Li Yang - US grants

We have found that Gr-1+CD11b+ cells are significantly increased in lungs of mice bearing mammary adenocarcinomas prior to tumor cell arrival. In the premetastatic lungs, these immature myeloid cells significantly decrease IFN-gamma production and increase pro-inflammatory cytokines. In addition, they produce large quantities of MMP9 and promote vascular remodeling. Deletion of MMP9 normalizes aberrant vasculature in the premetastatic lung, and diminishes lung metastasis. The production and activity of MMP9 is selectively restricted to lungs and organs with a large number of Gr-1+CD11b+ cells. Our work reveals a novel pro-tumor mechanism for Gr-1+CD11b+ cells that changes the premetastatic lung into an inflammatory and proliferative environment, diminishes immune protection and promotes metastasis through aberrant vasculature formation. Thus inhibition of Gr-1+CD11b+ cells could normalize the premetastatic lung environment, improve host immunosurveillance, and inhibit tumor metastasis. We are currently investigating the effect of myeloid specific TGFbeta singling in the metastatic process.

We have made steady progress in the past year. We have produced and bred mouse colonies in which TGFbeta R2 receptor is specifically deleted in host immature myeloid cells. We have observed significantly decreased tumor progression in myeloid TGFbeta R2 ko mice. We are currently investigating mechanisms which involves systemic immune response as well as direct interaction of myeloid cells with tumor cells in the microenvironment and distant metastatic organ. We hope to develop new translational opportunities with the research information obtained. We are utilizing technical core resources and collaborating with several labs for this project.

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.