Adipocyte and lipid metabolism in cancer drug resistance

Abstract

Development of novel and effective therapeutics for treating various cancers is probably the most congested and challenging enterprise of pharmaceutical companies. Diverse drugs targeting malignant and nonmalignant cells receive clinical approval each year from the FDA. Targeting cancer cells and nonmalignant cells unavoidably changes the tumor microenvironment, and cellular and molecular components relentlessly alter in response to drugs. Cancer cells often reprogram their metabolic pathways to adapt to environmental challenges and facilitate survival, proliferation, and metastasis. While cancer cells' dependence on glycolysis for energy production is well studied, the roles of adipocytes and lipid metabolic reprogramming in supporting cancer growth, metastasis, and drug responses are less understood. This Review focuses on emerging mechanisms involving adipocytes and lipid metabolism in altering the response to cancer treatment. In particular, we discuss mechanisms underlying cancer-associated adipocytes and lipid metabolic reprogramming in cancer drug resistance.

Figure 1. Mechanisms of cancer-associated adipocytes in tumor growth, metastasis, and cachexia.

Malignant cells produce various soluble and cell surface signaling molecules to reprogram metabolic activity and production of growth factors/cytokines in adipocytes through endocrine, paracrine, and juxtacrine signaling mechanisms. After receiving signals from malignant cells, cancer-associated adipocytes (CAAs) produce various growth factors, adipokines, and adipocytokines that directly affect tumor cell growth and invasion. Alternatively, the adipocyte-derived factors have a significant impact on nontumor cells in the tumor microenvironment to modulate tumor growth, metastasis, and cachexia. The tumor cell–triggered metabolic reprograming in adipocytes releases metabolic products such as free fatty acids (FFAs) that will be used as energy fuel molecules to support tumor growth and metastasis. Lipolysis is also one of the key processes causing adipose atrophy and cachexia in cancer patients.

Figure 2. Mechanistic principles underlying cancer treatment and obesity-associated treatment resistance.

(A) Mechanistic principles of cancer drugs. Conventional treatment approaches, including chemotherapeutics and radiation therapy, indistinguishably target malignant and nonmalignant cells in the tumor microenvironment and elsewhere in the body. Numerous targeted therapeutics targeting cancer cells have been developed, such as trastuzumab. Other targeted therapeutics, including antiangiogenic drugs, immune regulators, and antiinflammatory and antifibrotic drugs, aim to interfere with or enhance the interaction between nonmalignant cells and cancer cells. (B) Possible mechanisms of obese adipocytes in contributing to anticancer resistance. Obese adipocytes may have altered metabolism, pharmacokinetics, expression of tumor cell survival factors, immune cell functions, vascular functions, and drug distribution to affect anticancer drug responses. These alterations often lead to the development of resistance to cancer drugs.

Figure 3. The mechanism of adipocyte metabolic reprogramming in antiangiogenic drug resistance.

Treatment of tumors with antiangiogenic drugs reduces the tumor vascular density, leading to tissue hypoxia. Hypoxia triggers lipolysis in tumor-infiltrating and peritumoral CAAs to produce excessive FFAs. Hypoxia also upregulates the expression levels of CD36, the fatty acid translocase or receptor, in cancer cells to increase FFA uptake. Within tumor cells, FFA through the β-oxidation pathway is metabolized to produce ATP that supports tumor cell proliferation and migration in the presence of a minimal number of microvessels. This mechanism explains in part how CAAs contribute to antiangiogenic drug resistance.