The difficulty in successfully eradicating mesothelioma, an asbestos-caused cancer, is that even after many cycles of chemotherapy, the primary treatment protocol, many of the elusive cancer cells continue to thrive or regenerate. Now, researchers report that in order to successfully eliminate cancer they must first focus on eliminating cancer stem cells – and they know how to do just that.
A team of researchers from the Max Delbrück Center for Molecular Medicine (MDC) in Berlin, led by Liang Fang, report they have found a molecule that interrupts the stem cell survival mechanism, effectively killing off the cancer. The researchers report these errant stem cells are “Wnt-addicted cancer stem cells,” named for the Wnt signaling pathway on which they flourish. When functioning properly, the molecular network maintains the integrity of cells, according to the researchers, but when switched on inappropriately, it can lead to uncontrolled cancer growth and metastases.
According to various studies, metastasis is the cause of nearly 90 percent of cancer deaths. Even though cancer stem cells make up just one percent of cancer cells, according to one study, it is these cells that survive the effects of anti-cancer drugs leaving mesothelioma patients with a seemingly indestructible cancer.
Various researchers have reported that Wnt signaling is activated in mesothelioma cells. In one 2013 study reporting on the effect of the Wnt signaling pathway in mesothelioma, researchers concluded: “Modulation of Wnt signaling in MM [malignant mesothelioma] may prove a means of targeting proliferation and drug resistance in this cancer.”
In the recent study, the German researchers report they found a molecule that interrupts the “biochemical signals essential for the survival of a certain type of cancer stem cell.” They found that beta-catenin, one component in the Wnt pathway, and the TCF4 protein bind together and activate genes that then provide the stimulation cancer stem cells need to thrive. They then turned their research to finding a way to interrupt the connection between the two proteins.
Through trial and error testing by introducing different compounds one at a time, the researchers settled on the LF3 compound that “strongly inhibited binding” and was the “most potent inhibitor.”
When the compound was tested on tumor cells, they found “LF3 blocked several crucial features: it interrupted the cell cycle, preventing them from replicating, and strongly reduced their ability to migrate. LF3 didn’t seem to affect healthy cells at all.”
“We observed a strong reduction of tumor growth,” says Walter Birchmeier, leader of the Screening Unit and Medicinal Chemistry Group, of the results on a mouse model. “What remained of the tumors seemed to be devoid of cancer stem cells – LF3 seemed to be powerfully triggering these cells to differentiate into benign tissue. At the same time, no signaling systems other than Wnt were disturbed. All of these factors make LF3 very promising to further develop as a lead compound, aiming for therapies that target human tumors whose growth and survival depend on Wnt signaling.”
Physicians, oncologists and mesothelioma patients are anxious to find a new treatment for the incurable disease, and focusing on the Wnt pathway may be the breakthrough needed for increasing survival in mesothelioma patients.
The study was published Dec. 8 online in Cancer Research.