Lipids in the tumor microenvironment: From cancer progression to treatment

Abstract

Over the past decade, the study of metabolic abnormalities in cancer cells has risen dramatically. Cancer cells can thrive in challenging environments, be it the hypoxic and nutrient-deplete tumor microenvironment or a distant tissue following metastasis. The ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment and adjacent stroma. Adipocytes can be activated by cancer cells to lipolyze their triglyceride stores, delivering secreted fatty acids to cancer cells for uptake through numerous fatty acid transporters. Cancer-associated fibroblasts are also implicated in lipid secretion for cancer cell catabolism and lipid signaling leading to activation of mitogenic and migratory pathways. As these cancer-stromal interactions are exacerbated during tumor progression, fatty acids secreted into the microenvironment can impact infiltrating immune cell function and phenotype. Lipid metabolic abnormalities such as increased fatty acid oxidation and de novo lipid synthesis can provide survival advantages for the tumor to resist chemotherapeutic and radiation treatments and alleviate cellular stresses involved in the metastatic cascade. In this review, we highlight recent literature that demonstrates how lipids can shape each part of the cancer lifecycle and show that there is significant potential for therapeutic intervention surrounding lipid metabolic and signaling pathways.

Keywords: Immune Response; Lipid Metabolism; Lipid Signaling; Metastasis; Radiation Therapy; Tumor Microenvironment.

Fig. 1:. Complex interactions within the tumor microenvironment (TME).

The TME consists of a complex mixture of cancer cells, immune cells, and stromal cells. As cancer cells invade through the basement membrane and into the stromal compartment, they activate nearby stromal cells, such as adipocytes and fibroblasts, and influence lipid metabolism [24,26,29,30,45,46]. The recruitment of fibroblasts and immune cells can result in significant ECM deposition, which can restrict metabolites such as glucose and oxygen from diffusing into the core of the tumor [10]. Fatty acids secreted by tumor-associated stromal cells can have a tumor-promoting effect on many of the immune cells that are recruited to the TME, including macrophages, natural killer cells, dendritic cells, neutrophils, and T cells. The lipid metabolic reprogramming of tumor cells due to these interactions may provide survival advantages for cells in treatment and metastasis.

Fig. 2:. Exogenous fatty acids from the TME promote cancer progression and survival.

As cancer cells invade into the surrounding stroma, they come into contact with and activate stromal cells, including adipocytes and fibroblasts [24,45,46]. Activation of adipocytes, potentially by pro-inflammatory cytokines, induces lipolysis of stored triglycerides and secretion of fatty acids [24,26,29,30]. Adipokines such as FABP4 increase the expression of fatty acid transporters, including CD36, to facilitate the uptake of these fatty acids by cancer cells [34,35]. Unsaturated fatty acids that are acquired and stored in LDs provide benefits to cells during hypoxia, where de novo synthesis of unsaturated fatty acids is blocked [63,64]. Unsaturated fatty acids prevent lipotoxicity and allow for membrane synthesis with sufficient fluidity to promote tumor cell migration and invasion [65]. These fatty acids can also be utilized in FAO when oxygen levels are sufficient [–9]. Activated CAFs and other stromal cells secrete LPC that is hydrolyzed from adipocyte- and cancer cell-secreted ATX to promote cancer cell migration, invasion, and proliferation [–12].

Fig. 3:. The impact of lipid metabolism on treatment response and metastasis.

Altered lipid metabolism profiles in tumor cells may provide survival advantages following therapy as well as in detached conditions promoting metastasis. RT, CT, and detachment can induce the formation of ROS, leading to DNA damage and ER stress [–173]. Interestingly, LD formation has been correlated with UPR activation and ER stress reduction [–177]. Cells that survive these stresses tend to have high expression of CPT1, the rate-limiting enzyme of FAO that transports long-chain fatty acids into the mitochondria, and high FAO rates [–157,160,164,186,187]. This enables increased glutathione production through allowing high rates of aerobic glycolysis, facilitating the shuttling of glycolytic intermediates into the PPP [189], or the production of NADPH from cytosolic reactions of FAO-generated acetyl-CoA [162,163]. Adipocytes in the TME may influence these processes as pro-inflammatory cytokines secreted from damaged cells may induce lipolysis [26,29,30], resulting in a release of FFAs that can be taken up by fatty acid transporters. ATX secreted by treatment-damaged stromal cells [178] acts on serum LPC to produce LPA, which can signal through LPARs to improve DNA repair mechanisms and promote CT and RT cancer cell survival [ – 184].

Fig. 4:. Overarching themes of lipids in the tumor microenvironment.

Lipids impact the TME at every stage of cancer progression. Lipids can be released from stromal cells as the tumor spreads into the surrounding microenvironment, providing fuel for new cell growth, inducing signaling to enhance migration, and suppressing the immune response. Utilizing lipids through FAO or lipid synthesis can promote survival for cancer cells experiencing cellular stress from RT, CT, or intravasation into the circulation. Targeting lipid metabolism reprogramming in cancer cells may lead to promising therapeutic strategies to ultimately improve patient outcomes.