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A Better Understanding of Metastasis

A single malignant cell becomes two, then four, then eight. As a tumor grows, these multiplying cells eventually put a strain on local resources and grow away from blood vessels, starving them of oxygen. But while oxygen deprivation might be a death sentence for normal cells, it can be the opposite for cancer. Studies have shown that a lack of oxygen causes cells to stabilize the production of proteins called hypoxia-inducible factors (HIFs), which affect the activity of hundreds of genes involved in chemotherapy resistance and metastasis—the migration of cancer cells that is responsible for most cancer deaths.

Although some drugs directed toward HIFs have been tested in clinical trials, they haven’t been very successful at treating metastatic cancers, says breast cancer researcher Daniele Gilkes, Ph.D. One reason for this failure, she adds, is that relatively little is known about exactly what happens to cells that produce HIFs.

“If we could get a better handle on the timeline of events after cells are deprived of oxygen,” she says, “we might find subpopulations of cancer patients for whom these drugs could be helpful.”

Funded by a $150,000 grant from the Emerson Collective Cancer Research Fund, Gilkes and her colleagues are using a novel method to better understand the superpowers that malignant cells develop once they’re oxygen-starved.

She is using an animal breast cancer model that her lab developed that shows which cancer cells are deprived of oxygen. In this mouse model, breast cancer cells glow red when they’re exposed to light. But once they become oxygen deprived, they glow green.

If we could get a better handle on the timeline of events after cells are deprived of oxygen, we might find subpopulations of cancer patients for whom these drugs could be helpful.

By harvesting these cells, both within the tumor and after they metastasize to locations such as the lungs, liver, bone and brain, the researchers can use a technique called flow cytometry to sort cells by their color and analyze which genes may have developed mutations between the two groups and which have differences in activity that may enhance their ability to metastasize.

This technique will help researchers figure out which cells are oxygen-deprived among the diverse cellular mix of tumors. It will also help them establish when genetic changes that affect cellular behavior take place. This knowledge could help answer questions, such as do spreading cancer cells maintain these changes or do the cells “reset” when they reach their new environment, says Gilkes.

This fundamental knowledge could lead to better ways to fight cancers, she adds. As part of this line of research, she and her colleagues plan to test whether oxygen deprivation is what triggers resistance to chemotherapies in triple-negative cancer, a type of breast cancer that often becomes untreatable with conventional medicines, leading to a poor prognosis. They also plan to study if targeting the hypoxic cells—essentially using a genetic modification to kill them before they migrate—can prevent reduced sensitivity to chemotherapies.

“We need a different strategy to treat metastatic cancers,” Gilkes says. “Right now there is no cure. Our goal is to change that.”

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