Introduction
CAAs secrete inflammatory factors that modify the behavior of breast cancer cells
Chemokines
CCL2
CCL5
Inflammatory factors
IL-6 and IL-1β
TNF-α
VEGF
Adipokines
Leptin and adiponectin
Parathyroid hormone-related protein
The metabolic reprogramming of CAAs drives cancer progression
Glycolysis and monocarboxylate extrusion
Fatty acids and ketone bodies
Amino acids
Exosomes interconnect cancer and cancer-associated adipocytes to promote tumor progression
miRNA | Tumor/cell | Mechanism | References |
---|---|---|---|
miRNA-144 | Breast cancer | miR-144 from cancer cells is able to target the MAP3K8 gene and reduce the phosphorylation level of ERK1/2, which leads to a decrease in the phosphorylation level of PPARγ S273 in adipocytes, ultimately leading to an increase in the expression of UCP1. | [66] |
miRNA-126 | Breast cancer | miR-126, derived from breast cancer cells, can target the IRS-1 gene to downregulate the expression of glut4 in adipocytes, which leads to a decrease in glucose uptake of adipocytes. And then AMPK is activated and protein levels of HIF-1α and MCT4 are increased, resulting in an increase of glycolysis and the secretion of metabolites, such as lactic acid and pyruvic acid. | [66] |
miRNA-155 | Breast cancer | miR-155 promotes beige/brown differentiation and remodels metabolism in adipocytes by downregulating the PPARγ expression. | [114] |
miRNA-122 | Breast cancer | miR-122 suppresses the uptake of glucose in premetastatic niche cells by decreasing the glycolytic enzyme pyruvate kinase, thereby facilitating disease progression. | [115] |
miRNA-105 | Breast cancer Hepatocellular carcinoma Pancreatic cancer | miR-105 activates MYC signaling in CAFs and CAAs to induce a metabolic program. And miR-105-reprogrammed CAFs enhance the metabolism of glucose and glutamine, fueling neighboring cancer cells in sufficient nutrient conditions, while these CAFs convert metabolic wastes such as lactic acid and ammonium into energy-rich metabolites in situations of nutrient deficiency. | |
ciRS-133 | Gastric cancer | Exosomes released from gastric cancer cells deliver ciRS-133 to pre-adipocytes, modulating the differentiation of pre-adipocytes to brown-like adipocytes through activating PRDM16 and inhibiting miRNA-133. | [119] |
miRNA-21 | Breast cancer Colorectal cancer Ovarian cancer | miR-21 is transported from CAAs to cancer cells, inhibiting the apoptosis of ovarian cancer cells and producing chemotherapy resistance by combining with its direct new target APAF1. | |
miRNA-210 | Endothelial cell | miR-210 released from adipose-derived stem cells promoted the proliferation, invasion and migration of endothelial cells by targeting RUNX3, suggesting that exosomal miR-210 may mediate tumor angiogenesis. | [130] |
Adipocytes play an important role in cancer
Adipocytes are mediators between obesity and cancer
Adipocytes are a pivotal immunomodulatory factor in cancer
Potential drugs targeting CAAs
Agent | Target | In vitro effect | Preclinical and clinical effects | References |
---|---|---|---|---|
Cenicriviroc | CCR2 | Inhibitor of CCR2 | Inhibition of monocyte recruitment, Prevent virus from entering into a human cell | |
Maraviroc | CCR5 | Inhibitor of CCR5 | Blockade the HIV from entering macrophages and T cells | [139] |
Tocilizumab | IL-6R | Monoclonal antibody against IL-6R | Hindering IL-6 from exerting its pro-inflammatory effects. | [140] |
Canakinumab | IL-1β | Monoclonal antibody against IL-1β | Treatment of cryopyrin-associated periodic syndromes | [141] |
Infliximab | TNF-α | Monoclonal antibody against TNF-α | Treatment of autoimmune diseases | |
Bevacizumab (Avastin) | VEGF | Monoclonal antibody against VEGF-A | Angiogenesis inhibitor | [145] |
AZD3695 | MCT1 | MCT1 inhibition | Reduce tumor growth, Increase intra-tumor lactate | [146] |
Nivolumab | PD-1 | Monoclonal antibody against PD-1 | Checkpoint inhibitor | [147] |
Durvalumab | PD-L1 | Monoclonal antibody against PD-L1 | Blocking the interaction of PD-L1 with the PD-1 and CD80 (B7.1) molecules. | [148] |
Avelumab | PD-L1 | Monoclonal antibody against PD-L1 | Blocking the interaction of PD-L1 binding to PD-1 | [149] |