Cancers are notorious for their ability to rebound uncontrollably after a first round of successful treatment. In a new study, researchers at OHSU have uncovered how a fraction of a tumor’s cells conspire with the immune system to establish an inviting niche for the growth of new tumors that are resistant to anti-cancer drugs.
Image: Tissue section showing how increased TGF-β producing immune cells (green) in the stroma accumulate around TGF-β reporter+ tumor-initiating cells (pink) at the invasive tumor front.“To overcome that drug resistance, we have to target these tumor-initiating cells and their surrounding niche,” says Naoki Oshimori, Ph.D., senior author of a paper in Science presenting the research. “We already have some data for a promising therapeutic effect of targeting that pathway,” he adds. Oshimori is an assistant professor of cell, developmental and cancer biology in the OHSU School of Medicine.
In a given cancer, only a small fraction of cells are capable of starting new tumors. These tumor-initiating cells also have the ability to withstand radiation and chemotherapy, and they play an important role in cancer relapse and unstoppable progression. But researchers haven’t been able to find treatments that effectively target tumor-initiating cells.
Oshimori and colleagues decided to find out if tumor-initiating cells send a specific signaling molecule to nearby non-cancer cells to start the process of building a cancer-supporting niche.
They had already developed a mouse model of squamous cell carcinoma and used it to study the role of a protein called transforming growth factor β, or TGF-β, which acts as a tumor suppressor or promoter at different stages of cancer development. They found that tumor cells that respond to TGF-β can survive chemotherapy and give rise to recurrent tumors, that is, function as drug-resistant tumor-initiating cells.
In the new study using the same mouse model, the researchers discovered a signaling loop between tumor-initiating cells and nearby non-cancer cells that generates the niche microenvironment that is required for invasive progression and drug resistance.
First, antioxidant activity in tumor-initiating cells opens the door to the release of a cytokine, interleukin-33. The cytokine delivers a signal that draws in a specific type of macrophage, a kind of immune cell. These macrophages use the growth factor TGF-β to send signals to tumor-initiating cells that promote invasive and drug-resistant properties. The signals also boost the production of interleukin-33, completing a feedforward loop.
Oshimori’s team also showed that the signaling loop can be targeted to stop tumor growth in the mouse model. When they depleted the specific type of macrophages using antibodies, tumor growth was stunted compared with tumors in untreated mice. They’ve also tested the effect of a drug that blocks interleukin-33 and found that it reduces the frequency of tumor-initiating cells.
The ultimate goal is to find therapies to stop tumor-initiating cells from reviving the spread of new cancers after initial treatment. “I have hope that the intercellular communications we have identified may be a good target for reducing drug resistance and tumor recurrence in cancer patients,” Oshimori says.
“Our main focus is finding out how we can prevent tumor recurrence,” he says. After a first round of treatment, when most cancer cells have died, tumor-initiating cells set to work reorganizing their microenvironment to restore a cancer-promoting niche. That’s when a drug targeting interleukin-33 signaling or the implicated macrophages could be deployed to stop tumor initiating cells.
Tumor-initiating cells establish an IL-33–TGF-β niche signaling loop to promote cancer progression by Sachiko Taniguchi, Ajit Elhance, Avery Van Duzer, Sushil Kumar, Justin J. Leitenberger, and Naoki Oshimori. Science (July 17, 2020)
TGF-β Promotes Heterogeneity and Drug Resistance in Squamous Cell Carcinoma by Naoki Oshimori, Daniel Oristian and Elaine Fuchs. Cell (Feb. 26, 2015)