Loss of adipocyte specification and necrosis augment tumor-associated inflammation

Abstract

Most tumors are typified by a chronic, unresolved inflammatory response that potentiates angiogenesis and therefore enables tumor progression. We have determined that dysfunctional tumor-associated adipocytes contribute to tumor-associated inflammation. In three tumor models, tumor-associated adipose tissue was characterized by thin and fragile adipocyte membranes, necrosis, robust expression of the pro-inflammatory factor HMGB1, and loss of the lipid storage mediator, perilipin-1. By transmission electron microscopy, macrophages in tumor-associated adipose tissue contained lipid droplets and resembled foam cells, which are commonly observed in inflamed tissues. In vitro co-culture studies showed that tumor-associated adipose tissue conditioned-medium stimulated monocyte-to-macrophage differentiation, adhesion, spreading, and lipid uptake. Compared with normal adipose tissue, tumor-associated adipose tissue secreted 3-fold higher levels of IL-6 and IL-6 was sufficient to stimulate macrophage differentiation and adhesion. These results suggest that, in tumors, loss of adipocyte specification, necrosis, and scavenging of adipocyte debris directly activates macrophages and contributes to tumor-associated inflammation. Thus, adipocyte dysfunction may facilitate tumor progression, especially in tumors closely aligned with adipose tissue, in particular, breast cancer.