It is well established that chronic inflammation contributes to cancer development. Many studies have demonstrated that inflammatory leukocytes promote epithelial cancer by providing soluble growth and survival factors to initiated cells and contribute to tissue remodeling and angiogenesis via synthesis of extracellular proteases; thus, physiological processes necessary for tumor development (enhanced cell survival, tissue remodeling and angiogenesis) are regulated, in part, by leukocytes and the soluble mediators they deliver. However, molecular mechanisms mediating the dialogue between infiltrating immune cells with initiated epithelia are poorly characterized. Moreover, the degree to which these interactions alter stem cell niches in neoplastic environments have not been explored. We hypothesize that infiltrating immune cells regulate niche autonomy of putative lung cancer stem cells through activation of Wnt and Sonic hedgehog (Shh) signaling cascades in initiated lung epithelia; thus, the goals of this project are to define the lineages of functionally significant immune cells that potentiate cancer development in lung, determine which of these regulate Wnt and Shh signaling in lung epithelia, and determine if in so doing, they confer stem cell niche autonomy to initiated epithelial cells and therefore enhance tumorigenic potential. To assess our hypothesis, we propose to, 1) define the profile of immune cells associated with human and mouse lung carcinogenesis and determine how these correlate with presence of CD133+ cells and activation of Wnt and Shh signaling cascades, 2) define functional significance of recruited immune cells as regulators of Wnt and Shh signaling during lung carcinogenesis, and 3) Define the functional significance of immune cells as regulators of Wnt and Shh signaling and their combined effects on putative lung cancer stem cells. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA132566-01
Application #
7410327
Study Section
Special Emphasis Panel (ZCA1-SRRB-U (O1))
Program Officer
Howcroft, Thomas K
Project Start
2008-05-01
Project End
2013-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
1
Fiscal Year
2008
Total Cost
$293,391
Indirect Cost
Name
University of California San Francisco
Department
Surgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Bosco-Clément, G; Zhang, F; Chen, Z et al. (2014) Targeting Gli transcription activation by small molecule suppresses tumor growth. Oncogene 33:2087-97
Ganesan, Anusha-Preethi; Johansson, Magnus; Ruffell, Brian et al. (2013) Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma. J Immunol 191:2009-17
Zhang, Yi; He, Jianxing; Zhang, Fang et al. (2013) SMO expression level correlates with overall survival in patients with malignant pleural mesothelioma. J Exp Clin Cancer Res 32:7
Li, Hui; Lui, Natalie; Cheng, Tiffany et al. (2013) Gli as a novel therapeutic target in malignant pleural mesothelioma. PLoS One 8:e57346
Kratz, Johannes R; He, Jianxing; Van Den Eeden, Stephen K et al. (2012) A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies. Lancet 379:823-32
Ruffell, Brian; Affara, Nesrine I; Coussens, Lisa M (2012) Differential macrophage programming in the tumor microenvironment. Trends Immunol 33:119-26
Ruffell, Brian; Au, Alfred; Rugo, Hope S et al. (2012) Leukocyte composition of human breast cancer. Proc Natl Acad Sci U S A 109:2796-801
DeNardo, David G; Brennan, Donal J; Rexhepaj, Elton et al. (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1:54-67
Daldrup-Link, Heike E; Golovko, Daniel; Ruffell, Brian et al. (2011) MRI of tumor-associated macrophages with clinically applicable iron oxide nanoparticles. Clin Cancer Res 17:5695-704
Okamoto, Junichi; Kratz, Johannes R; Hirata, Tomomi et al. (2011) Downregulation of EMX2 is associated with clinical outcomes in lung adenocarcinoma patients. Clin Lung Cancer 12:237-44

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