Introduction:
Data supporting an association between environmental variables and cancer rates are increasing. Environmental aspects of lifestyle choices, such as the consumption of large amounts of high-carbohydrate and high-fat foods, are closely associated with metabolic disorders that lead to obesity, insulin resistance, and even metabolic syndrome. Type 2 diabetes mellitus, hypertension, cardiovascular disease, and hepatic steatosis are just some of the chronic diseases that are closely related to obesity, which is caused by the excessive systemic formation of adipose tissue. According to some scientists, it is also associated with the development and spread of several malignancies, including breast, ovarian, prostate, liver, colon, and pancreatic cancer. Cancer is a type of metabolic disorder. Obesity is found to be a prognostic but not an independent predictor of survival outcomes in cancer patients in a meta-analysis of 33 studies involving different types of cancer.
What Is Altered Lipid Metabolism in Cancer?
Alteration of lipid metabolism has been considered one of the more significant metabolic changes associated with tumor cell growth and cancer progression, as lipids are essential for cell metabolism, signaling, and membrane structure. Fatty acid (FA), arachidonic acid (AA), and cholesterol metabolism, along with peroxisome proliferator-activated receptor (PPAR) signaling, have been shown by some studies to be major interventions of altered lipid metabolic pathways. Furthermore, altered lipid uptake, storage, recycling, and de novo synthesis have been associated with cancer progression and metastasis. Thus, lipid metabolism enzymes may be promising targets for cancer therapy.
What Is NAFLD/NASH-HCC?
Nonalcoholic steatohepatitis, nonalcoholic fatty liver disease, and even hepatocellular carcinoma (HCC) are all significantly affected by altered lipid metabolism. The defining feature of NAFLD/NASH is a fatty liver disease (hepatic steatosis), which is often the initial event in the cancer cascade. According to epidemiology, one in four people worldwide will develop NAFLD at some point in their lives. Alarmingly, the frequency of this worldwide epidemic has increased by approximately eight percent over the past five years. According to some studies, ASH is a more severe type of NAFLD in which steatosis is accompanied by inflammation and hepatocellular ballooning, with or without fibrosis. Ten to twenty percent of patients with NAFLD/NASH may eventually develop HCC, making viral hepatitis the primary cause of HCC worldwide. NAFLD/NASH is a substantial risk factor for HCC. HCC involves significant metabolic reprogramming, such as altered lipid metabolism, and is not solely driven by oncogenic mutations or malignancy arising from persistent inflammation.
What Is the Role of Adipocytes in Tumor Development?
The participation of adipocytes in the lipid-rich tumor microenvironment may help partially explain the association between obesity and cancer development. Adipocytes produce proinflammatory cytokines such as IL-6, IL-8, and TNF, as well as angiogenic factors such as VEGF, prostaglandins, and leukotrienes, all of which are associated with immune evasion, cancer progression, and metastasis. Obesity may also lead to increased collagen IV production within the breast tumor microenvironment, which could indicate persistent inflammation and tissue fibrosis. Inhibition of hypoxia-inducible factor 1 (HIF1) has been shown to reduce obesity-related fibrosis and inflammation by preventing adipocyte activation. Additionally, it has been shown that excessive accumulation of adipocytes, particularly in visceral regions close to tumor sites, can create a hypoxic environment that promotes angiogenesis and promotes cancer spread.
What Are Lipid Metabolism and Cancer-Associated Fibroblasts?
Cancer-associated fibroblasts (CAFs) are a newly discovered cell type that has been shown to significantly affect tumor growth and metastasis inside the TME. These cells are known to modulate the TME through a variety of mechanisms, including, but not limited to, extracellular matrix remodeling, immune cross-talk through chemokine and cytokine production, soluble factor secretions, which include angiogenic and growth factors (VEGF and HGF), microRNAs (in exosomes). Few studies suggest that ectosomes directly transport lipids from CAFs to cancer cells, promoting the spread of the disease. The lipidomic reprogramming of CAFs in CRC with increased de novo FA synthesis and decreased lipid catabolism phenotype. According to the study, FASN overexpression in CAFs, together with CD36 upregulation in CRC cells, increases this close metabolic communication and aids in the migration and proliferation of CRC cells. According to related research on lung cancer cells, under glucose starvation, CAF-derived lipids, in particular oleic acid, can stimulate lipid metabolism in cancer cells via upregulating SCD1.
What Is Metabolic Reprogramming of Myeloid Cells in Cancer?
Macrophages: Several researchers found that different populations of macrophages had unique effects on homeostasis and disease beyond phagocytosis. The idea of tumor-associated macrophages (TAMs) was later developed when the polarization spectrum of M1-M2 macrophages was presented. Indeed, in a wide variety of disorders, macrophages can play a role as either “friend” or “foe” at almost every stage of disease pathogenesis and development. Reprogramming of CAF blood monocytes leads to their transformation into lipid-associated macrophages with an immunologically suppressive character, according to recent research.
Dendritic Cells: Dendritic cells (DCs) in cancer have a macrophage-like metabolic profile. In addition to increased accumulation of lipids that may aid antigen presentation. However, the effect of metabolic dysregulation on DC phenotype is more pronounced in tumors. Lipid-saturated DCs have impaired antigen processing and presentation, which impairs T-cell activation. PPAR is required for the metabolic reprogramming of DCs from glycolysis to FAO, which has an immunosuppressive impact comparable to M2 activation.
Myeloid-Derived Suppressor Cells: A diverse collection of immunosuppressive myeloid cells known as myeloid-derived suppressor cells (MDSCs) develop in chronic inflammatory situations such as cancer.
What Is Obesity-Mediated Reprogramming of Tumor-Infiltrating Lymphocytes?
Recent research has begun to clarify the relationship between obesity and anti-cancer immune responses. Understanding how altered lipid metabolism affects the function of cytotoxic lymphocytes within the tumor microenvironment is becoming more important as cancer immunotherapy gains ground.
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T-Cells: CD8 T-cell count has been shown by extensive research to be the most accurate indicator of a favorable response to anti-PD-1/PD-L1 therapy in various types of cancer.
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Natural Killer Cells: Obesity has recently been shown to affect antitumor immunity mediated by natural killer (NK) cells, as well as T cells. In a study of human patients of normal weight and those who were obese, there were fewer NKG2D+ and CD56dim cytotoxic NK cells in the peripheral blood.
Conclusion
Most research on the carcinogenic effects of obesity on tumor hosts has been performed in HCC, where hepatic steatosis is the main cause of malignancy. Despite a large amount of research on altered lipid metabolism, most studies focus primarily on describing the metabolic changes that alter the bioenergetics of tumor cells. Obesity-enhanced microbiota and metabolites in the gut-liver axis can significantly influence host immune responses during tumor growth. A new study compared gut microbiota and bile acids of HCC responders and non-responders after immune checkpoint inhibition.
