New Cancer Drugs Found to Inadvertently Promote Growth of Tumors

Researchers exploring how cancer metastasizes into bone have made an unforeseen discovery that suggests several research anticancer therapeutic agents about to enter the drug-development pipeline may not have the required effect. The new research revealed that these drugs inadvertently may trigger cancer.

The study’s findings were published October 14, 2013, in the Journal of Experimental Medicine. The researchers, from Washington University School of Medicine in St. Louis (MO, USA), were concentrating on cells that can be found in great numbers in several types of cancer. These cells, called myeloid-derived suppressor cells (MDSCs), interfere with T-cells from the immune system, making it problematic for T-cells to attack and kill tumor cells.

The cancer agents being developed target a signaling protein expressed in high amounts in some cancer cells. The protein, beta-catenin, is thought to enhance the growth of tumors; however, the investigators discovered that by blocking in myeloid cells in bone marrow may have the unintended consequence of increasing the number of MDSCs and making it harder for the body’s immune system to attack growing tumors.

“The idea is that cancer cells often have elevated beta-catenin signaling, leading to more tumor cell proliferation, so many scientists have hypothesized that drugs that lower beta-catenin levels could fight cancer,” said senior investigator Roberta Faccio, PhD. “But we think that such a strategy actually could contribute to the proliferation of tumors. Our findings suggest that although some inhibitors of beta-catenin may interfere with tumor cell growth, they also could expand the population of the MDSCs and contribute to the development and spread of cancer.”

Dr. Faccio, an associate professor of orthopedic surgery whose laboratory studies how cancer spreads into bone, worked with first author Aude-Hélène Capietto, PhD, to learn exactly how MDSCs inhibit the immune system’s capability to fight off cancer. In a series of research experiments, they examined genetically modified mice to learn how those cells help in the proliferation and metastasizing mechanisms of tumor cells.

The scientists found, as expected, that mice with tumors had more myeloid-derived suppressor cells, raising the probability that their tumors would grow and spread. Remarkably, the MDSCs in mice with tumors also had lower amounts of beta-catenin. That is significant because some agents being considered as possible cancer treatments block beta-catenin. This study’s findings suggest that could be damaging.

MDSCs are immature immune cells that are supposed to “grow up” to become specialized immune cells. But in the presence of tumors, the cells do not develop correctly. Instead, they inhibit the immune system’s T-cells, making it easier for tumors to grow and spread. That is what occurred in the genetically engineered mice. They had lower levels of beta-catenin in MDSCs, leading to more such cells as well as more aggressive tumors. But the process also worked in reverse. When the researchers raised beta-catenin levels in the MDSCs of mice with cancer, the number of their myeloid-derived suppressor cells fell, and their tumor growth slowed.

“A lot of cancer treatments don’t work very well, and they kill both cancer cells and healthy cells,” said Dr. Capietto. “But our findings indicate that myeloid-derived suppressor cells may be good targets for therapy because we know they induce tumor growth.”

Dr. Faccio believes the pathway involving beta-catenin behaves the same way in people as it does in mice because they got the same results in studies of MDSCs from cancer patients. “When we isolated cells from patients with pancreatic cancer, we found the very same things we had observed in mice with cancer,” he said. “So it was a confirmation that this pathway is quite relevant in the progression of cancer.”

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Washington University School of Medicine in St. Louis