Date on Master's Thesis/Doctoral Dissertation

5-2012

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Microbiology and Immunology

Committee Chair

Suttles, Jill

Author's Keywords

Cancer; Obesity; Fatty acid binding proteins; Metastasis; Macrophage; Inflammation

Subject

Cancer--Etiology; Inflammation; Metastasis; Macrophages

Abstract

It has been estimated that 30% of all cancer deaths in the U.S. are associated with obesity. It is well-established that obesity promotes low-grade chronic inflammation, however the mechanisms by which obesity-induced chronic inflammation may promote cancer development and progression are not well-defined. Fatty acid binding proteins (FABPs), which are intracellular lipid chaperones, regulate both metabolic and inflammatory pathways. Of the nine FABP family members, adipocyte/macrophage-FABP (A-FABP) has been found to be highly expressed in macrophages in both mice and humans and its expression is increased in response to a high-fat diet. In the present study we examined the influence of A-FABP expression on tumor growth and metastasis in mice under conditions of normal or high-fat feeding. Wild-type (WT) and A-FABP knockout (A-FABP KO) mice were placed on a normal or high-fat diet prior to the injection of Lewis Lung Carcinoma cells (LLl2). When fed a normal diet, LLl2 tumor metastasis was significantly reduced in A-FABP KO mice relative to WT mice, whereas tumor growth in A-FABP KO and WT mice was similar. However, a high fat diet resulted in a Significant increase in both tumor growth and metastasis in WT, but not A-FABP KO mice. Western blot and RT-PCR analysis demonstrated that tumor-infiltrating macrophages isolated from A-FABP KO mice on a normal or high-fat diet have reduced pro-inflammatory cytokine production, NF-kB activation, and decreased expression of metastasis-promoting proteins, MMP-9 and MMP-12. Immunohistochemical analysis showed reduced expression of CD31 in tumors from A-FABP KO mice on either diet compared to tumors from WT mice. Taken together, our data suggest that A-FABP contributes to tumor growth and metastasis and implicate A-FABP as a link between fat consumption and cancer progression.

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