Targeting of the Peritumoral Adipose Tissue Microenvironment as an Innovative Antitumor Therapeutic Strategy

Abstract

The tumor microenvironment (TME) plays a key role in promoting and sustaining cancer growth. Adipose tissue (AT), due to its anatomical distribution, is a prevalent component of TME, and contributes to cancer development and progression. Cancer-associated adipocytes (CAAs), reprogrammed by cancer stem cells (CSCs), drive cancer progression by releasing metabolites and inflammatory adipokines. In this review, we highlight the mechanisms underlying the bidirectional crosstalk among CAAs, CSCs, and stromal cells. Moreover, we focus on the recent advances in the therapeutic targeting of adipocyte-released factors as an innovative strategy to counteract cancer progression.

Mutual impact of adipocytes and colorectal cancer cells growing in co-culture conditions

“…As mentioned, under exposure to cancer cells, adipocytes can transform into cancer-associated adipocytes [ 7 ]. Zoico et al revealed that during interaction with colon cancer cells, adipocytes obtained from 3T3-L1 cells can be reprogrammed into CAAs or dedifferentiated into “fibroblast-like cells” in vitro [ 35 ].…”

“…Due to the production and secretion of a wide array of effectors, including exosomes, lipids, and adipokines, AT can have paracrine and endocrine effects that control metabolic homeostasis [ 6 ]. Aside from their physiological functions, these secreted factors may play a crucial role in cancer proliferation, invasion, and resistance to therapies [ 7 ] and may be involved in the initiation and progression of CRC [ 8 ].…”

“…Tight and long-standing contact between cancer cells and adipocytes was demonstrated to induce the reprogramming of adipocytes into cancer-associated adipocytes (CAAs). Their presence has been observed in various malignancies, including colon, breast, ovarian, prostate, and pancreatic cancers [ 7 ].…”

“…CAAs also indicate a lower expression of genes related to adipocyte differentiation, such as peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (c/EBPα), fatty acid binding protein 4 (FABP4), and hormone-sensitive lipase (LIPE). As a consequence of delipidation and changes in fat storage capacity [ 7 ], the metabolism of CAAs is switched toward catabolic processes, leading to the release of high‑energy metabolites, including free fatty acids (FFAs), lactate, pyruvate, and ketone bodies [ 11 ].…”

“…Adipocytes’ contribution to tumorigenesis involves crosstalk between these cells and cancer since the reprogramming of the adipocytes into CAAs occurs as a consequence of the impact of cancer cells [ 7 ]. Additionally, cancer cells may promote lipolysis in neighboring adipocytes, take in the released FFAs through specific transporters (e.g.…”