. After confirmation of preneoplasia, the mice were divided into three groups to receive: food ad libitwn, 20% dietary restriction, or 20% dietary restriction plus recombinant IGF-I administered via osmotic minipumps. Serum IGF-I level was lowered 24% by dietary restriction but was completely restored in
1096-6374/001020041+02
$35.00/O
National
Institute
of Health,
Research
Triangle
Park, North
the mice undergoing both IGF-I treatment and dietary restriction. Although tumour progression was reduced by dietary restriction, the restoration of IGF-I serum levels in diet-restricted mice led to an increase in cancer stage. We then stained bladder tissues for Factor VIII in order to identify microvessels, which would indicate the presence of neovasculatization. Interestingly, microvessel density was sixfold higher in mice that had received IGF-I than in mice with dietary restriction only. These data therefore demonstrate that the systemic modulation of IGF-I stimulates angiogenesis in our bladder cancer model. These findings led us to postulate that IGF-I signalling may affect angiogenesis in other tissues such as breast cancer. Indeed, we have found that IGF-I stimulates VEGF in a wide range of breast cancer cell lines, including MDA-MB-435 and the highly invasive MDA-ME23 1. In summary, our data suggest that IGF-I may increase the risk of developing cancer by stimulating neovascularization. Disrupting the IGF-IGF-I receptor pathway as a means to block angiogenesis is a novel approach that undoubtedly warrants further investigation. Attacking neovascularization is an attractive chemotherapeutic target for cancer therapy because neovascularization is a process that is germane only to wound healing and the growth of solid tumours.
REFERENCES 1. Akagi Y, Liu W, Zebrowski B, Xie K, Ellis LM. Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-I. Cancer Res 1998; 58: 4008-4014.
0 2000 US Government
42
S. E. Dunn
2. Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-controI anah&. J NatI Cancer Inst 1999; 9 1: 151-156. 3. Ma J, PolIak MN, Giovammcci E et aL Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF-I) and IGF-binding protein-3. J Natl Cancer Inst 1999; 91: 620-625. 4. Chart JM, Stampfer MJ, Giovarmucci E et al. Plasma insulin-like growth factor-I and prostate cancer risk a prospective study. Science 1998; 279: 563-566.
5. 6.
Z
Hank&on SE, Willett WC, Cold&z GA et al. Circulating insulinIike growth factor-1 and the risk of breast cancer. Iancet 1998; 351: 1393-1396. DUM SE, Rari FW, French J et al Dietary restriction reduces insulin-like growth factor-I levels which modulates apoptosis, cell proliferation, and tumor progression in p53 deficient mice. Cancer Res 1997; 57: 4667-4672. Dunn SE, Ehrlich M, Sharp NJH et al A dominant negative mutant of the insuRn-Iike growth factor-I receptor inhibits the adhesion, invasion, and metastasis of breast cancer. Cancer Res 1998; 58: 3353-3361.
A, S41-S42
Insulin-like growth factor I .stimulates angiogenesis and the production of vascular endothelial growth factor Sandra E. Dunn Laboratory of Molecular Carolina. USA
Carcinogenesis.
National
institute
of Environmental
Health Sciences,
Clinical studies show that tumour angiogenesis correlates with a high incidence of metastases and a poor prognosis for cancers of the breast, bladder, prostate and skin. As a result of these studies, intense research efforts are under way to elucidate how the process of angiogenesis is regulated. The recent finding that insulin-like growth factor I (IGF-I) stimulates an angiogenesis factor known as vascular endothelial growth factor (VEGF) in human colon cancer cell lines is therefore timely’. This finding is very interesting in light of epidemiological data showing that elevated serum IGF-I levels impose an increased risk for developing lung*, colorecta13, prostate4 and breast5 cancers. Given these data, we embarked on testing the theory that IGF-I facilitates cancer progression by stimulating angiogenesis. This idea is supported by some of our previous work, which demonstrated that lowering IGF-I by dietary restriction decreased the progression of bladder cancefl. In a separate study, we showed that inhibition of the IGF-I receptor significantly suppressed breast cancer metastases to the lymph nodes, lung and lymph’. It is therefore possible that disruption of the IGF-I-IGF-I receptor interaction will slow cancer progression, in part by decreasing angiogenesis. To test this hypothesis, neovascularization was measured in our bladder cancer model. Heterozygous p53deficient mice received a bladder carcinogen, p-cresidine, to induce pre-neoplasia. After confirmation of preneoplasia, the mice were divided into three groups to receive: food ad libitwn, 20% dietary restriction, or 20% dietary restriction plus recombinant IGF-I administered via osmotic minipumps. Serum IGF-I level was lowered 24% by dietary restriction but was completely restored in
1096-6374/001020041+02
$35.00/O
National
Institute
of Health,
Research
Triangle
Park, North
the mice undergoing both IGF-I treatment and dietary restriction. Although tumour progression was reduced by dietary restriction, the restoration of IGF-I serum levels in diet-restricted mice led to an increase in cancer stage. We then stained bladder tissues for Factor VIII in order to identify microvessels, which would indicate the presence of neovasculatization. Interestingly, microvessel density was sixfold higher in mice that had received IGF-I than in mice with dietary restriction only. These data therefore demonstrate that the systemic modulation of IGF-I stimulates angiogenesis in our bladder cancer model. These findings led us to postulate that IGF-I signalling may affect angiogenesis in other tissues such as breast cancer. Indeed, we have found that IGF-I stimulates VEGF in a wide range of breast cancer cell lines, including MDA-MB-435 and the highly invasive MDA-ME23 1. In summary, our data suggest that IGF-I may increase the risk of developing cancer by stimulating neovascularization. Disrupting the IGF-IGF-I receptor pathway as a means to block angiogenesis is a novel approach that undoubtedly warrants further investigation. Attacking neovascularization is an attractive chemotherapeutic target for cancer therapy because neovascularization is a process that is germane only to wound healing and the growth of solid tumours.
REFERENCES 1. Akagi Y, Liu W, Zebrowski B, Xie K, Ellis LM. Regulation of vascular endothelial growth factor expression in human colon cancer by insulin-like growth factor-I. Cancer Res 1998; 58: 4008-4014.
0 2000 US Government
42
S. E. Dunn
2. Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case-controI anah&. J NatI Cancer Inst 1999; 9 1: 151-156. 3. Ma J, PolIak MN, Giovammcci E et aL Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF-I) and IGF-binding protein-3. J Natl Cancer Inst 1999; 91: 620-625. 4. Chart JM, Stampfer MJ, Giovarmucci E et al. Plasma insulin-like growth factor-I and prostate cancer risk a prospective study. Science 1998; 279: 563-566.
5. 6.
Z
Hank&on SE, Willett WC, Cold&z GA et al. Circulating insulinIike growth factor-1 and the risk of breast cancer. Iancet 1998; 351: 1393-1396. DUM SE, Rari FW, French J et al Dietary restriction reduces insulin-like growth factor-I levels which modulates apoptosis, cell proliferation, and tumor progression in p53 deficient mice. Cancer Res 1997; 57: 4667-4672. Dunn SE, Ehrlich M, Sharp NJH et al A dominant negative mutant of the insuRn-Iike growth factor-I receptor inhibits the adhesion, invasion, and metastasis of breast cancer. Cancer Res 1998; 58: 3353-3361.