Researchers at the Max Delbrück Centrum for Molecular Medicine (MDC) have identified the stem cells responsible for clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer. Kidney cancer is the 12th most common malignancy in the western world and while treatments have been used successfully on patients with kidney cancer, two thirds of patients with metastases progress within 2 years. Once the cancer has metastasized, the 5-year survival rate drops from 70%-80% to 10%-20%.
Cancer stem cells are responsible for metastases, so the identification of the stem cells provides scientists with an opportunity to develop effective treatment to prevent the spread of cancer; however, not all cancer stem cells give rise to metastases, and those that do are often very rare and difficult to find. Not only have the researchers identified the cancer stem cells responsible for ccRCC, they have also devised a method for blocking the growth of tumors in three models of the disease.
Dr. Annika Fendler, first author of the paper, and her team at the Charité Urology Department found three proteins on the surface of the cancer stems cells that allowed them to be tagged and isolated using fluorescence-activated cell sorting (FACS). The stem cells were rare, and only accounted for about 2% of the total present in human ccRCC tumors.
The researchers found the cancer stem cells have a weakness that can be targeted. They rely on two biochemical signals passed along the WNT and NOTCH networks. The lab, assisted by the Screening Unit of the Leibniz Institute FMP, had previously developed an inhibitor of WNT signals and along with a NOTCH inhibitor, they were able to stop the growth ccRCC tumors. Blocking either or both signals was found to interfere with the cancer stem cells.
In their tests, three quarters of cell cultures taken from patients with ccRCC tumors responded to one of the inhibitors and 50% of the remaining quarter responded if both inhibitors were used. While the results were certainly encouraging, it does not mean that the inhibitors will work in vivo in human patients. The researchers tested the inhibitors on mice that had been injected with ccRCC cancer stem cells taken from human patients and had developed kidney tumors. The researchers used the WNT and NOTCH inhibitors and found that the best results were obtained using both inhibitors together.
The discovery that WNT and NOTCH play in ccRCC could potentially lead to new strategies to treat the disease, however, further research is required on animal models before the inhibitors could be considered for use in human clinical trials.
You can read more about the research in the paper – Inhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients – which was recently published in the journal. Nature Communications. DOI: 10.1038/s41467-020-14700-7