When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance

Abstract

The role of fatty acid metabolism, including both anabolic and catabolic reactions in cancer has gained increasing attention in recent years. Many studies have shown that aberrant expression of the genes involved in fatty acid synthesis or fatty acid oxidation correlate with malignant phenotypes including metastasis, therapeutic resistance and relapse. Such phenotypes are also strongly associated with the presence of a small percentage of unique cells among the total tumor cell population. This distinct group of cells may have the ability to self-renew and propagate or may be able to develop resistance to cancer therapies independent of genetic alterations. Therefore, these cells are referred to as cancer stem cells/tumor-initiating cells/drug-tolerant persisters, which are often refractory to cancer treatment and difficult to target. Moreover, interconversion between cancer cells and cancer stem cells/tumor-initiating cells/drug-tolerant persisters may occur and makes treatment even more challenging. This review highlights recent findings on the relationship between fatty acid metabolism, cancer stemness and therapeutic resistance and prompts discussion about the potential mechanisms by which fatty acid metabolism regulates the fate of cancer cells and therapeutic resistance.

Adipocyte extracellular vesicles carry enzymes and fatty acids that stimulate mitochondrial metabolism and remodeling in tumor cells

“…In particular, adipocytes provide a local supply of fatty acids (FA) that can serve as an energy source for tumors. FAO has recently emerged as a pro-tumoral pathway involved in cancer cell proliferation, stemness, and invasion (Carracedo et al, 2013;Kuo & Ann, 2018), but many of the molecular mechanisms behind these effects remain elusive. FAO has recently emerged as a pro-tumoral pathway involved in cancer cell proliferation, stemness, and invasion (Carracedo et al, 2013;Kuo & Ann, 2018), but many of the molecular mechanisms behind these effects remain elusive.…”

“…Indeed, tumor secretions trigger lipolysis in neighboring adipocytes (Dirat et al, 2011), and the released FA fuel fatty acid oxidation (FAO) in tumors, which increases tumor aggressiveness (Nieman et al, 2011;Balaban et al, 2017;Wang et al, 2017;Zhang et al, 2018). FAO has recently emerged as a pro-tumoral pathway involved in cancer cell proliferation, stemness, and invasion (Carracedo et al, 2013;Kuo & Ann, 2018), but many of the molecular mechanisms behind these effects remain elusive.…”

Adipocyte vesicles: ‘all-in-one’ packages that stimulate tumor mitochondrial metabolism and dynamics

“…Indeed, tumor secretions trigger lipolysis in neighboring adipocytes, and the released FA fuel fatty acid oxidation (FAO) in tumors, which increases tumor aggressiveness (Balaban et al, 2017;Nieman et al, 2011;Wang et al, 2017;Zhang et al, 2018). FAO has recently emerged as a pro-tumoral pathway involved in cancer cell proliferation, stemness and invasion (Carracedo et al, 2013;Kuo & Ann, 2018), but the molecular mechanisms behind this effect remain elusive.…”

RhoC modulates metabolic networks in cervical cancer by transcriptionally regulating the expression of genes involved in metabolism

“…Apart from this, lipids also play a pertinent role in oncogenic signaling pathways. Processes involved in advanced stages of cancer like EMT (epithelial to mesenchymal transition), angiogenesis and evasion of the immune system depend on molecular signaling mechanisms that are largely regulated by lipids (Beloribi-Djefaflia, Vasseur, & Guillaumond, 2016; Kuo & Ann, 2018; Rohrig & Schulze, 2016). In fact, RhoC (also known to regulate invasion, migration and angiogenesis), requires prenylation for its membrane localization and activity (Zhang & Casey, 1996).…”