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

SIMPLE SUMMARY: Cancer cells that grow near adipose tissue inevitably exchange signals with adipocytes. The dynamic crosstalk between these two cell types facilitates the alteration of their cellular properties. The transformation of normal adipocytes into cancer-associated adipocytes (CAAs) provides a pro-tumorigenic niche for rapid tumor progression. However, the cancer-originated signals that mediate adipocyte transformation remain largely unknown. In this review, we discuss various inflammatory signals amplified in both obese and peritumoral adipose tissue. These inflammatory signals could mediate adipocyte transformation to phenotypes similar to CAAs by promoting adipocyte dedifferentiation and lipolysis. Epidemiological studies indicate a higher efficacy of nonsteroidal anti-inflammatory drugs in obese patients with cancer. Therefore, delivering anti-inflammatory agents can be a plausible therapeutic strategy to ameliorate the activation of tumor microenvironment components, especially 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.