Successful chemoprevention of lung cancer requires delineation of those events regulating tumor formation. Mice develop lung tumors with molecular characteristics and histogenesis similar to human pulmonary adenocarcinoma, thus providing a useful model. The only reversible stage in lung tumor progression is promotion, where benign lesions can be induced to revert to silent, non-dividing, mutated cells. We study mechanisms underlying lung tumor promotion by separating induction of the Kras protooncogene mutation that initiates tumorigenesis from application of an agent that promotes tumor development but cannot initiate it, namely, butylated hydroxytoluene (BHT). Reactive metabolites of BHT cause compensatory hyperplasia and inflammation in lungs; we have provided evidence that inflammation plays a major role in promotion. In the next funding period, we will determine how inflammation encourages lung tumor growth.
Three Aims are proposed.
In Aim I, we will identify genes regulating susceptibility to both the promotion and inflammation induced by BHT using refined linkage analysis with two sets of recombinant inbred (RI) mouse strains that are sensitive and resistant to these actions of BHT, the CXB and AXB, BXA RI strains. Adoptive transfer of bone marrow between sensitive and resistant strains will determine whether these susceptibility genes act through macrophages.
In Aim II, possible effects of BHT on allele-specific expression of Kras will be determined; we will learn if BHT enhances tumor growth in mice with an inherited Kras mutation. Also we will modulate the proliferative and inflammatory status in lungs using partial pneumonectomy as a proliferative stimulus along with application of pro-inflammatory drugs or by the use of transgenic mice that over-express pro-inflammatory mediators.
In Aim llI, we examine the cell signaling distal to Kras that involves ERK phosphorylation and prostaglandin production in bronchiolar Clara and alveolar type 2 cells isolated from promotion sensitive and resistant mice. We will also examine Cx43 and CD44 as downstream markers of prostaglandin actions on cells. These studies should lead to insights for developing novel diagnostic, preventive, and therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA033497-24
Application #
7354126
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Poland, Alan P
Project Start
1982-09-01
Project End
2011-02-28
Budget Start
2008-03-01
Budget End
2011-02-28
Support Year
24
Fiscal Year
2008
Total Cost
$326,580
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Ramasamy, Kumaraguruparan; Dwyer-Nield, Lori D; Serkova, Natalie J et al. (2011) Silibinin prevents lung tumorigenesis in wild-type but not in iNOS-/- mice: potential of real-time micro-CT in lung cancer chemoprevention studies. Clin Cancer Res 17:753-61
Fritz, Jason M; Dwyer-Nield, Lori D; Malkinson, Alvin M (2011) Stimulation of neoplastic mouse lung cell proliferation by alveolar macrophage-derived, insulin-like growth factor-1 can be blocked by inhibiting MEK and PI3K activation. Mol Cancer 10:76
Reynolds, Susan D; Malkinson, Alvin M (2010) Clara cell: progenitor for the bronchiolar epithelium. Int J Biochem Cell Biol 42:1-4
Rice, Pamela L; Barrett, Bradley S; Fritz, Jason M et al. (2010) Regulation of cytokine-induced prostanoid and nitric oxide synthesis by extracellular signal–regulated kinase 1/2 in lung epithelial cells. Exp Lung Res 36:558-71
Dwyer-Nield, Lori D; McQuillan, Jay; Hill-Baskin, Annie et al. (2010) Epistatic interactions govern chemically-induced lung tumor susceptibility and Kras mutation site in murine C57BL/6J-ChrA/J chromosome substitution strains. Int J Cancer 126:125-32
Redente, Elizabeth F; Higgins, David M; Dwyer-Nield, Lori D et al. (2010) Differential polarization of alveolar macrophages and bone marrow-derived monocytes following chemically and pathogen-induced chronic lung inflammation. J Leukoc Biol 88:159-68
Fritz, Jason M; Dwyer-Nield, Lori D; Russell, Bridgette M et al. (2010) The Kras mutational spectra of chemically induced lung tumors in different inbred mice mimics the spectra of KRAS mutations in adenocarcinomas in smokers versus nonsmokers. J Thorac Oncol 5:254-7
Redente, Elizabeth F; Dwyer-Nield, Lori D; Barrett, Bradley S et al. (2009) Lung tumor growth is stimulated in IFN-gamma-/- mice and inhibited in IL-4Ralpha-/- mice. Anticancer Res 29:5095-101
Tyagi, Alpna; Singh, Rana P; Ramasamy, Kumaraguruparan et al. (2009) Growth inhibition and regression of lung tumors by silibinin: modulation of angiogenesis by macrophage-associated cytokines and nuclear factor-kappaB and signal transducers and activators of transcription 3. Cancer Prev Res (Phila) 2:74-83
Lin, Sui; Ikegami, Machiko; Xu, Yan et al. (2008) Misexpression of MIA disrupts lung morphogenesis and causes neonatal death. Dev Biol 316:441-55

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