1.5. Cancer-associated adipocytes (CAAs):
Cancer-associated adipocytes (CAAs) are a type of stromal cells and an important factor in TME that play a role in resistance to apoptosis, angiogenesis, metastasis, drug resistance, and cancer cell invasion [134-136]. CAAs promote cancer cell malignancy and tumor growth by secreting pro-inflammatory cytokines, hormones, adipokines, adiponectin, resistin, and leptin [109, 137, 138]. CAAs can also cause chemoresistance by secreting exosomes, for instance, exosomal miR21s derived from CAAs can inhibit apoptosis of cancer cells and promote chemoresistance by binding to apoptotic protease-activating factor 1 (APAF1) in ovarian cancer [62, 109].
In general, CAAs cause treatment resistance through the following actions:
1. Secretion of various factors: Adipose tissue acts both as a site for energy storage and as an endocrine organ, producing a wide range of exosomes, adipokines, leptin, growth factors, and adipocytokines that lead to treatment resistance [112, 139, 140].
2. Extracellular matrix remodeling: CAAs are a crucial source for ECM components, also, the property of ECM dynamic adaptation has an important role in the invasion and progression of cancer, as well as drug resistance [112]. CAAs release factors such as matrix metalloproteinases (MMPs) and collagen VI protein, resulting in the remodeling of ECM and chemotherapy resistance [141-144]. On the whole, according to several studies, lipid metabolism and CAAs have an intricate role in the regulation of cancer sensitivity to anticancer drugs [112].
3. Metabolism regulation: Since adipocytes perform energy storage, the metabolic relationship between tumor cells and adipocytes can naturally contribute to tumor progression [112]. Similar to CAFs, the ”Warburg effect” and ”reverse Warburg effect” could also cause drug resistance mediated by adipocytes [139]. The amount of lactate produced by adipocytes under hypoxia conditions increases significantly [145]. Adipocytes also provide lipids for cancer cells to supply their main energy, which can cause treatment resistance and tumor progression, for instance, cancer cells take up exogenous free fatty acids (FAAs) released by adipocytes and these endogenous lipid molecules enhance the rate of fatty acid β-oxidation (FAO), leading to extensive synthesis of َATP [112, 146].
4. Alteration in the pharmacokinetics of chemotherapy: Pharmacokinetics of chemotherapy is altered by CAAs commonly via two actions:
(a) Increase in drug clearance, (b) Alteration in drug distribution [112]. Since the concentration of active drugs during treatment plays a key role in the efficacy of cancer therapy, in adipocyte-rich microenvironments such as adipose tissue, it is observed a local decrease in cytotoxic chemotherapy activity due to decreased concentration, which could contribute to chemoresistance [112, 147].