Potential Anticancer Drug Blocks the TGF-Beta Pathway

A metabolic pathway responsible for regulating the asymmetric development of fetal organs has been linked to processes that occur when normal cells become cancerous and begin to proliferate and spread.

The transforming growth factor beta (TGF-beta) pathway is named after a protein that 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.

Investigators at North Carolina State University (Raleigh, USA) became interested in the TGF-beta pathway when they discovered that a TGF-beta inhibitor called heterotaxin disrupted left-right asymmetry in developing Xenopus embryos. Many cellular events are shared by developing embryos and by developing cancer cells.

Results published in the February 24, 2011, issue of the journal Chemistry & Biology revealed that analogs of heterotaxin possessed highly desirable antitumor properties, inhibiting epithelial-mesenchymal transition, angiogenesis, and tumor cell proliferation in mammalian systems.

"For the intestinal tract to form properly, it has to develop asymmetrically. This compound disrupts asymmetry, so it could be quite useful in helping us to determine when and where intestinal development goes wrong in embryos,” said senior investigator Dr. Nascone-Yoder, assistant professor developmental biology at North Carolina State University. "We also noticed that the compound prevents normal blood-vessel formation and prevents cells from migrating by increasing cellular adhesion – basically, the cells are stuck together and cannot move.”

"This was exciting, because tumors have to have cells that can migrate and form a blood supply in order for the cancer to spread,” said Dr. Nascone-Yoder. "Heterotaxin inhibits those processes, which may make it a good "lead” candidate for the development of an antitumor drug.”

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