The formyl peptide receptor 1 exerts a tumor suppressor function in human gastric cancer by inhibiting angiogenesis

Abstract

N-formyl peptide receptors (FPR1, FPR2 and FPR3) are involved in innate immunity, inflammation and cancer. FPR expression, initially described in immune cells, was later observed in non-hematopoietic cell populations and tissues. Several studies suggested a role for FPRs in the progression of various tumor histotypes, including gastric cancer (GC), for which a positive association with a specific FPR1 polymorphism has recently been described. We previously showed that FPRs are expressed on gastric epithelium and are required for wound repair and restitution of barrier integrity. Here we assess the role of FPRs in GC. We characterized the functions of FPRs in GC epithelial cells (MKN28, AGS and MKN45) cultured in vitro by assessing migration, proliferation, resistance to apoptosis and activation of the epithelial-to-mesenchymal transition. Activation of each FPR induced the epithelial-to-mesenchymal transition, proliferation, resistance to apoptosis and migration of GC cells in culture. Blocking compounds or RNA interference of each FPR reverted these effects. We also defined the in vivo tumorigenic potential of GC epithelial cells silenced for FPRs by xenograft experiments in immunocompromised mice. Interestingly, FPR1 silencing in GC cells (shFPR1) significantly enhanced xenograft growth with respect to shCTR, shFPR2 and shFPR3 xenografts, because of augmented vessel density and cell proliferation. Accordingly, HIF-1α and VEGF mRNA levels were higher in shFPR1 xenografts than in controls. Moreover, the in vitro production of proangiogenic factors in response to FPR2/3 agonists (WKYMVm, LL-37, uPA, uPAR84-95, AnxA1) or to other proinflammatory mediators (IL-1α) was higher in shFPR1 GC cells than in shCTR, shFPR2 and shFPR3 cells, suggesting that FPR1 functions as an inhibitor of CG angiogenesis. Thus, we propose that FPR1 stimulation may represent a novel therapeutic approach to counteract tumor angiogenesis.

Impact of chemotactic factors and receptors on the cancer immune infiltrate: a bioinformatics study revealing homogeneity and heterogeneity among patient cohorts

“…61–69 The role of FPR1 in tumor progression remains controversial as it has been associated with tumor invasion in colorectal cancer but with tumor suppression in gastric cancer. 70,71 As far as P2RY6 is concerned, Placet et al recently suggested its role in cancer cell survival. 72 Overall, these 13 chemotactic receptors and chemokines may constitute universal targets for cancer therapy.…”

Regulation of inflammation by members of the formyl-peptide receptor family

“…However, it is interesting that FPR1 silencing in GC cells significantly enhanced their tumorigenicity in mice because of augmented vessel density and tumor cell proliferation with high levels of HIF-1α and VEGF mRNA in xenografts tumor. Thus, FPR1 functions as GC suppressor by inhibiting tumor-induced angiogenesis (30). These observations, in contrast to those with FPR2 in GC, call for more careful evaluation of individual receptors in tumor growth, particularly in the context of microenvironment whether complex composition of tumor and stroma may determine the outcome of FPR signaling.…”

“…For instance, FPRs expressed by human gastric cancer cells, mediate epithelial-mesenchymal transition, cell proliferation, migration, and resistance to apoptosis (30). The prototype FPR, FPR1, selectively expressed by highly malignant glioblastoma multiforme (GBM) cells, responds to an endogenous chemotactic ligand anexin 1 (ANXA1) released by necrotic GBM cells (31).…”

The resolution of inflammation: New mechanisms in patho-physiology open opportunities for pharmacology

“…Thus, endocrine and metabolic diseases like diabetes and obesity fall within the ever-increasing group of inflammatory pathologies. All this without even considering cancer, where the nature of the inflammatory response is subverted and exploited by the proliferating tumoral cells [4][5][6].…”