Deletion of tumor suppressor genes in stromal fibroblasts induces epithelial cancer development, suggesting an important role of stroma in epithelia homeostasis. The precise molecular mediators remain to be identified. In a mouse model in which the Tgfbr2 gene in stromal fibroblasts was inactivated, we found that stromal deletion of Tgfbr2 resulted in genetic and epigenetic changes in the adjacent epithelia including a loss of the cyclin dependent kinase (CDK) inhibitors p15 and p16. In addition, there was increased methylation at the p53-binding site of the p21 promoter region in the tumor cells. The mechanisms mediating the crosstalk between the epithelia and the stroma involved COX-2-mediated inflammation. Our studies demonstrate that attenuation of stromal TGFb signaling induces inflammation that, in turn, causes DNA damage as well as epigenetic and genetic alterations in epithelia. Therefore, therapeutic targeting of inflammation and the tumor microenvironment may be useful in treating cancers with downregulation of TGFb signaling in the stroma. Wa are currently investigating how these findings affect cancer metastatic process.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011165-06
Application #
8937988
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Yang, L; Karin, M (2014) Roles of tumor suppressors in regulating tumor-associated inflammation. Cell Death Differ 21:1677-86
Seton-Rogers, Sarah (2013) Microenvironment: Making connections. Nat Rev Cancer 13:222-3
Achyut, B R; Bader, David A; Robles, Ana I et al. (2013) Inflammation-mediated genetic and epigenetic alterations drive cancer development in the neighboring epithelium upon stromal abrogation of TGF-? signaling. PLoS Genet 9:e1003251
Yan, Hannah H; Pickup, Michael; Pang, Yanli et al. (2010) Gr-1+CD11b+ myeloid cells tip the balance of immune protection to tumor promotion in the premetastatic lung. Cancer Res 70:6139-49