Autophagy Required for Cancer Metastasis

If researchers can shut down metastasis by targeting a fundamental mechanism common to all or even many cancers, then cancer becomes much more manageable and much less threatening. That is why it is worth paying attention to research that might produce useful results along those lines. This link between metastasis and the cellular maintenance process of autophagy is intriguing:

Researchers have shown that inhibiting autophagy, a self-devouring process used by cells to degrade large intra-cellular cargo, effectively blocks tumor cell migration and breast cancer metastasis in tumor models. "Using genetic and chemical means, we showed that autophagy is required for the motility and invasion of highly metastatic tumor cells. Our work suggests that inhibiting autophagy in the clinical setting may be an effective approach to block metastatic dissemination."

Metastasis is responsible for 90 percent of cancer deaths. Rapidly growing tumor cells are tightly packed. They quickly exhaust their available supplies of oxygen and nutrients. By breaking away from the original tumor, migrating cancer cells have a chance to escape starvation and wind up in a less crowded environment with more nutrients. "We began by asking, what would happen if we shut down autophagy in metastatic cancer cells." The researchers noticed that when they placed metastatic breast cancer cells on a dish and monitored them with time-lapse microscopy, the control cells were "active, constantly moving around the dish." But cancer cells that the team had altered, by knocking down autophagy-related genes Atg5 and Atg7, "didn't move at all. They appeared to be stuck."

When they injected these gene-altered cancer cells into the mammary fat pad of female mice, the cells multiplied, forming large primary breast tumors, but these cancer cells were unable to metastasize to the usual distant sites, the lungs, liver or bone. A closer look showed that these cells were morphologically very different. Their focal adhesions, large structures at the edge of the cell that are crucial for cell movement, were more numerous and abnormally large. As the cell travels forward, focal adhesions form at the front of the cell and establish dynamic connections to the extracellular matrix. As the cell passes over them, these adhesions drift back to the trailing edge of the cell. Then autophagy intervenes, disassembling the focal adhesion, breaking down its contents and allowing the back edge of the cell to disengage from the extracellular matrix and be pulled forward by traction from the front end. The researchers have now shown that if autophagy is inhibited, these metastatic tumor cells cannot move. Adhesions that don't get turned over grow larger and larger. They anchor the cell in place. "They literally just get stuck. Through the microscope, you can see the cell wobbling, trying to move, to put out new protrusions, to migrate. But it can't, because it is stuck, unable to dissolve the adhesions at the back end of the cell."

Link: http://www.eurekalert.org/pub_releases/2016-05/uocm-sci050916.php

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