Increased evidence suggests that chronic inflammation is closely related with cancer development, metastasis and invasion. The possible mechanisms by which inflammation can contribute to carcinogenesis include lymphocytes infiltration, cytokines and chemokines secretion, tissue remodeling and angiogenesis, etc. The inflammatory mediators facilitate the communication between tumor cells and tumor-associated host stromal tissue, thereby accelerating tumor progression. Tumor-associated macrophages (TAM) are key regulators of the link between inflammation and cancer. Previous studies found macrophage in non-small cell lung cancer (NSCLC) specimens by immunohistochemistry staining, and also discovered interplay of cancer cells and macrophages would induce secretion of certain cytokines and chemokines, but the involved mechanism is still obscure. It is also unclear the regulatory mechanisms in change of macrophages from M1 to M2 phase affected by tumor cells. In this study, we attempt to investigate the roles of TAM-mediated molecules using different characteristics of NSCLC cell lines (H2126, CL1-1, H1437, H23, H838, CL1-5, and H2009) as the study model. We will explore TAM mediators in NSCLC cell lines to detect and compare the phenotypic characteristics; then, we may investigate the transcriptional signaling pathways that are associated with expression of TAM mediators. Finally, we will correlate the expression of TAM mediators/proteins that are associated with TAM-mediated regulatory signaling in tumor progression to the outcome of NSCLC patients. We believe that these proteins may serve as therapeutic targets for NSCLC patients in the future. In our pilot study, we analyzed migration activities of these cell lines that co-cultured with macrophages. Interestingly, we found that two of the seven cell lines would reduce their migratory ability, while the other cell lines increased. Similar results were also noted in invasion experiments ( see the preliminary results). Furthermore, we have also assayed the secretion stimulation of cytokines (MCP-1, IL-6, IL-7, IL-8, IL-10, and TNF-a) and MMPs (MMP-8, MMP-9, MMP-10 and TIMP-1) from cancer cells under the effect of macrophages. In the current study, we will deeply concern that the ambivalent interactions between TAM phenotypes and biological behavior of cancer cells, because the paradoxical responses between cancer cells and TAMs in a to and fro way are potentially evident. The specific aims of this study therefore will be: 1) To investigate TAM-mediated molecules involved in tumor progression. (Years 1 and 2) 2) To study the molecular regulatory mechanisms of TAM-mediated molecules in tumor progression. (Years 2 and 3) 3) To study the regulatory mechanisms in changes of macrophage phenotypes (from M1 to M2) by NSCLC cells. (Years 1 to 3) 4) To correlate TAM-mediated molecules in surgical specimens to the outcomes of NSCLC patients, and define their prognostic significance. (Years 2 and 3)
|Effective start/end date||8/1/10 → 7/31/11|
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