Experimental treatment approach targets cancer stem cells in mice
Despite remarkable advances in recent decades, cancer often remains an elusive foe. A major reason is treatment resistance—when a tumor no longer responds to a chemotherapy drug—coupled with metastasis, in which the cancer spreads to other parts of the body. Most cancer-related deaths are caused by metastases.
To improve treatments, scientists need to better understand how cancers gain the ability to evade therapy and then spread to distant areas. New NIDCR-funded research adds to growing evidence that the underlying culprits may be cancer stem cells, a type of tumor cell.
UCLA School of Dentistry scientists led by Cun-Yu Wang, DDS, PhD, found that targeting cancer stem cells holds promise for overcoming treatment resistance and metastasis of a type of head and neck cancer, at least in mice. This cancer, known as squamous cell carcinoma, grows in the inner lining of the mouth, nose, throat, and salivary glands. The findings might eventually lead to more effective therapies for head and neck squamous cell carcinoma, which has a low survival rate caused in part by treatment resistance. The team's findings were published May 4, 2017, in Cell Stem Cell.
Much like normal stem cells, cancer stem cells can stay alive indefinitely and turn into any of the cell types that make up a tumor. Scientists think that cancer stem cells trigger the initial growth of a tumor and may even drive its invasion into nearby tissues and other places in the body.
Because cancer stem cells are relatively rare compared to the rest of the tumor cells (called the tumor bulk), it’s been hard for researchers to detect the stem cells in living organisms to define their exact role in tumor growth.
In the past, scientists have taken cancer stem cells out of human tumors, transplanted them into mice, and characterized their behavior. "But it's more ideal to study the tumors as they spontaneously develop in live animals, because cancer stem cells may behave differently when they're taken out of their natural environment and placed into a different species," Wang says. "Few researchers have looked at the behavior of cancer stem cells in live animals, because it takes a long time to induce a tumor and an even longer time for it to metastasize," he explains.
Wang's research was supported in part by an NIDCR Method to Extend Research in Time (MERIT) award—a long-term grant that enables outstanding scientists to conduct high-risk, high-reward research. The MERIT award allowed Wang and his team to devote the time and resources needed to develop this challenging mouse model for head and neck squamous cell carcinoma.
The UCLA group experimentally induced tongue tumors in mice and then traced the cellular offspring of the rare cancer stem cells. Using a method called genetic lineage tracing, the team employed a fluorescent tag to pinpoint the origin and movement of tumor cells expressing Bmi1—a protein linked to self-renewal and a likely hallmark of cancer stem cells.
The researchers found that the Bmi1-expressing cells displayed typical stem-cell-like behavior, including the ability to self-renew and turn into different tumor cell types. These qualities strongly suggested that Bmi1-expressing cells are indeed cancer stem cells. The Bmi1 cells also drove tumor development, invasion through the various layers of the tongue, and metastasis to nearby lymph nodes in the neck.
When mice were treated with cisplatin, the standard chemotherapy drug, the cells making up the tumor bulk were destroyed, but Bmi1 cells were spared and continued to proliferate. This finding supported the researchers’ hypothesis that cancer stem cells are a major cause of cancer relapse after chemotherapy.
The scientists then treated mice with both cisplatin and a drug that inhibits Bmi1. The drug combination overcame the stem cells’ chemotherapy resistance and prevented metastasis. In another experiment, a similar drug targeting a different critical cancer stem cell protein, AP-1, yielded the same effect when added to cisplatin.
The results suggest that combination therapies that target both cancer stem cells and the tumor bulk may be more effective than chemotherapy alone in preventing drug resistance and metastasis in head and neck squamous cell carcinoma. The UCLA team is focused on improving the effectiveness of the cancer stem cell inhibitors, potential therapeutic approaches that might one day be tested in humans.
The findings add to basic knowledge of cancer stem cells, offering support to the hypothesis that cancer stem cells drive treatment resistance and metastasis. Scientists might apply the experimental approach to other cancer types, extending the one-two punch beyond head and neck cancer.
Targeting BMI1+ cancer stem cells overcomes chemoresistance and inhibits metastases in squamous cell carcinoma. Chen D, Wu M, Li Y, Yuan Q, Ekimyan-Salvo M, Deng P, Yu B, Yu Y, Dong J, Szymanski JM, Ramadoss S, Li J, and Wang CY. Cell Stem Cell. 2017 May 4. PMID: 28285905.