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Growth Factor Binding to 7,12-Dimethylbenz(a)anthracene-induced Mammary Tumors from Rats Subject to Chronic Caloric Restriction¹

The Wistar Institute of Anatomy and Biology [B. A. R., D. M. K., D. K.]; Department of Biochemistry and Biophysics, University of Pennsylvania [B. A. R.]; Department of Pediatrics, University of Pennsylvania School of Medicine and Division of Endocrinology/Diabetes, Children's Hospital of Philadelphia [R. W. F.]; Philadelphia, Pennsylvania 19104

Caloric restriction (CR) inhibits tumorigenesis in rodents. To understand the basis for this effect the binding of insulin, insulin-like growth factor I/somatomedin C (IGF-I/Sm-C), insulin-like growth factor II/multiplication stimulating activity (IGF-II/MSA), and epidermal growth factor were examined to membrane preparations of 7,12-dimethylbenz(a)anthracene-induced mammary adenocarcinomas and several normal tissues from female Sprague-Dawley rats. Animals were fed ad libitum (AL) or 25% and 40% calorically restricted diets. Large, palpable (LP) and small, 100 mg, nonpalpable (SNP) tumors were evaluated. Growth factor binding to tumors was differentially affected by CR. IGF-I/Sm-C binding was comparable for AL-LP, AL-SNP, and 25% CR-LP tumors, but elevated in 25% CR-SNP tumors. Scatchard analysis revealed high and low affinity IGF-I/Sm-C binding sites, with AL-SNP and 25% CR-SNP tumors exhibiting similar levels of high affinity sites and at a greater concentration than AL-LP and 25% CR-LP tumors. Insulin binding to mammary tumors was low, i.e., 8- to 13-fold lower than IGF-I/Sm-C binding. The 25% CR-LP and SNP tumors bound 2- to 5-fold more insulin than corresponding AL-LP and SNP tumors. Binding of IGF-II/MSA to these tumor preparations was high, approximately 11- to 25-fold greater than insulin binding, and was unaffected by CR or tumor size. The binding of epidermal growth factor was not detected in any tumor preparations. Receptor binding studies were confirmed with covalent cross-linking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analyses. Normal tissues exhibited tissue- and growth factor-specific alterations in binding with host CR. Thus, alterations in growth factor binding were not tumor specific, but were less pronounced than in mammary tumors. These findings suggest alterations in IGF-I/Sm-C and insulin binding properties to tumors in relation to CR and tumor size may contribute, in part, to the inhibitory effects of CR on tumorigenesis.

¹ Supported by a training grant (CA-09485) from NIH; Best Foods, a division of CPC International, Inc.; Grants CA-38981 and CA-43856 from the National Cancer Institute; and a Research Career Award (HL-00734) from NIH.

² To whom requests for reprints should be addressed, at the Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104.

³ Present address: University of Rochester School of Medicine, Department of Pediatrics, Rochester, NY 14642.

Received 9/23/88. Revised 5/ 1/89. Accepted 5/ 4/89.

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