Researchers have now identified one pathway that lung cancer cells use to avoid chemotherapy, which may lead to new approaches for treatment.
Although various cancer therapies, such as chemotherapy, can be very effective, some cancers are able to develop resistance to treatments. Researchers have now identified one pathway that lung cancer cells use to avoid chemotherapy, which may lead to new approaches for treatment.
Scientists at the Medical College of Georgia and Georgia Cancer Center at Augusta University worked to determine the mechanisms of action of a tumor inhibitor, TIMP-1. When found at high levels in lung cancer, it is associated with a poor prognosis.
TIMP-1 stimulates the expression of an immune system modulator called IL-6. IL-6 is also associated with treatment resistance. When lung cancer is treated with chemotherapy, the levels of both TIMP-1 and IL-6 increase.
The researchers, led by Mumtaz Rojiani, a cancer biologist, studied whether TIMP-1 enabled cancer cells’ ability to avoid a chemotherapy drug. What they saw was an increase of IL-6, which can modulate inflammation and appears to regulate TIMP-1 in some cancers. But in lung cancer, specifically non-small cell lung cancer, it was the other way around—TIMP-1was regulating IL-6.
“At least in lung cancer, we are showing that it is TIMP-1 that is controlling IL-6,” Mumtaz Rojiani, corresponding author of the study, said.
“We have shown for the first time that if TIMP-1 goes up, IL-6 goes up and if TIMP-1 goes down, IL-6 decreases … and we have shown it in multiple different ways,” said Amyn Rojiani, chair of the MCG Department of Pathology and study coauthor.
They evaluated human non-small cell lung cancer (NSCLC) cells and also human cells where the TIMP-1 was knocked out. They then treated the cells with common chemotherapeutic drugs, gemcitabine and cisplatin. In the cells with TIMP-1 missing, IL-6 production went down and cell death went up.
“We gave the two chemotherapy drugs and when we looked at the effect of those drugs we found that TIMP-1 was affecting apoptosis in cell lines and when we knocked it down, we found more apoptosis even in the presence of these drugs,” said Mumtaz Rojiani. “So we know TIMP-1 is affecting apoptosis.”
Adding TIMP-1 resulted in IL-6 levels going back up and cell survival increasing. But the cancer cells that survived the experiments were even more treatment-resistant than the original cancer cells and had higher levels of both TIMP-1 and IL-6. In other words, the resulting surviving clones have even more resistance than the original cancer cells, which makes sense.
In an analysis of the Cancer Genome Atlas database, which is run by the National Cancer Institute, they found that patients with NSCLC who had both low TIMP-1 and IL-6 levels had higher survival rates, and the genes for both were typically elevated together, according to Wei Xiao, MCG postdoctoral fellow and the study’s first author. IL-6 alone being elevated didn’t affect survival as much as just TIMP-1 levels being elevated. But when both were elevated, survival was significant worse than when TIMP-1 levels alone were elevated.
“The two-gene signature became very important,” said Mumtaz Rojiani.
They investigated further, also studying STAT3, a gene regulator that is found downstream of the IL-6 signaling pathway. When IL-6 levels were high, STAT3 moved into the nucleus of the cells, which meant it was also activated. This is the first report where this pathway, where TIMP-1 affects IL-6, which activates STAT3, is found in the most common type of lung cancer.
The research was published in the journal Cancers.
