Abstract
Based on the notion that inflammation favors tumorigenesis, our experiments comparatively assessed the influence of acute and chronic inflammation on the development of a murine mammary tumor (4T1). In addition, we characterized angiogenic and inflammatory markers in the tumor tissue and systemically. Subcutaneous implantation of polyether-polyurethane sponge discs in Balb/c mice was used to host 4T1 tumor cells (1x106), which were inoculated intraimplant 24h or 10 days post implantation. Flow cytometric analysis of enzyme-digested implants revealed that, after 24 hours, the population of leukocytes was primarily characterized by neutrophils (42.53% +/- 8.45) and monocytes (37.53% +/- 7.48), with some lymphocytes (16.27% +/- 4.0) and a few dendritic cells (1.82% +/- 0.36). At 10 days, macrophages were predominant (37.10% +/- 4.54), followed by lymphocytes (28.1% +/- 4.77), and monocytes (22.33% +/- 3.05), with some dendritic cells (13.60% +/- 0.55) and neutrophils (11.07% +/- 2.27). A mammary tumor grown in a chronic inflammatory environment was 2-fold when compared with one grown in acute inflammation and 5-fold when compared with tumor alone. The levels of pro-angiogenic cytokine (VEGF-Vascular Endothelial Growth Factor) were higher in implant-bearing tumor when 4T1 cells were grown in 10-day old implants as compared to the VEGF levels of the two other groups. Overall, the levels of the inflammatory markers evaluated (NAG -N-acetylglucosaminidase, TNF-α –Tumor Necrosis Factor- α) were higher in both groups of implant-bearing tumors and in serum from those animals when compared with the tumor alone levels. This inflammation-related difference in tumor growth may provide new insights into the contribution of different inflammatory cell populations to cancer progression.
Highlights
Compelling evidence has indicated that inflammation in neoplastic progression plays a decisive role
To determine whether the pro angiogenic (VEGF) and pro inflammatory (TNFα) cytokines were involved in both phases of the inflammatory process induced by the synthetic matrix; their levels were measured in the supernatant
Tumor microenvironment is characterized by the presence of inflammatory cells and by a number of independent studies showing that many malignancies arise from areas of infection and inflammation [1, 2, 4, 27]
Summary
Compelling evidence has indicated that inflammation in neoplastic progression plays a decisive role. Contribution of Acute and Chronic Inflammation in Murine 4T1 Tumors processes due to parasites, viruses, bacterial infections, and carcinogenesis that occur in a number of organs and tissues [1,2,3,4,5] Further support for this notion comes from the fact that the inflammatory tumor microenvironment is characterized by the presence of inflammatory cells (macrophages, neutrophils, lymphocytes, eosinophils, and mast cells). TNF-α, a major mediator of inflammation, is a tumor promoter factor contributing to stromal development, inflammation, and tumor spread, when chronically produced [7, 8] Another cytokine, chemokine, CCL2, is responsible for recruiting inflammatory monocytes to the tumor site. The expression of this chemokine and macrophage infiltration is correlated with poor prognosis and metastasis in human breast cancer [9, 10]
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