Leptin, Insulin-Like Growth Factor-1, and Insulin-Like Growth Factor-2 Are Mitogens in ApcMin/+ but not Apc+/+ Colonic Epithelial Cell Lines

Abstract

The obese state is associated with elevated circulating levels of insulin, insulin-like growth factors (IGF), and leptin. Research is contradictory regarding the role of these elevated growth factors in colon cancer risk. We hypothesized that colonic epithelial cells that were Apc deficient (Apc Min/+ ) but not those expressing wild-type Apc (Apc +/+ ) would experience a hyperproliferative and antiapoptotic phenotype when exposed to these growth factors. This hypothesis was addressed using two nontumorigenic murine colonic epithelial cell lines with distinct Apc genotypes: Apc +/+ YAMC cells and Apc Min/+ IMCE cells. Cells were treated for 48 hours with various concentrations of leptin (0.001-50 ng/mL), IGF-1 (0.1-200 ng/mL), or IGF-2 (0.1-600 ng/mL). In YAMC cells, leptin caused a significant decrease in cell proliferation (P < 0.01) compared with controls due to induction of caspase activity and apoptosis. In contrast, in the IMCE cells, leptin induced a 75% increase in cell proliferation compared with controls (P < 0.0001). IGF-1 and IGF-2 also induced 50% greater proliferation in the IMCE cells (P < 0.001) compared with controls. Cotreatment of IMCE cells with leptin and either IGF-1 or IGF-2 induced greater proliferation than either growth factor alone (P < 0.0001). IMCE cell proliferation caused by leptin only treatment was associated with activation of p42/44 mitogen-activated protein kinase (MAPK), p38 MAPK, and nuclear factor-KB nuclear translocation but not with MAPK kinase or Janus-activated kinase/ signal transducers and activators of transcription activation. These data provide the first evidence that leptin may interact with IGFs to promote survival and expansion of colonic epithelial cells that were Apc deficient (Apc Min/+ ) but not those expressing wild-type Apc (Apc +/+ ). (Cancer Epidemiol Biomarkers Prev 2005;14(7):1646 -52)

Repetitive Deformation Activates Focal Adhesion Kinase and ERK Mitogenic Signals in Human Caco-2 Intestinal Epithelial Cells through Src and Rac1

“…Although the magnitude of the effects that we have observed here are relatively small, typically in the range of 30 -100%, signals of similar magnitude have been studied and are reported to be biologically significant by others in response to repetitive deformation in other cell types (22, 51, 82, 84 -90) and in intestinal epithelial cells in response to various mitogens (91)(92)(93)(94). Intestinal epithelial proliferation is tightly regulated.…”

Metabolic surgery and cancer

“…It acts on the hypothalamus to increase energy expenditure and decrease food intake, although in obese individuals leptin levels are chronically high. Leptin can stimulate the proliferation of cancer cells and may contribute to cellular carcinogenesis, 96 whereas a decrease in leptin levels (in the context of an enriched environment for rodents) is associated with reduced tumor growth and increased cancer remission. 97 Adiponectin is exclusively synthesized from adipose tissue and demonstrates both anti-inflammatory and antidiabetic properties.…”

Accelerated Tumor Formation in a Fatless Mouse with Type 2 Diabetes and Inflammation

“…Multiple factors from adipose tissue, such as leptin, adiponectin, cytokines, and other secreted products, influence processes involved in carcinogenesis (5,6). In addition, reduction of adiposity by calorie restriction (7,8) or physical activity suppresses tumor development (9) and lowers circulating levels of many adipokines, further implicating them in tumor development.…”