Mayo Clinic researchers have uncovered a new cellular secret that may explain how certain cancers move and spread -- a feature of cancers that makes treatment especially difficult. If the mechanism that drives cancer movement -- also called metastasis -- can be understood well enough to manipulate it, new and better treatments can be developed for patients with metastatic cancers.
Significance of the Mayo Clinic Research
The Mayo researchers focused on odd protrusions observable by microscope on the surface of certain cancer cells: circular waves. Until now, no one has fully understood the function of these waves. The Mayo findings in the current edition of Cancer Research http://cancerres.aacrjournals.org/current.shtml are the first to show one role the waves play. They selectively round up activated growth-promoting proteins from the cell surface and take them to the interior of the cell. Under normal conditions, this process would help terminate signals from these growth-promoting proteins. However, in cancer cells it appears that either these waves may not function properly, or that the internalized proteins may remain active longer, which allows them to "instruct" a cell to acquire cancerous traits such as excessive growth and invasive movement that constitute metastasis. These waves are important for helping to keep these cancer-growth commands at bay.
Studying human pancreatic tumor cells, the Mayo researchers found that the waves store up to half the activated Epidermal Growth Factor Receptors (EGFR) from the surface of the cell and take this cache to the interior of the cells. This is important for understanding cancer because aberrant activation of EGFR can promote the excessive growth typical of cancers.
"These findings have broad implications toward the general understanding of how specific processes in the wave may affect such things as cell growth, cell movement and metastasis," explains Mark McNiven, Ph.D., the lead researcher on the Mayo Clinic team. "Our work provides new insights into a novel mechanism by which cells can internalize growth factor information. Understanding this process is the first step toward one day halting it, preventing it or reversing it therapeutically."
Why Movement Matters
Cell growth and movement are vital topics in cancer research because cancer is a disease of uncontrolled cell growth in which the normal balance between growth promotion and growth inhibition is disrupted. Epidermal Growth Factor (EGF) and the EGFR to which it homes and docks are a hot topic in cancer research because EGF promotes growth through binding and activating its receptor and certain tumors exhibit elevated levels of EGFR. In addition, activated EGFR have been implicated in the development and spread of several human cancers, including cancers of the colon, ovary, breast and lung.
Waves are circular ruffled surface structures on the exterior plasma membrane of a cell that can be observed through a conventional light microscope. They form in response to stimulation from EGF and exist for 10 to 20 minutes before disappearing. Waves intrigue researchers because wave-based internalization of activated EGFR to the interior of the cell was a previously unknown mechanism. The wave pathway appears to be a parallel pathway vital for transmitting and regulating normal cellular communication. Waves occur less often in certain tumor cells, indicating they may play a role in modulating or terminating cancer-promoting signals. Persistent cancer-promoting signals in cells lacking waves could subsequently allow them to be more motile and invasive. Waves also are important for cell movement -- at least in normal cells -- by actively reorganizing some of the cellular infrastructure at the leading edge of a cell allowing the cell to form a pliable footlike structure (lamellipodia). Previous work by this Mayo Clinic team was the first to correlate the formation of lamellipodia with wave-induced reorganization within a cell.
Collaboration and Support
Others on the Mayo team included James Orth, Ph.D.; Eugene W. Krueger; and Shaun Weller. Their work was supported by Mayo Clinic and the National Institutes of Health.
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