The role of fibroblast Tiam1 in tumor cell invasion and metastasis

Abstract

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 knock-out mouse models. Conversely, tumors arising in Tiam1 knock-out 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 premalignant 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 play 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.

Balanced Tiam1-Rac1 and RhoA Drives Proliferation and Invasion of Pancreatic Cancer Cells

“…Tiam1 maintains the specificity of rac1 toward specific downstream effector pathways, whereas rac1 regulates cell survival and cell-cycle progression (7,8). Together, Tiam1-rac1 is a critical component in the biology of human tumors, in both transformed cells as and the cells in the tumor microenvironment (9)(10)(11). Tiam1 is a potent modifier of oncogenic Ras-induced skin tumor initiation, promotion, and progression.…”

Overexpression of Tiam1 promotes the progression of laryngeal squamous cell carcinoma

“…Tiam1-Rac signaling is capable of stimulating the p38 mitogen-activated protein kinase pathway, c-Jun N-terminal kinase pathway, and extracellular signal-regulated kinase pathway (19)(20)(21), which are considered to be associated with the regulation of gene transcription. Tiam1 is involved in modulating alteration of the actin cytoskeleton, cell migration (22)(23)(24), tumor microenvironment (25) and cell polarity (26), which are considered relevant to tumor progression. The relationship between Tiam1 overexpression and various types of cancer has been previously identified (7)(8)(9)(10)(11)(12)(13)(14).…”

Clinical implication of Tiam1 overexpression in the prognosis of patients with serous ovarian carcinoma

“…Tiam1 maintains the specificity of Rac1 toward specific downstream effector pathways, whereas Rac1 regulates cell survival and cell cycle progression (8,9). Together, Tiam1-Rac1 is a critical component in the biology of human tumors, affecting the transformed cells themselves and the tumor microenvironment (10)(11)(12). Tiam1 is a potent modifier of oncogenic Ras-induced skin tumor initiation, promotion and progression (13).…”