Inflammation and Lung Tumorigenesis:
Increasing evidence supports a direct link between inflammation and cancer, and lung cancer in particular. Epidemiologic data in humans has shown an increased cancer risk in patients with various inflammatory diseases of the lung, including chronic obstructive pulmonary disease and asthma. In mouse models, inflammation was found to enhance the development of lung tumors and many of the Quantitative Trail Loci (QTLs) that control genetic susceptibility to lung inflammation, also co-localize with QTLs that regulate lung tumor susceptibility in mice. These associations between inflammation and lung cancer suggest that pulmonary inflammation appears to be a key tumor promotion step during the lung tumorigenesis process. Our work is aimed to identify the particular susceptibility genes involved in the tumor promotion process and describe their mechanism of action. This involves using a mouse model of butylated hydroxytoluene promoted methylcholanthrene-induced lung carcinogenesis. We have also begun studies testing the role of various inflammatory cells in the tumor promotion process. Delineation of the role of these cells will be seminal to future genetic and positional cloning efforts.
These studies will identify candidate pulmonary inflammation susceptibility genes that may also contribute to genetic susceptibility to lung cancer in humans and in the future permit identification of therapeutic and preventive drug targets.
MCA + BHT
Figure 1. Butylated hydroxytoluene (BHT) enhances methylcholanthrene (MCA)-induced tumorigenesis at 20 weeks in Balb/cByJ mice. Lung sections stained with hematoxylin promote the growth of lung tumor nodules in MCA + BHT treated mice.
Most cancer deaths are a result of metastasis. To extend our understanding of the factors that influence the process, we have developed a mouse model of pulmonary metastasis that can be assayed in multiple inbred mouse strains, which permits genetic mapping studies of the underlying susceptibility loci. We utilize intravenous injection of Sarcoma 180 (S180) cells, which can be tracked and quantified by bioluminescence imaging. We observe growth of S180 cells solely in the lung and observe a wide range of pulmonary metastasis among inbred mouse strains. Interestingly we have noted that the BTBRT+tf/J strain exhibits complete clearance and one possible mechanism of resistance to pulmonary metastasis in BTBRT+tf/J mice may require T-cell function. These observations present a new mouse model for further characterization of the genetics and mechanisms of pulmonary metastasis.
Figure 2. Pulmonary metastasis susceptibility in A/J versus BTBRT mice. A/J and BTBRT mice were tail vein injected with 7 x 105 S180-Fluc cells and bioluminescence was followed in the area over the lungs on days 1 and 7.
Vikis HG, Jackson EN, Krupnick AS, Franklin A, Gelman AE, Chen Q, Piwnica-Worms D, You M. Strain- Specific Susceptibility for Pulmonary Metastasis of Sarcoma 180 Cells in Inbred Mice. Cancer Res. 2010 Jun 15;70(12):4859-67.
Lu Y, Liu P, James M, Vikis HG, Liu H, Wen W, Franklin A, You M. Genetic variants cis-regulating Xrn2 expression contribute to the risk of spontaneous lung tumor. Oncogene. 2010 Feb 18;29(7):1041-9.
Liu PY, Vikis H, James M, Lu Y, Wang DL, Liu HB, Wen WD, Wang Y, You M. Identification of Las2, a major modifier gene affecting the Pas1 mouse lung tumor susceptibility locus. Cancer Res. 2009 Aug 1;69(15):6290-8. Epub 2009 Jul 21.
Liu P, Vikis HG, Wang D, Lu Y, Wang Y, et al. Familial aggregation of common sequence variants on 15q24-25.1 in lung cancer. J Natl Cancer Inst. 2008 Sep 17;100(18):1326-30. Epub 2008 Sep 9.
Liu P, Vikis H, Lu Y, Wang D, and You M. Large-scale in Silico Mapping of Complex Quantitative Traits in Inbred Mice. PLoS ONE. 2007 Jul 25;2:e651.
Vikis H, Sato M, James M, Wang D, Wang Y et al. EGFR-T790M Is a Rare Lung Cancer Susceptibility Allele with Enhanced Kinase Activity. Cancer Res. 2007 May 15;67(10):4665-70.
Wang M, Vikis HG, Wang Y et al. Identification of a novel tumor suppressor gene p34 on human chromosome 6q25. 1 Cancer Res. 2007 Jan 1;67(1):93-9.
Liu P, Wang Y, Vikis H, Maciag A, Wang D, Lu Y, Liu Y, You M. Candidate lung tumor susceptibility genes identified through whole-genome association analyses in inbred mice. Nat Genet. 2006 Aug;38(8):888- 95. 2006 Jul 23.