The fat and the bad: Mature adipocytes, key actors in tumor progression and resistance

Abstract

Growing evidence has raised the important roles of adipocytes as an active player in the tumor microenvironment. In many tumors adipocytes are in close contact with cancer cells. They secrete various factors that can mediate local and systemic effects. The adipocyte-cancer cell crosstalk leads to phenotypical and functional changes of both cell types, which can further enhance tumor progression. Moreover, obesity, which is associated with an increase in adipose mass and an alteration of adipose tissue, has been established as a risk factor for cancer incidence and cancer-related mortality. In this review, we summarize the mechanisms of the adipocyte-cancer cell crosstalk in both obese and lean conditions as well as its impact on cancer cell growth, local invasion, metastatic spread and resistance to treatments. Better characterization of cancer-associated adipocytes and the key molecular events in the adipocyte-cancer cell crosstalk will provide insights into tumor biology and suggest efficient therapeutic opportunities.

Keywords: adipocytes; adipose tissue; cancer progression; invasion; resistance.

Figure 1. In breast cancers, adipocytes localized at the tumor invasive front undergo decrease in size and lipid content, a process that can be recapitulated in vitro, in co-culture assays

(A) Histological examination of an invasive breast tumor after H&E staining (original magnification ×100). AD, adipose tissue; IF, invasive front (indicated by a dashed line); (C) tumor center. Note that at the invasive front, the size of adipocytes is reduced. (B) Mature adipocytes cocultivated in the presence (C) or absence (NC) of breast cancer cells were stained with oil Red O. The cocultivated adipocytes exhibit a decrease in the number and size of lipid droplets.

Figure 2. Adipocytes promote tumor invasion and metastasis

Secretion of cytokines and chemokines by mature adipocytes favor the homing of tumor cells to surrounding adipose tissue. Once the adipose tissue is invaded, a crosstalk is established between cancer cells and mature adipocytes that undergo phenotypical changes towards a Cancer Associated Adipocytes (CAAs) phenotype. Their ability to secrete soluble factors, exosomes and extra-cellular matrix components stimulate invasive properties of tumor cells. These invasive cells can enter the blood stream and colonize distant organs including bone which is also an adipocyte-rich organ.