Phospholipase A(2) Drives Tumorigenesis and Cancer Aggressiveness through Its Interaction with Annexin A1

Phospholipids are suggested to drive tumorigenesis through their essential role in inflammation. Phospholipase A(2) (PLA(2)) is a phospholipid metabolizing enzyme that releases free fatty acids, mostly arachidonic acid, and lysophospholipids, which contribute to the development of the tumor microenvironment (TME), promoting immune evasion, angiogenesis, tumor growth, and invasiveness. The mechanisms mediated by PLA(2) are not fully understood, especially because an important inhibitory molecule, Annexin A1, is present in the TME but does not exert its action. Here, we will discuss how Annexin A1 in cancer does not inhibit PLA(2) leading to both pro-inflammatory and pro-tumoral signaling pathways. Moreover, Annexin A1 promotes the release of cancer-derived exosomes, which also lead to the enrichment of PLA(2) and COX-1 and COX-2 enzymes, contributing to TME formation. In this review, we aim to describe the role of PLA(2) in the establishment of TME, focusing on cancer-derived exosomes, and modulatory activities of Annexin A1. Unraveling how these proteins interact in the cancer context can reveal new strategies for the treatment of different tumors. We will also describe the possible strategies to inhibit PLA(2) and the approaches that could be used in order to resume the anti-PLA(2) function of Annexin A1.