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.
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This work was supported by grants from the NIH (RB: CA 095559 and CK: CA12555), the Landmann Family Fund of the Vermont Community Foundation (RB), the Breast Cancer Research Foundation (CK), the Diane Connolly-Zaniboni Research Scholarship in Breast Cancer (RB), the Tufts Medical Center GRASP Digestive Disease Center (RB, P30-DK34928) and the Design and Data Resource Center of the Tufts Clinical and Translational Science Institute (National Center for Research Resources: UL1 RR025752).
The work of Dr Buchsbaum, Dr Kuperwasser and Dr Garlick has been funded by the NIH. Dr Garlick has received compensation as a member of the scientific advisory board of Organogenesis Inc. and the Boston Biomedical Research Institute. He has also been the consultant for Organogenesis Inc., L’Oreal and the American Type Culture Collection (ATCC Inc.), and received compensation. Drs Xu, Rajagopal, Dong, Ji, Liu, Naber and Ms Klebba declare no potential conflict of interest.
Supplementary Information accompanies the paper on the Oncogene website
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Xu, K., Rajagopal, S., Klebba, I. et al. The role of fibroblast Tiam1 in tumor cell invasion and metastasis. Oncogene 29, 6533–6542 (2010) doi:10.1038/onc.2010.385
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