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].