Reprogrammed skin cells shrink brain tumors in mice

New method could attack aggressive cancers like glioblastoma

Original source: Science

Imagine cells that can move through your brain, hunting down cancer and destroying it before they themselves disappear without a trace. Scientists have just achieved that in mice, creating personalized tumor-homing cells from adult skin cells that can shrink brain tumors to 2% to 5% of their original size. Although the strategy has yet to be fully tested in people, the new method could one day give doctors a quick way to develop a custom treatment for aggressive cancers like glioblastoma, which kills most human patients in 12–15 months. It only took 4 days to create the tumor-homing cells for the mice.

Glioblastomas are nasty: They spread roots and tendrils of cancerous cells through the brain, making them impossible to remove surgically. They, and other cancers, also exude a chemical signal that attracts stem cells—specialized cells that can produce multiple cell types in the body. Scientists think stem cells might detect tumors as a wound that needs healing and migrate to help fix the damage. But that gives scientists a secret weapon—if they can harness stem cells’ natural ability to “home” toward tumor cells, the stem cells could be manipulated to deliver cancer-killing drugs precisely where they are needed.

Other research has already exploited this method using neural stem cells—which give rise to neurons and other brain cells—to hunt down brain cancer in mice and deliver tumor-eradicating drugs. But few have tried this in people, in part because getting those neural stem cells is hard, says Shawn Hingtgen, a stem cell biologist at the University of North Carolina in Chapel Hill. Right now, there are three main ways. Scientists can either harvest the cells directly from the patient, harvest them from another patient, or they can genetically reprogram adult cells. But harvesting requires invasive surgery, and bestowing stem cell properties on adult cells takes a two-step process that can increase the risk of the final cells becoming cancerous. And using cells from someone other than the cancer patient being treated might trigger an immune response against the foreign cells.

To solve these problems, Hingtgen’s group wanted to see whether they could skip a step in the genetic reprogramming process, which first transforms adult skin cells into standard stem cells and then turns those into neural stem cells. Treating the skin cells with a biochemical cocktail to promote neural stem cell characteristics seemed to do the trick, turning it into a one-step process, he and his colleague report today in Science Translational Medicine.

But the next big question was whether these cells could home in on tumors in lab dishes, and in animals, like neural stem cells. “We were really holding our breath,” Hingtgen says. “The day we saw the cells crawling across the [Petri] dish toward the tumors, we knew we had something special.” The tumor-homing cells moved 500 microns—the same width as five human hairs—in 22 hours, and they could burrow into lab-grown glioblastomas. “This is a great start,” says Frank Marini, a cancer biologist at the Wake Forest Institute for Regenerative Medicine in Winston-Salem, North Carolina, who was not involved with the study. “Incredibly quick and relatively efficient.”

The team also engineered the cells to deliver common cancer treatments to glioblastomas in mice. Mouse tumors injected directly with the reprogrammed stem cells shrank 20- to 50-fold in 24–28 days compared with nontreated mice. In addition, the survival times of treated rodents nearly doubled. In some mice, the scientists removed tumors after they were established, and injected treatment cells into the cavity. Residual tumors, spawned from the remaining cancer cells, were 3.5 times smaller in the treated mice than in untreated mice.

Marini notes that more rigorous testing is needed to demonstrate just how far the tumor-targeting cells can migrate. In a human brain, the cells would need to travel a matter of millimeters or centimeters, up to 20 times farther than the 500 microns tested here, he says. And other researchers question the need to use cells from the patient’s own skin. An immune response, triggered by foreign neural stem cells, could actually help attack tumors, says Evan Snyder, a stem cell biologist at Sanford Burnham Prebys Medical Discovery Institute in San Diego, California, and one of the early pioneers of the idea of using stem cells to attack tumors.

Hingtgen’s group is already testing how far their tumor-homing cells can migrate using larger animal models. They are also getting skin cells from glioblastoma patients to make sure the new method works for the people they hope to help, he says. “Everything we’re doing is to get this to the patient as quickly as we can.”