Energy Balance Modulates Colon Tumor Growth: Interactive Roles of Insulin and Estrogen

Mol Carcinog. 2011 May;50(5):370-82. doi: 10.1002/mc.20720. Epub 2010 Dec 28.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Caloric Restriction
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colorectal Neoplasms / blood
  • Colorectal Neoplasms / metabolism*
  • Colorectal Neoplasms / pathology
  • Cytokines / blood
  • Dietary Fats / adverse effects
  • Energy Metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Estrogens / metabolism*
  • Estrogens / pharmacology
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • Hypoglycemic Agents / metabolism
  • Hypoglycemic Agents / pharmacology
  • Insulin / metabolism*
  • Insulin / pharmacology
  • Leptin / metabolism
  • Leptin / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Neoplasm Transplantation
  • Obesity / blood
  • Obesity / etiology
  • Obesity / metabolism
  • Ovariectomy
  • Phosphorylation / drug effects
  • Random Allocation

Substances

  • Cytokines
  • Dietary Fats
  • Estrogens
  • Hypoglycemic Agents
  • Insulin
  • Leptin
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases