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Leptin stimulates the proliferation of human colon cancer cells in vitro but does not promote the growth of colon cancer xenografts in nude mice or intestinal tumorigenesis in Apc^Min/+ mice

INSERM, U 683, IFR 02, Faculté de Médecine Xavier Bichat, Paris, France

Correspondence to:
Correspondence to:
Dr T Lehy
INSERM U 683, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, BP 416, Paris, Cedex 18, F-75870, France; tlehy{at}bichat.inserm.fr

ABSTRACT
Background and aims: Leptin, the product of the ob gene, has been suggested to increase the risk of colon cancer. However, we have shown that although leptin stimulates epithelial cell proliferation it reduces the development of carcinogen induced preneoplastic lesions in the rat colon. Here, we explored the effect of leptin in vitro on proliferation of human colon cancer cells, and in vivo on the growth of HT-29 xenografts in nude mice and the development of intestinal tumours in Apc^Min/+ mice.

Methods: Proliferation of HT-29, LoVo, Caco2, and SW 480 cells was assessed in the absence or presence of leptin (20–500 ng/ml) by ³H-thymidine incorporation and cell count. Leptin (800 µg/kg/day) or its vehicle was delivered for four weeks to nude mice, inoculated with HT-29 cells on day 0, and for six weeks to Apc^Min/+ mice.

Results: Leptin dose dependently stimulated cell DNA synthesis and growth in all cell lines. In nude mice, leptin caused a 4.3-fold increase in plasma leptin levels compared with pair fed controls. This hyperleptinaemia, despite leptin receptor expression in tumours, did not induce significant variation in tumour volume or weight. Tumour Ki-67 index was even inhibited. In leptin treated Apc^Min/+ mice, a 2.4-fold increase in plasma leptin levels did not modify the number, size, or distribution of intestinal adenomas compared with pair fed controls.

Conclusions: Leptin acts as a growth factor on colon cancer cells in vitro but does not promote tumour growth in vivo in the two models tested. These findings do not support a pivotal role for hyperleptinaemia in intestinal carcinogenesis.

Abbreviations: FCS, fetal calf serum; PCR, polymerase chain reaction; BSA, bovine serum albumin; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis

Keywords: hormone; carcinogenesis; animal models; cell lines; TdT, terminal deoxynucleotidyl transferase; TUNEL, terminal deoxynucleotidyl transferase mediated dUTP nick end labelling

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