Pathobiology of the neutrophil-intestinal epithelial cell interaction: role in carcinogenesis

The role of chronic inflammation, acting as an independent factor, on the onset of gastrointestinal carcinogenesis is now well accepted. However, even if there is an increase in the number of elements directly involving polymorphonuclear leukocytes (PMNL), as a major actor in digestive carcinogenesis, the different cellular and molecular events occurring in this process are still not completely understood. The transepithelial migration of PMNL, which is the ultimate step of the afflux of PMNL into the digestive mucosa, is a complex phenomenon involving sequential interaction of molecules expressed both on PMNL and on digestive epithelial cells. Chronic inflammatory areas rich in PMNL [so-called (chronic active inflammation)] and iterative transepithelial migration of PMNL certainly evoke intracellular signals, which lead toward progressive transformation of epithelia. Among these different signals, the mutagenic effect of reactive oxygen species and nitrates, the activation of the nuclear factor-κB pathway, and the modulation of expression of certain microRNA are key actors. Following the initiation of carcinogenesis, PMNL are involved in the progression and invasion of digestive carcinomas, with which they interact. It is noteworthy that different subpopulations of PMNL, which can have some opposite effects on tumor growth, in association with different levels of transforming growth factor-β and with the number of CD8 positive T lymphocytes, could be present during the development of digestive carcinoma. Other factors that involve PMNL, such as massive elastase release, and the production of angiogenic factors, can participate in the progression of neoplastic cells through tissues. PMNL may play a major role in the onset of metastases, since they allow the tumor cells to cross the endothelial barrier and to migrate into the blood stream. Finally, PMNL play a role, alone or in association with other cell parameters, in the initiation, promotion, progression and dissemination of digestive carcinomas. This review focuses on the main currently accepted cellular and molecular mechanisms that involve PMNL as key actors in digestive carcinogenesis.