TGF-β Signals Can Influence Melanoma Cells’ Vulnerability To Drugs

TGF-β Signals Can Influence Melanoma Cells’ Vulnerability To Drugs

shutterstock_169068299 (1)A recent study published in Cell and titled The Harmonies Played By TGF-β in Stem Cell Biology,” assessed how cancer cells respond to transforming growth factor beta (TGF-β) signals. These discoveries can lead to new approaches to treat melanoma.

A tumor consists of a group of many clones of the original cancer cell, however tumor cells do not always act as copies or duplicates and they display unpredictable behaviors to improve their chances of growth and proliferation. Sometimes some cancer cells succumb to anti-cancer drugs while others might survive and result in cancer recurrence years later.

Senior researcher Elaine Fuchs explained in a press release: “There are several reasons why some cancer stem cells, the cells at the root of tumors and metastases, can withstand therapy meant to eradicate them. Our results point to the importance of the environment immediately surrounding the skin cancer stem cells, specifically, their exposure to the signal TGF-β. Ultimately, we hope this new insight could lead to better means for preventing the recurrence of these life-threatening cancers, which can occur in the skin, head, neck, esophagus, and lung, and often evade treatment.”

The research group led by Dr. Naoki Oshimori focused on squamous cell carcinomas in mice skin. The stem cells that synthesize squamous cell tumors can be categorized as those that divide and proliferate quickly and those that do so more slowly. This led researchers to wonder whether more dormant stem cells in a tumor might get away from cancer drugs. To evaluate this phenomenon, researchers focused on TGF-β (that restricts growth in several healthy tissues) to understand how it can both suppress cancer cells and promote them, as supported by previous research.

“We found that the TGF-β heterogeneity in the tumor microenvironment produces some cancers stem cells that divide rapidly and lead to accelerated tumor growth, and other cancer stem cells that invade surrounding healthy tissue and escape cancer therapies. Moreover, conventional wisdom might say that a leisurely pace of cell division, like that seen in the TGF-β responders, makes it possible for these cells to circumvent anticancer treatments that target rapidly dividing cells. While this may be true for some types of anticancer drugs, we found changes in antioxidant activity in these cells are more important for their resistance to cisplatin,” Dr. Fuchs explained.

Unexpectedly, researchers observed a high expression of genes that encode enzymes involved in glutathione usage, an important antioxidant that prevents TGF-β responders from critical harm due to anti-cancer drugs and oxidative stresses.

“If TGF-β signaling and elevated antioxidant activity plays the same role predisposing cancer stem cells to thwart chemotherapy in humans as we have shown it does in mice, this work may serve as a foundation for designing new therapeutics and combinatorial regiments to overcome drug resistance by this devastating cancer,” Dr. Fuchs concluded.

 

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