2013 Grant Award - Bing Li, Ph.D.

Regulation of Tumor Associated Macrophages by A-FABP in Obese Mice

Bing Li, Ph.D.
The Hormel Institute, University of Minnesota

Obesity and cancer are two major epidemics worldwide. While obesity is associated with an increased risk of cancer, the molecular mechanisms underlying these associations remain poorly understood. Adipocyte/macrophage fatty acid binding protein (A-FABP) is traditionally recognized as cytoplasmic lipid chaperones, enabling lipid distribution and coordinating their responses inside cells. However, emerging evidence suggests that cytoplasmic A-FABP can be released into the circulation in obesity and circulating A-FABP can serve as a plasma biomarker for obesity, metabolic syndrome and cancer. Our preliminary studies demonstrate that A-FABP is significantly upregulated in macrophages and in the circulation of obese mice. In response to tumor stimulation, cytoplasmic A-FABP expression is markedly elevated in tumor associated macrophages (TAMs). More importantly, A-FABP deficiency alters macrophage phenotype and protects mice against tumor growth and metastasis. Thus, A-FABP may exert its effects through both local (cytoplasmic) and systemic (circulating) actions in tumor development. The objective of this proposal is to establish A-FABP as a new link between obesity and cancer. We hypothesize that A-FABP promotes obesity-associated cancer development through targeting both macrophages and cancer cells. Thus, modulating A-FABP activity will represent a novel strategy for treatment of cancer. Two specific aims are designed to address our hypothesis. In specific aim 1, we will determine how intracellular A-FABP regulates TAM functions for tumor development. We will analyze whether and how intracellular A-FABP impacts macrophage infiltration, immunoregulation and proangiogenesis in mammary tumors. In Specific Aim 2, we will explore the mechanisms of action of the released circulating A-FABP in obesity to understand how it contributes to cell transformation and carcinogenesis through activation of oncogenic signaling pathways in tumor cells. Successful completion of this proposal will establish A-FABP as a new link between obesity and cancer. The data obtained will not only have basic science ramifications for understanding mechanisms of how A-FABP promotes breast tumorigenesis and progression, but will also have clinical impact for the treatment of obesity-associated cancer.