Get access

Energy balance modulates colon tumor growth: Interactive roles of insulin and estrogen

Authors

  • Elizabeth A. Rondini,

    1. Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan
    Search for more papers by this author
  • Alison E. Harvey,

    1. Division of Nutritional Sciences, University of Texas, Austin, Taxes
    Search for more papers by this author
  • Juan P. Steibel,

    1. Department of Animal Science, Michigan State University, East Lansing, Michigan
    Search for more papers by this author
  • Stephen D. Hursting,

    1. Division of Nutritional Sciences, University of Texas, Austin, Taxes
    2. Department of Carcinogenesis, UT-M.D. Anderson Cancer Center, Smithville, Taxes
    Search for more papers by this author
  • Jenifer I. Fenton

    Corresponding author
    1. Department of Food Science and Human Nutrition, Michigan State University, East Lansing, Michigan
    2. College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan
    • Department of Food Science and Human Nutrition, Michigan State University, 208B GM Trout Bldg, East Lansing, MI 48824.
    Search for more papers by this author

  • Elizabeth A. Rondini and Alison E. Harvey contributed equally to this work.

Abstract

Obesity increases colorectal cancer (CRC) risk and progression. However, the impact of obesity on CRC in women is dependent on ovarian hormone status. The purpose of this study was to determine the interactive roles of obesity and ovarian hormones on serum markers of inflammation, cell signaling, and transplanted colon tumor growth. Female C57BL/6 mice (6 wk) were either ovariectomized (OVX) or ovaries left intact (nonovariectomized, NOVX) and randomized to receive a (1) control, (2) 30% calorie-restricted (CR), or (3) diet-induced obese (DIO) diet regimen for 20 wk to induce differing levels of adiposity. Serum was collected and inflammatory and metabolic markers were measured using an antibody array (62 proteins) and ELISAs. Mice were subcutaneously injected with syngeneic MC38 colon cancer cells after 20 wk and sacrificed 4 wk later. CR mice had the smallest tumors irrespective of hormone status, whereas the largest tumors were observed in DIO-OVX mice. Glucose tolerance was impaired in OVX mice, being most severe in the DIO-OVX group. Cytokine arrays suggested that in CR animals, inhibition of tumor growth paralleled insulin sensitivity and associated changes in leptin, adiponectin, and IGF-BPs. Conversely, in DIO-OVX animals, tumor growth was associated with insulin and leptin resistance as well as higher levels of pro-inflammatory proteins. In vitro, leptin and adiponectin had no effect, whereas insulin induced MC38 cell proliferation and MAPK activation. Co-treatment with estrogen blocked the stimulatory effects of insulin. Thus, our in vitro and in vivo data indicate female reproductive hormones have a modulating effect on obesity-induced insulin resistance and inflammation, which may directly or indirectly influence CRC progression. ©2010 Wiley-Liss, Inc.

Ancillary