Emphasis on Adipocyte Transformation: Anti-Inflammatory Agents to Prevent the Development of Cancer-Associated Adipocytes

Abstract

Of the various cell types in the tumor microenvironment (TME), adipocytes undergo a dynamic transformation when activated by neighboring cancer cells. Although these adipocytes, known as cancer-associated adipocytes (CAAs), have been reported to play a crucial role in tumor progression, the factors that mediate their transformation remain elusive. In this review, we discuss the hypothesis that inflammatory signals involving NF-ĸB activation can induce lipolysis and adipocyte dedifferentiation. This provides a mechanistic understanding of CAA formation and introduces the concept of preventing adipocyte transformation via anti-inflammatory agents. Indeed, epidemiological studies indicate a higher efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) in obese patients with cancer, suggesting that NSAIDs can modulate the TME. Inhibition of cyclooxygenase-2 (COX-2) and prostaglandin production leads to the suppression of inflammatory signals such as NF-ĸB. Thus, we suggest the use of NSAIDs in cancer patients with metabolic disorders to prevent the transformation of TME components. Moreover, throughout this review, we attempt to expand our knowledge of CAA transformation to improve the clinical feasibility of targeting CAAs.

Tertiary Lymphoid Structures (TLSs) and Stromal Blood Vessels Have Significant and Heterogeneous Impact on Recurrence, Lymphovascular and Perineural Invasion amongst Breast Cancer Molecular Subtypes

“…The TLS crosstalk to stromal vasculature seems to be modulated by endothelial cell specific gene signatures, most probably due to Notch signaling pathway involvement [ 31 ]. Current data support the theory that endothelial cell gene expression signature associated with TLSs seems to be organ specific [ 16 ] as has been stated for RCC [ 44 ] and breast cancer [ 51 ].…”

“…Together with intratumor TLSs we described two different types of stromal TLSs characterized by their proximity to peritumor adipose tissue and tumor cells. We found this observation interesting considering that adipose tissue has both well certified proinflammatory and angiogenic properties in several tumor types but not in breast cancer [ 44 , 45 , 46 ]. Associations between TLS formation and adipocyte have been described for Crohn’s disease but not for cancer [ 47 ].…”

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

“…Adiponectin and resistin belong to the adipokine family and are secreted by mature adipocytes. FABP4 and LIPE (hormone-sensitive lipase) are markers of adipocyte differentiation [ 19 ], just like PPARγ (peroxisome proliferator-activated receptor γ), a key regulator of adipogenesis and adipocyte differentiation, whereas perilipin protects lipid droplets from lipolysis [ 20 ]. Real-time PCR analysis showed that expression levels of LIPE , resistin , perilipin , FABP4 , adiponectin, and PPARγ were significantly reduced in adipocytes co-cultured with all CRC cells used in comparison to the control consisting of mono-cultured adipocytes (Fig.…”

Beclin1-Deficient Adipocytes Promote Tumor Progression by YAP/TAZ-dependent Adipocyte Transformation

“…It is broadly accepted that CAAs undergo dedifferentiation, a complex process characterized by the morphological changes, downregulation of mature adipocyte markers, loss of lipid contents, and acquisition of mesenchymal stem cell phenotype (Na et al, 2023;Song & Kuang, 2019). Wnt and Notch signaling have previously been identified as mediators of adipocyte dedifferentiation for CAA generation (Bi et al, 2016;Zoico et al, 2016).…”