Metastasis is responsible for the great majority of deaths in cancer patients. There are three primary ways tumors metastasize to other organs: through the circulatory system, through the lymphatic system, and through the body wall into the abdominal and chest cavities. By using mouse models of lung and breast cancer, researchers at Rockefeller University discovered that cancer cells enlist nearby blood vessels to gain access to a signaling pathway used by neurons, allowing them to escape into the bloodstream and metastasize.

Their findings, “Tumoral activation of TLR3–SLIT2 axis in endothelium drives metastasis,” is published in Nature and led by Sohail Tavazoie MD, PhD, the Leon Hess professor at Rockefeller University.

Previously, scientists in Tavazoie’s lab observed that tumors that eventually metastasize tend to recruit more vessels than those that don’t, adding to the suspicion that infiltrating vasculature isn’t merely helping tumors survive and grow. “We hypothesized that cells in the inner lining of blood-vessels send a signal that instructs cancer cells within the primary tumor to metastasize,” Tavazoie explained.

“Blood vessels support tumors by providing nutrients and oxygen, while also acting as conduits for the dissemination of cancer. Here we use mouse models of breast and lung cancer to investigate whether endothelial cells also have active ‘instructive’ roles in the dissemination of cancer,” wrote the researchers.

“We purified genetically tagged endothelial ribosomes and their associated transcripts from highly and poorly metastatic tumors. Deep sequencing revealed that metastatic tumors induced expression of the axon-guidance gene Slit2 in endothelium, establishing differential expression between the endothelial (high Slit2 expression) and tumoral (low Slit2 expression) compartments,” noted the researchers.

Slit proteins act as axon guidance cues for corticofugal, callosal, thalamocortical, and olfactory neurons, and they regulate branching of axons and dendrites. Slits are a group of secreted glycoproteins that play a role in the regulation of cell migration. Previous studies suggested that Slit2 might be a tumor-suppressor gene.

“Deleting endothelial Slit2 suppressed metastatic dissemination in mouse models of breast and lung cancer. Conversely, deletion of tumoral Slit2 enhanced metastatic progression. We identified double-stranded RNA derived from tumor cells as an upstream signal that induces expression of endothelial SLIT2 by acting on the RNA-sensing receptor TLR3. Accordingly, a set of endogenous retroviral element RNAs were upregulated in metastatic cells and detected extracellularly. Thus, cancer cells co-opt innate RNA sensing to induce a chemotactic signaling pathway in endothelium that drives intravasation and metastasis,” concluded the researchers.

The researchers discovered that breast and lung cancer cells use what Tavazoie calls “an intricate and elegant mechanism” to persuade blood-vessel cells into making and releasing Slit2 to help them start migrating. “The cells first activate normally silenced DNA to produce double-stranded RNA, which in turn acts as a signal to trigger their own movement out of the primary tumor and into the blood, from where they can spread to other organs,” he said.

These findings show that Slit2 and other molecules in the pathway could potentially serve as diagnostics. “There’s also a chance that inhibiting these pathways could open the door to novel cancer drugs that curb metastasis,” said Tavora.

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