Complex Molecular Pathway Leads to Increased Tumor Metastasis

They described their findings in the November 11, 2011, issue of the Journal of Biological Chemistry.

Perhaps the key discovery was how metastasis was linked to the action of fascin, an actin-bundling protein overexpressed in all carcinomas. Fascin proteins organize F-actin into parallel bundles, and are required for the formation of actin-based cellular protrusions. The encoded protein plays a critical role in cell migration, motility, adhesion, and cellular interactions. Expression of this gene is known to be regulated by several microRNAs, and overexpression of this gene may play a role in the metastasis of multiple types of cancer by increasing cell motility.

Fascin activity was found to depend on the cytokine transforming growth factor-beta (TGF-beta). The pathway named for this protein controls proliferation, cellular differentiation, and other functions in most cells. It plays a role in immunity, cancer, heart disease, and diabetes. TGF-beta acts as an antiproliferative factor in normal epithelial cells and at early stages of cancer development. In normal cells, TGF-beta, acting through its signaling pathway, stops the cell cycle at the G1 stage to stop proliferation, induce differentiation, or promote apoptosis. When a cell is transformed into a cancer cell, parts of the TGF-beta signaling pathway are mutated, and TGF-beta no longer controls the cell. These cancer cells and surrounding stromal cells (fibroblasts) begin to proliferate. Both types of cell increase their production of TGF-beta. This TGF-beta acts on the surrounding stromal cells, immune cells, endothelial, and smooth-muscle cells. It causes immunosuppression and angiogenesis, which makes the cancer more invasive. TGF-beta also converts effector T-cells, which normally attack cancer with an inflammatory reaction, into regulatory (suppressor) T-cells, which turn off the inflammatory reaction.

TGF-beta control of fascin activity was found to be mediated by a family of proteins known as SMADS. SMADs are intracellular proteins that transduce extracellular signals from TGF-beta ligands to the nucleus where they activate downstream TGF-beta gene transcription. The SMADs, which form a trimer of two receptor-regulated SMADs and one co-SMAD, act as transcription factors that regulate the expression of certain genes.

Ultimately, the TGF-beta-fascin pathway promotes the formation of invasive membrane protrusions associated with high tumor invasiveness and more metastatic disease.

“Our data suggests that fascin is an immediate TGF-beta target gene essential for its pro-invasion activity in cancer metastasis,” said senior author Dr. Shengyu Yang, assistant member in tumor biology at the Moffit Cancer Center. “The finding that TGF-beta only induces fascin overexpression in highly metastatic tumor cells is especially interesting. Therapies targeting fascin may block TGF-beta mediated metastasis without interfering with the tumor suppressor role of TGF-beta in normal tissues.”

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Moffitt Cancer Center