Within lung adenocarcinoma, histology is heterogeneous and associated with tissue invasion and clinical outcomes. The spectrum of intra-tumoral histological heterogeneity in adenocarcinoma suggests nvasiveness represents a continuum of disease from noninvasive bronchioloalveolar carcinoma (BAG) to adenocarcinoma mixed subtype with BAG component to pure invasive adenocarcinoma. The molecular events essential to this transition in the lung are presently unknown. In this study, we focus on invasion, a significant biological and morphological characteristic of cancer with direct clinical implications in terms of metastasis and outcome. In preliminary gene expression profiling experiments, we identified the type II TGF- /? receptor (TGF/SRII), which was expressed at significantly lower levels in invasive tumors, as one of the most interesting genes in the acquisition of lung invasiveness classifiers. We hypothesize that repression of TGFBRII in lung adenocarcinoma is required to mediate tumor/stromal interactions that precede the acquisition of invasiveness in lung adenocarcinoma. In this grant proposal, we will address the main hypothesis in the following Specific aims: 1. Determine the direct role of Tgfbr2 repression on adenocarcinoma invasiveness in vivo using genetic model of murine lung adenocarcinoma. We will create a novel animal model of invasive lung adenocarcinoma in mice with pulmonary targeted deletion of Tgfbr2 and mutation of K-Ras.
In Aim 2, we will determine the requirement for CCL5 (Rantes) in mediating tumor- stromal interactions that are important for invasion of TGFBRII knock-down cells. CCL5 was identified as a potential downstream mediator of TGFB signaling in invasive tumors.
In Aim 3, we will create a large adenocarcinoma tumor microarray to examine the clinical significance of TGFBRII immunostaining human lung adenocarcinoma. In these studies, we will demonstrate the importance of TGFBR2 pathways in modulating tumor epithelial/stromal interactions important for the acquisition of invasiveness in lung adenocarcinoma and we expect to identify the mechanisms of this activity. The results of these studies will facilitate the attainment of the long-term goals, which are to develop clinically available assays to predict invasive propensity in adenocarcinoma tissue specimens and to develop and test pharmacologic agents that will reduce invasiveness in patients with lung cancer or prevent the development of invasive tumors in individuals at high risk for lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA120174-04
Application #
7738519
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Mohla, Suresh
Project Start
2007-01-01
Project End
2011-12-31
Budget Start
2010-01-05
Budget End
2010-12-31
Support Year
4
Fiscal Year
2010
Total Cost
$349,359
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Bulman, William; Saqi, Anjali; Powell, Charles A (2012) Acquisition and processing of endobronchial ultrasound-guided transbronchial needle aspiration specimens in the era of targeted lung cancer chemotherapy. Am J Respir Crit Care Med 185:606-11
Borczuk, Alain C; Sole, Marieta; Lu, Ping et al. (2011) Progression of human bronchioloalveolar carcinoma to invasive adenocarcinoma is modeled in a transgenic mouse model of K-ras-induced lung cancer by loss of the TGF-ýý type II receptor. Cancer Res 71:6665-75
Yatabe, Yasushi; Borczuk, Alain C; Powell, Charles A (2011) Do all lung adenocarcinomas follow a stepwise progression? Lung Cancer 74:7-11
Halmos, Balazs; Powell, Charles A (2011) Update in lung cancer and oncological disorders 2010. Am J Respir Crit Care Med 184:297-302
Travis, William D; Rekhtman, Natasha; Riley, Gregory J et al. (2010) Pathologic diagnosis of advanced lung cancer based on small biopsies and cytology: a paradigm shift. J Thorac Oncol 5:411-4
Toonkel, Rebecca L; Borczuk, Alain C; Powell, Charles A (2010) Tgf-beta signaling pathway in lung adenocarcinoma invasion. J Thorac Oncol 5:153-7
Cheng, Haiying; Xu, Xunhai; Costa, Daniel B et al. (2010) Molecular testing in lung cancer: the time is now. Curr Oncol Rep 12:335-48
Dubey, Sarita; Powell, Charles A (2009) Update in lung cancer 2008. Am J Respir Crit Care Med 179:860-8
Powell, Charles A (2009) Rounding up apoptosis resistance targets in lung cancer. Am J Respir Cell Mol Biol 41:7-8
Borczuk, Alain C; Qian, Fang; Kazeros, Angeliki et al. (2009) Invasive size is an independent predictor of survival in pulmonary adenocarcinoma. Am J Surg Pathol 33:462-9

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