Exposure to TGF-beta prompts changes that help mouse tumor stem cells evade drugs

IMAGE:To see how the growth signal TGF-beta influences cancer cells, the researchers used a red tag (top) to mark mouse tumor stem cells that received the signal, and a green... view more

Credit: Laboratory of Mammalian Cell Biology and Development

In theory, a tumor is an army of clones, made up of many copies of the original cancerous cell. But tumor cells don't always act like duplicates, and their unpredictable behavior can create problems for treatment. For while some cells within a tumor succumb to anti-cancer drugs, others may survive to bring the cancer back to life once therapy has ended.

In a study published today (February 26) in Cell, researchers at Rockefeller University home in on one culprit that fuels this variable vulnerability within squamous cell cancers: exposure to a signal known as TGF-, given off by immune cells that congregate next to a tumor's blood vessels.

"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-," says senior researcher Elaine Fuchs, Rebecca C. Lancefield Professor, head of the Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development and a Howard Hughes Medical Institute investigator. "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."

Her team, which included first author Naoki Oshimori, a postdoctoral research associate in the lab and lab technician Daniel Oristian, focused on squamous cell carcinomas in the skin of mice. Like many normal tissue stem cells, the stem cells that produce squamous cell tumors can be classified into two types: those that divide and proliferate rapidly, and those that do so more slowly. This has led scientists to wonder whether the more dormant stem cells in a tumor might evade cancer drugs.

To investigate this possibility, the team zeroed in on TGF- (transforming growth factor beta) which is known to restrict growth in many healthy tissues. The lab's previous research has shown that mice whose normal skin stem cells cannot respond to TGF- become susceptible to develop tumors that grow rapidly. Paradoxically, however, TGF- contributes to metastasis in many cancers. The researchers wanted to know: How can TGF- act both to suppress cancers and promote them?

By visualizing TGF- signaling within developing mouse tumors, the researchers found that the cancer stem cells located nearest to the blood vessels of the tumor receive a strong TGF- signal, while others further away don't receive any. To see this difference and its effects, they used a red tag to illuminate those cells exposed and responding to TGF-, and a green genetic tag, which they could switch on, to track the stem cells' progeny. Over time, they saw that TGF--responding stem cells proliferate more slowly but they simultaneously invade, scatter and move away from the tumor. The opposite was true of cancer stem cells too far away to receive TGF-, which proliferated rapidly, but were less invasive, growing as a tumor mass.

"We tested the implications for drug resistance by injecting cisplatin, a commonly used chemotherapy drug for these types of cancers, into the mice with tumors. While the drug killed off most of the TGF- nonresponding cancer cells, it left behind many of the responders," Oshimori says. "When the drug was withdrawn, the lingering TGF- responding cancer stem cells grew back the tumor."

More here:
Growth signal can influence cancer cells' vulnerability to drugs, study suggests