The Many Long, Intrusive Arms of Cancer Cell Invasion

In Brief:

• This time-lapse video shows cancer cells can sprout long appendages to force their way into healthy tissue.
• This research offers a new lead in determining whether a cancer is starting to spread in a patient thought to be in remission.

Cancer cells resort to all kinds of bad behavior to spread, or metastasize, from one part of the body to another. That includes the recent discovery that metastatic cancer cells can sprout long, sinewy appendages that literally take matters into their own hands to force their way into healthy tissue.

This time-lapse video, which condenses about 15 hours into 14 telling seconds, shows this brute force method in action. The video starts with breast cancer cells that have self-assembled into two round structures called spheroids. They are embedded in a 3D collagen gel to mimic how cancer cells leave tumors to invade normal tissues.

Though you can’t see it at this magnification, the outer surface of each spheroid is surrounded by a clear, fibrous sheet of basement membrane. This ubiquitous connective tissue covers almost every human tissue, where it acts as a natural barrier to keep out, among other things, cancer cells attempting to form new tumors.

At about two seconds into the video, finger-like appendages called prehensile protrusions (dark lines) appear on the mostly smooth surfaces of each spheroid. A second later, both surfaces turn fuzzy with lengthening protrusions. They are outpouchings of the cancer cell, not structures created on the spot, that are rich in muscle-related proteins. As shown in the image below, they are packed with supportive molecular scaffolding and energy-producing machinery (mitochondria) that help drive their unusual growth. In some cases, protrusions will extend about 100 micrometers, which is the average diameter of a human hair and many times longer than the cancer cell body.

At four seconds, notice the lengthening protrusions slope downward. They are breaking through the surrounding basement membrane. At about nine seconds and running to the end of the video, several protrusions move back and forth, grabbing onto collagen fibers. Though not shown in this video, they will eventually pull the cancer cell out of the spheroid and help direct it through the opening in the basement membrane for rapid invasion.

This unique video comes from the NIDCR lab of Kenneth Yamada, M.D., Ph.D., and its ongoing efforts to understand the physical and molecular interplay between cancer cells and basement membrane. Previously, the Yamada lab and others showed how cancer cells chew holes in basement membrane. Still unknown was how the cancer cells could pull through the basement membrane and invade into normal tissues.

In the lab’s latest work, published recently in the journal Cells, first author Shayan S. Nazari, Ph.D., and colleagues discovered that these prehensile protrusions can be wildly abundant on the surface of both breast and oral cancer cell spheroids.

Dr. Yamada suspects that as metastatic cells sprout protrusions, they may use distinctive protein markers that can be detected in biopsies or possibly even in blood and saliva. There’s still a long way to go before that determination can be made. But if this lead pans out, doctors could in theory test for these markers to help determine whether a cancer, including oral cancer, might be starting to spread in a patient thought to be in remission. They might also learn to use protrusion-blocking drugs to slow or stop the spread of cancer.

This research could also contribute to a greater understanding of why protease inhibitors, a common class of cancer drug, might not be effective in some cancer patients. Protease inhibitors interfere with the scissor-like protease enzymes that many cancer cells produce in abundance to degrade basement membranes. It may be that the protease inhibitors block the enzymes, but cancer cells can ramp up prehensile protrusions as a workaround to grab, pull, and metastasize.

That, of course, is still to be determined. But with the rapid advances now underway in cell imaging and the emergence of powerful laboratory tools like spheroids, one thing is certain. All that bad behavior that cancer cells exhibit will come into tighter focus, offering hope for greater resolution of the molecular underpinning of cancer biology and in the delivery of life-saving precision cancer care.

Related Links:

• The Creatures Crawling Within

Reference

Nazari SS, Doyle AD, Bleck CKE, Yamada KM. Long Prehensile Protrusions Can Facilitate Cancer Cell Invasion through the Basement Membrane. Cells. 2023 Oct 18;12(20):2474. doi:10.3390/cells12202474.

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Reprint this article in your own publication or post to your website. NIDCR News articles are not copyrighted. Please acknowledge NIH's National Institute of Dental and Craniofacial Research as the source.

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