In some melanoma patients, the tumor cells stay in the skin where they started, never migrating via the blood to a vital organ such as the brain or lungs — and if they do leave the skin, getting no farther than the lymph nodes before dying during the arduous journey. In other patients, the malignant cells dash out of the skin like sprinters at the starter’s gun, fighting off the perils in the bloodstream until they reach organs where they will soon prove lethal.
Why some melanomas turn fatally metastatic and others sit still has always been a black box. Research published on Wednesday, however, offers a peek inside: Melanoma cells are more likely to spread through the body if their surface bristles with molecules that grab a certain chemical in the blood and usher it into the cell, where it increases the cells’ chance of survival.
If those surface molecules are indeed what enable melanoma to spread to the lymph nodes (stage 3 cancer) and beyond (stage 4), then blocking them might prevent metastasis. In fact, when scientists administered just such a blocker to mice, incipient melanoma metastases were stopped cold, they reported in Nature, while melanomas that were left alone spread to the mice’s liver, kidneys, and pancreas.
Calling the paper “very persuasive,” melanoma expert Martin McMahon of the Huntsman Cancer Institute (who was not involved in the research) said it offered strong evidence that the surface molecule “gives melanoma cells a selective advantage in metastasis.” If the results hold up, he added, that molecule might be used to predict which melanoma patients need frequent monitoring to check for metastasis or might be targeted by drugs to prevent that in the first place.
Fortuitously, just such a blocking molecule has been developed by AstraZeneca and is being tested in a clinical trial.
Most cancer cells die when they leave the primary tumor and enter the bloodstream. For unknown reasons, the journey causes severe oxidative stress (a buildup of reactive, DNA-shredding free radicals inside the cells), biologist Sean Morrison of the Children’s Medical Center Research Institute at the University of Texas Southwestern Medical Center found in a 2015 study. “Oxidative stress kills them,” said Morrison, who also led the new research. “The vast majority of cells [leaving the primary tumor] die before they have an opportunity to grow at a distant site.”
“Vast majority” is not “all,” however, and it takes only a few cancer cells to seed a potentially fatal metastasis. If scientists could discover what separates tumor cells that die en route from those that reach their destination, Morrison figured, it might be possible to prevent metastasis, which is responsible for more than 90 percent of all cancer deaths.
Although immunotherapies are more successful against metastatic melanoma than most other cancers, only about one-quarter of patients respond, and melanoma will kill more than 7,000 people in the U.S. this year.
The main clue to what lets melanoma cells metastasize was that those that do chow down on lactate in the bloodstream. Once in the cells, lactate — best known for causing cramps — triggers a biochemical reaction that culminates in the production of antioxidants, which let the cells survive the otherwise-lethal oxidative stress they suffer en route to vital organs. (That, McMahon said, is more evidence that the antioxidant craze is dangerously misguided: Particularly taken as dietary supplements, antioxidants seem to promote metastatic cancer.)
The UT study explains how some tumor cells manage to vacuum up all that protective lactate: Their surface bristles with molecular portals that usher lactate inside like the starboard air lock on the Millennium Falcon in “Star Wars.”
As it happens, melanoma patients with high levels of the molecular portal, called MCT1, are more likely to develop metastatic cancer and die than are patients with low levels. When the UT Southwestern team injected mice with human melanomas that had either lots of MCT1 or very little, the former metastasized throughout the animals much more than the low-MCT1 cells.
“If I had melanoma,” Morrison said, “I’d want to know my MCT1 status.”
His team then gave mice implanted with human melanomas a weeklong regimen of an MCT1 blocker, AstraZeneca’s investigational AZD3965. Result: The animals had fewer melanoma cells in the blood and fewer metastases.
“Inhibiting MCT1 doesn’t have much effect on the primary tumor or on established metastases,” Morrison said. But for cells in between, it “can prevent metastasis” and, at least in the mice, extend survival.
Although AstraZeneca’s MCT1 inhibitor is being tested in an early-stage clinical trial, the participants have solid tumors that have already metastasized. Morrison thinks that’s too late: Oxidative stress kills cancer cells in the bloodstream, not once they’ve reached their destination. If blocking MCT1 and thereby exposing tumor cells to oxidative stress in the bloodstream has any benefit, he said, it will be around stage 3, when cancer cells have reached the bloodstream and lymph nodes but not beyond.
“Our prediction is that blocking MCT1 won’t have much activity against stage 4 melanoma, but if used as an adjuvant therapy in stage 3, it might decrease the percentage of patients who progress to stage 4,” Morrison said.
His discovery might extend beyond melanoma. Lung and pancreatic tumor cells also use MCT1 to grab lactate from the bloodstream, presumably enabling those cancers, too, to metastasize.
I was stage 3b and completed a year of opdivo. How could I get into this study to prevent spread?
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