期刊
ONCOGENE
卷 29, 期 50, 页码 6533-6542出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/onc.2010.385
关键词
Tiam1; Rac; tumor-associated fibroblasts; invasion; metastasis
资金
- NIH [CA 095559, CA12555]
- Vermont Community Foundation
- Breast Cancer Research Foundation
- Diane Connolly-Zaniboni Research Scholarship in Breast Cancer
- Tufts Medical Center GRASP Digestive Disease Center [P30-DK34928]
- Design and Data Resource Center of the Tufts Clinical
- Translational Science Institute (National Center for Research Resources) [UL1 RR025752]
The co-evolution of tumors and their microenvironment involves bidirectional communication between tumor cells and tumor-associated stroma. Various cell types are present in tumor-associated stroma, of which fibroblasts are the most abundant. The Rac exchange factor Tiam1 is implicated in multiple signaling pathways in epithelial tumor cells and lack of Tiam1 in tumor cells retards tumor growth in Tiam1 knockout mouse models. Conversely, tumors arising in Tiam1 knockout mice have increased invasiveness. We have investigated the role of Tiam1 in tumor-associated fibroblasts as a modulator of tumor cell invasion and metastasis, using retroviral delivery of short hairpin RNA to suppress Tiam1 levels in three different experimental models. In spheroid co-culture of mammary epithelial cells and fibroblasts, Tiam1 silencing in fibroblasts led to increased epithelial cell outgrowth into matrix. In tissue-engineered human skin, Tiam1 silencing in dermal fibroblasts led to increased invasiveness of epidermal keratinocytes with pre-malignant features. In a model of human breast cancer in mice, co-implantation of mammary fibroblasts inhibited tumor invasion and metastasis, which was reversed by Tiam1 silencing in co-injected fibroblasts. These results suggest that stromal Tiam1 may have a role in modulating the effects of the tumor microenvironment on malignant cell invasion and metastasis. This suggests a set of pathways for further investigation, with implications for future therapeutic targets. Oncogene (2010) 29, 6533-6542; doi:10.1038/onc.2010.385; published online 30 August 2010
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