Obesity and Fibrosis: Setting the Stage for Breast Cancer

Abstract

Obesity is a rising health concern and is linked to a worsened breast cancer prognosis. Tumor desmoplasia, which is characterized by elevated numbers of cancer-associated fibroblasts and the deposition of fibrillar collagens within the stroma, may contribute to the aggressive clinical behavior of breast cancer in obesity. A major component of the breast is adipose tissue, and fibrotic changes in adipose tissue due to obesity may contribute to breast cancer development and the biology of the resulting tumors. Adipose tissue fibrosis is a consequence of obesity that has multiple sources. Adipocytes and adipose-derived stromal cells secrete extracellular matrix composed of collagen family members and matricellular proteins that are altered by obesity. Adipose tissue also becomes a site of chronic, macrophage-driven inflammation. Macrophages exist as a diverse population within obese adipose tissue and mediate the development of fibrosis through the secretion of growth factors and matricellular proteins and interactions with other stromal cells. While weight loss is recommended to resolve obesity, the long-term effects of weight loss on adipose tissue fibrosis and inflammation within breast tissue are less clear. Increased fibrosis within breast tissue may increase the risk for tumor development as well as promote characteristics associated with tumor aggressiveness.

Keywords: adipocytes; breast cancer; cancer-associated fibroblasts; extracellular matrix; macrophages; mammary gland; obesity.

Figure 1

Interactions among cells within mammary adipose tissue enhance fibrosis in obesity. Adipose-derived stromal cells (ASC) and adipocytes increase (↑) secretion of collagen family members as well as growth factors and cytokines that promote adipose tissue fibrosis in obesity. Macrophages and mast cells are recruited into the obese adipose tissue microenvironment and interact with ASC to promote deposition of collagen and other extracellular matrix (ECM) proteins. Macrophages form characteristic crown-like structures surrounding adipocytes. Increased collagen, growth factors, and cytokines are produced by multiple cell types, while adiponectin secretion is decreased (↓) by adipocytes.

Figure 2

Obesity increases desmoplasia in mammary tumor microenvironment. Tumor-associated macrophages may activate adipose-derived stromal cells (ASC), which may then contribute to the CAF population. Through production of thicker and stiffer extracellular matrix (ECM), breast cancer cells may have increased (↑) exposure to growth factors, hypoxia (Hif-1α), and cytokines, leading to increased proliferation and invasion.

Figure 3

Weight loss modulates the adipose tissue microenvironment. Obesity leads to changes in adipocyte size, macrophage diversity, and collagen deposition, which are only partially reversed with weight loss.