Fatty acid oxidation: driver of lymph node metastasis

Abstract

Fatty acid oxidation (FAO) is the emerging hallmark of cancer metabolism because certain tumor cells preferentially utilize fatty acids for energy. Lymph node metastasis, the most common way of tumor metastasis, is much indispensable for grasping tumor progression, formulating therapy measure and evaluating tumor prognosis. There is a plethora of studies showing different ways how tumor cells metastasize to the lymph nodes, but the role of FAO in lymph node metastasis remains largely unknown. Here, we summarize recent findings and update the current understanding that FAO may enable lymph node metastasis formation. Afterward, it will open innovative possibilities to present a distinct therapy of targeting FAO, the metabolic rewiring of cancer to terminal cancer patients.

Keywords: Fatty acid oxidation; Immune suppression; Lymph node metastasis; Lymph node pre-metastatic niche; Metabolic reprogramming; Prognosis; YAP.

Fig. 1

FAO Basics. After entering into the cell via fatty acid protein transporters, fatty acids are activated to acyl-CoA. The carnitine carnitine palmitoyltransferase system then transports acyl-CoA from cytoplasm into mitochondrial matrix for oxidation: CPT1 converts acyl-CoA into acylcarnitines and CPT2 converts acylcarnitine back into acyl-CoA for oxidation

Fig. 2

FAO and EMT. Some markers of EMT, such as Vimentin, Snail and E-cadherin are regulated by FAO. Vimentin and Snail are upregulated but E-cadherin is decreased, which display a start of cancer invasion. FAO is enhanced via the p-AMPK pathway owing to TGF-β1 expression activating TGF-β1/Smad signaling to boost EMT

Fig. 3

Induction and formation of LNM by FAO. FAO is implicated in multiple aspects of tumorigenesis including cancer cell growth, survival, drug resistance, and metastasis. Once migration into circulation system, the first challenge for the survival of cancer cells is to restrain apoptosis and cancer cells utilize fatty acids to fuel the growth. Then, FAO in tumor-associated immune cells and endothelial cells is also reprogrammed to contribute to immune suppression and the formation of tumor-promoting microenvironment. Lymph nodes are induced by cancer cells to establish pre-metastatic niches where FAO is involved in lymphangiogenesis, the recruitment of immunosuppressive cells, the up-regulation of chemokines and cytokines as well as vascular remodeling, indicating that FAO may play roles in formation of lymph node pre-metastatic niches. Once cancer cells colonize within lymph nodes, LNM is formed successfully