Update on Adipose Tissue and Cancer

Abstract

Adipose tissue is the largest endocrine organ and an accepted contributor to overall energy homeostasis. There is strong evidence linking increased adiposity to the development of 13 types of cancer. With increased adiposity comes metabolic dysfunction and insulin resistance, and increased systemic insulin and glucose support the growth of many cancers, including those of the colon and endometrium. There is also an important direct crosstalk between adipose tissue and various organs. For instance, the healthy development and function of the mammary gland, as well as the development, growth, and progression of breast cancer, are heavily impacted by the breast adipose tissue in which breast epithelial cells are embedded. Cells of the adipose tissue are responsive to external stimuli, including overfeeding, leading to remodeling and important changes in the secretion of factors known to drive the development and growth of cancers. Loss of factors like adiponectin and increased production of leptin, endotrophin, steroid hormones, and inflammatory mediators have been determined to be important mediators of the obesity-cancer link. Obesity is also associated with a structural remodeling of the adipose tissue, including increased localized fibrosis and disrupted angiogenesis that contribute to the development and progression of cancers. Furthermore, tumor cells feed off the adipose tissue, where increased lipolysis within adipocytes leads to the release of fatty acids and stromal cell aerobic glycolysis leading to the increased production of lactate. Both have been hypothesized to support the higher energetic demands of cancer cells. Here, we aim to provide an update on the state of the literature revolving around the role of the adipose tissue in cancer initiation and progression.

Keywords: adipokines; adipose tissue; cancer; obesity.

Graphical Abstract

Figure 1.

Local and systemic effects of adipose tissue on tumor growth and metastasis. Tumors of the breast, prostate, kidney, and skin interact directly with adipose tissue. Crosstalk between tumor and adipose tissue involves the actions of adipokines, inflammatory mediators, estrogens, as well as the increased deposition of collagen/extracellular matrix (ECM) and the dedifferentiation of adipocytes. The accumulation of dedifferentiated adipocytes, adipose stromal cells (ASCs), or cancer-associated fibroblasts (CAFs) supports the growth and metastasis of tumors. Systemic factors originating from adipose tissue (eg, leptin) or produced as a result of dysfunctional adipose tissue (eg, glucose and insulin) can affect the growth of cancer cells, including in the uterus or the ovary, or cause changes in metabolic tissues that lead to cancer formation (eg, liver or pancreas). Metastatic cells, including lymphomas, breast, and prostate cancer cells, have been shown to hone to bone marrow adipose tissue.

Figure 2.

Tumor–adipose tissue interactions. There is important crosstalk between tumor cells and cells of the adipose tissue. Adipocytes secrete adipokines, including leptin, which have been shown to stimulate estrogen production from adipose stromal cells (ASCs) and alter their metabolism, as well as stimulate proliferation of normal epithelial cells and cause DNA damage, which can lead to tumorigenesis. Adipokines also stimulate cancer cell proliferation through direct mechanisms. Tumor cells alter metabolism of many cell types within the adipose tissue, including ASCs and adipocytes. By stimulating dedifferentiation of adipocytes and glycolysis in ASCs, tumor cells contribute to the generation of lactate, which they can then use as a fuel source. Stimulation of lipolysis from adipocytes also contributes to a pool of free fatty acids (FFAs) that can be used by tumor cells. Other changes that occur in the adipose tissue that contributes to tumor growth include the production of inflammatory mediators like PGE2 which act to stimulate hormone production from ASCs and tumors cell proliferation, accumulation of collagen and the release of endotrophin, as well as the release of extracellular vesicles (EVs).

Figure 3.

Effects of adipose tissue-derived factors on tumor cells. Adipose-derived factors, including estrogens, prostaglandin E2 (PGE₂), leptin, insulin, and fatty acids stimulate changes in gene expression, protein synthesis and cell metabolism that support the proliferation, migration, invasion and survival of cancer cells. Binding of estradiol to the estrogen receptor (ER) leads to genomic and nongenomic effects, including stimulation of expression of factors involved in cell cycle progression, as well as activation of MAPK and Akt signaling. PGE₂, via binding to its receptors, also stimulates MAPK and Akt signaling. Insulin stimulation of the IGF-I or insulin receptors leads to activation of Akt signaling, as well as stimulation of glucose uptake to support the energy demands of cancer cells. Fatty acids are also taken up by cancer cells and further metabolized to produce ATP or used as building blocks for cell division.

Figure 4.

Pathways involved in regulation aromatase expression in adipose tissue of healthy individuals or those with obesity. Metabolically healthy individuals have higher circulating levels of adiponectin, ghrelin and unacylated ghrelin. These peptide hormones act to stimulate AMPK, associated with stabilization of p53, or inhibit cAMP production, leading to the suppression of aromatase transcript expression. In adipose tissue of individuals with obesity, factors including leptin or PGE₂, suppress the activity of AMPK and stimulate pathways that activate HIF1α, ATF2, CREB, LRH-1, and PGC1α, leading to the increased expression of aromatase and the biosynthesis of estrogens.