The Inflammatory Profile of the Tumor Microenvironment, Orchestrated by Cyclooxygenase-2, Promotes Epithelial-Mesenchymal Transition

Abstract

The tumor microenvironment (TME) corresponds to a complex and dynamic interconnection between the extracellular matrix and malignant cells and their surrounding stroma composed of immune and mesenchymal cells. The TME has constant cellular communication through cytokines that sustain an inflammatory profile, which favors tumor progression, angiogenesis, cell invasion, and metastasis. Although the epithelial-mesenchymal transition (EMT) represents a relevant metastasis-initiating event that promotes an invasive phenotype in malignant epithelial cells, its relationship with the inflammatory profile of the TME is poorly understood. Previous evidence strongly suggests that cyclooxygenase-2 (COX-2) overexpression, a pro-inflammatory enzyme related to chronic unresolved inflammation, is associated with common EMT-signaling pathways. This review article summarizes how COX-2 overexpression, within the context of the TME, orchestrates the EMT process and promotes initial metastatic-related events.

Keywords: cancer; cyclooxygenase-2; epithelial-mesenchymal transition; inflammation; tumor microenvironment.

Graphical Abstract

Figure 1

Increase in the COX-2 expression during tumor progression. COX-2 favors tumor progression from the initial stages of tumor promotion (dysplasia). In advanced stages of tumor progression (carcinoma), COX-2 is overexpressed, and it is associated with partial EMT (pEMT) and EMT events.

Figure 2

The overexpression of the COX-2/PGE2 axis in cells within the tumor microenvironment (TME) promotes EMT in tumor cells through PGE2/EP4 paracrine signaling. The overexpression of the COX-2/PGE2 axis in cells within the TME promotes EMT in tumor cells through PGE2/EP4 paracrine signaling. The COX-2/PGE2 axis overexpression favors the EMT phenomenon in tumor cells as a consequence of the inhibition of E-cadherin expression. The COX-2/PGE2 overexpression promotes signaling related to ROS and hypoxia, which explains the inflammatory profile of the tumor microenvironment (TME) in solid tumors. Carcinoma-associated fibroblasts (CAFs); cancer stem cells (CSCs); myeloid-derived suppressor cells (MDSCs); and tumor-associated macrophages (TAMs).

Figure 3

The COX-2/PGE2 axis overexpression is associated with EMT promotion in tumor cells and the presence of cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME). The COX-2/PGE2 axis overexpression is associated with EMT promotion in cancer cells and the presence of CAFs in the TME. The inflammatory profile of the TME favors the overexpression of the COX-2/PGE2 axis and promotes CAFs activation, which maintain the COX-2/PGE2 axis over-activation. Also, the COX-2/PGE2 axis causing nuclear translocation of β-catenin and the induction of Snail/Slug/Zeb transcription factors expression that repress the E-cadherin and promotes EMT.

Figure 4

Intracellular pathways in tumor cells that associate COX-2/PGE2 axis overexpression with the promotion of EMT. Inflammatory components of the tumor microenvironment (TME), such as TNF-a and TGF-b, promote the up-regulation of the COX-2/PGE2 axis. Besides, the COX-2/PGE2 axis maintains its autocrine regulation through the activation of the PGE2 EP receptor. The COX-2/PGE2 axis overexpression activates the TGF-β non-canonical pathway (Smad-independent) at the expense of inhibiting the canonical-Smad dependent signaling, along with activation of integrins and secretion of MMPs. Further, the COX-2/PGE2 axis overexpression increases the intracellular ROS levels and activates NF-κB oncogenic functions, which promotes pro-inflammatory signaling pathways and inhibits the GSK3βfactor. The inhibition of GSK3β triggers the activation of master-EMT transcription factors (snail, slug, zeb1/2, and twist), which inhibit E-cadherin expression and finally facilitate the initiation and continuity of the EMT phenomenon.  There is a potential EMT modulation associated with RhoA/Rac1, according to the presence of microRNAs that would maintain a dynamic context-dependent role activating EMT transcription factors. #, their participation is established, but their presence does not determine the process; P, phosphorylation.