Role of Rip2 in development of tumor-infiltrating MDSCs and bladder cancer metastasis

• Published in: PloS one Vol. 9; no. 4; p. e94793
• Main Authors: Zhang, Hanwei, Chin, Arnold I
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2014; Public Library of Science (PLoS)
• Subjects: Animal models; Animals; Autocrine signalling; Biology and Life Sciences; Bladder; Bladder cancer; Cancer; CD11b antigen; Cell Line, Tumor; Colony-stimulating factor; Cytokines; Development and progression; Epithelial-Mesenchymal Transition; Female; Flow cytometry; Gene expression; Granulocyte colony-stimulating factor; Hazards; Immunity; Infiltration; Inflammation; Innate immunity; Kinases; Laboratory animals; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - pathology; Medical research; Medicine and Health Sciences; Mesenchyme; Metastases; Metastasis; Mice, Inbred C57BL; Microscopy; Myeloid Cells - metabolism; Myeloid Cells - pathology; Neoplasm Metastasis; Neutrophils; Paracrine signalling; Pathogens; Physiological aspects; Protein kinases; Protein-tyrosine kinase; Proteins; R&D; Receptor mechanisms; Receptor-Interacting Protein Serine-Threonine Kinases - deficiency; Receptor-Interacting Protein Serine-Threonine Kinases - metabolism; Receptors; Research & development; Rodents; Stem cells; Suppressor cells; T cells; Threonine; Tumor Burden; Tumor-infiltrating lymphocytes; Tumors; Tyrosine; Urinary bladder; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - pathology; Urology; United States; Los Angeles California; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094793

Tumor invasion and metastases represent a complex series of molecular events that portends a poor prognosis. The contribution of inflammatory pathways mediating this process is not well understood. Nod-like receptors (NLRs) of innate immunity function as intracellular sensors of pathogen motifs and danger molecules. We propose a role of NLRs in tumor surveillance and in programming tumor-infiltrating lymphocytes (TILs). In this study, we examined the downstream serine/threonine and tyrosine kinase Rip2 in a murine model of bladder cancer. In Rip2-deficient C57Bl6 mice, larger orthotopic MB49 tumors developed with more numerous and higher incidence of metastases compared to wild-type controls. As such, increased tumor infiltration of CD11b+ Gr1hi myeloid-derived suppressor cells (MDSCs) with concomitant decrease in T cells and NK cells were observed in Rip2-deficient tumor bearing animals using orthotopic and subcutaneous tumor models. Rip2-deficient tumors showed enhanced epithelial-to-mesenchymal transition, with elevated expression of zeb1, zeb2, twist, and snail in the tumor microenvironment. We found that the absence of Rip2 plays an intrinsic role in fostering the development of granulocytic MDSCs by an autocrine and paracrine effect of granulocytic colony stimulating factor (G-CSF) expression. Our findings suggest that NLR pathways may be a novel modality to program TILs and influence tumor metastases.