Abstract

Transforming growth factor beta (TGF() promotes epithelial differentiation and inhibits cell growth. Defects in TGF( signaling are common in cancer and frequently associated with reduced apoptosis and more aggressive tumor behavior. Though many TGF( signaling components function as tumor suppressors in breast, colon, and skin cancers, TGF( signaling in lung cancer is largely unexplored. My hypotheses are that defective TGF( signaling promotes tumor growth in LSCC and that specific TGF( signaling defects are associated with distinct clinical tumor behavior and distinct tracheal epithelial cell behavior. I have observed frequent loss of TGF( signaling molecules in human LSCC samples.
In Aim 1 I will define the spectrum and consequences of TGF( signaling defects in human LSCC.
In Aim 2 I will use cultured tracheal epithelial cells to determine the effect of specific TGF( signaling defects on apoptosis, cell cycle arrest, migration, and endogenous TGF( production.
In Aim 3 I will create a novel mouse model of LSCC to examine TGF( signaling in vivo. In summary, these studies examine how TGF( signaling defects modulate behavior of airway epithelial cells in vivo and in vitro and how these changes promote the growth of LSCC. ? ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA131483-01A1
Application #
7529232
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2008-09-23
Project End
2013-08-31
Budget Start
2008-09-23
Budget End
2009-08-31
Support Year
1
Fiscal Year
2008
Total Cost
$136,900
Indirect Cost

  Institution

Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045

  Publications

Haeger, Sarah M; Thompson, Joshua J; Kalra, Sean et al. (2016) Smad4 loss promotes lung cancer formation but increases sensitivity to DNA topoisomerase inhibitors. Oncogene 35:577-586
Du, L; Chen, X; Cao, Y et al. (2016) Overexpression of PIK3CA in murine head and neck epithelium drives tumor invasion and metastasis through PDK1 and enhanced TGF? signaling. Oncogene 35:4641-52
van Waardenburg, Robert C A M (2016) Tyrosyl-DNA Phosphodiesterase I a critical survival factor for neuronal development and homeostasis. J Neurol Neuromedicine 1:25-29
Malkoski, Stephen P; Cleaver, Timothy G; Thompson, Joshua J et al. (2014) Role of PTEN in basal cell derived lung carcinogenesis. Mol Carcinog 53:841-6
Malkoski, Stephen P; Haeger, Sarah M; Cleaver, Timothy G et al. (2012) Loss of transforming growth factor beta type II receptor increases aggressive tumor behavior and reduces survival in lung adenocarcinoma and squamous cell carcinoma. Clin Cancer Res 18:2173-83
Hudish, Tyler M; Opincariu, Laura I; Mozer, Anthony B et al. (2012) N-nitroso-tris-chloroethylurea induces premalignant squamous dysplasia in mice. Cancer Prev Res (Phila) 5:283-9
Deng, Yu; Deng, Hui; Liu, Jing et al. (2012) Transcriptional down-regulation of Brca1 and E-cadherin by CtBP1 in breast cancer. Mol Carcinog 51:500-7
Malkoski, Stephen P; Wang, Xiao-Jing (2012) Two sides of the story? Smad4 loss in pancreatic cancer versus head-and-neck cancer. FEBS Lett 586:1984-92
Mitra, Doyel; Malkoski, Stephen P; Wang, Xiao-Jing (2011) Cancer stem cells in head and neck cancer. Cancers (Basel) 3:415-27
Hegab, Ahmed E; Ha, Vi Luan; Gilbert, Jennifer L et al. (2011) Novel stem/progenitor cell population from murine tracheal submucosal gland ducts with multipotent regenerative potential. Stem Cells 29:1283-93

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