Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Microbiology and Immunology

Tumors are characterized by persistent inflammation that have important roles in progression of tumors and survival of cancer patients. Inflammatory immune cells specifically tumor-associated neutrophils (TAN) are considered essential components in the tumor microenvironment. In invasive breast cancer, TAN represent a significant portion of the tumor mass and are associated with increased angiogenesis and metastasis. Identifying the regulatory factors that control TAN behavior will help in developing new and specific therapeutic targets for cancer treatment. Vacuolar ATPases (V-ATPases), multi-subunit proton pumps, are highly expressed in metastatic breast cancer cells. A cleaved peptide from a2 isoform V-ATPase (a2NTD) has immunomodulatory role in tumor microenvironment. In this study, we report for the first time the role of V-ATPase in neutrophils modulation. In invasive breast cancer cells, a2NTD was detected and a2V was highly expressed on the surface. Immunohistochemical analysis in invasive breast cancer tissues revealed that increased neutrophil recruitment and blood vessel density were correlated with increased a2NTD levels. In order to determine the direct regulatory role of a2NTD on neutrophils, recombinant a2NTD was used for the treatment of neutrophils isolated from the peripheral blood of healthy volunteers. Neutrophils treated with a2NTD (a2Neu{u0278}) showed increased secretion of IL-1RA, IL-10, CCL-2 and IL-6 that are important in cancer related inflammation

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