Altering malignant cells' structure said to possibly slow spread of cancer

December 18, 2009

Cancer may spread throughout the human body when malignant cells travel in the blood stream. But it may be possible to slow or even stop those cells from spreading by altering their structure, according to a recent investigation led by a Texas A&M University researcher.

The team - assembled by Gonzalo Rivera, an assistant professor in the Department of Veterinary Pathobiology in the Texas A&M University College of Veterinary Medicine & Biomedical Sciences, and scientists from The University of Connecticut Health Center and the University of California, San Francisco - published its findings recently in Molecular Cell, a peer-reviewed scientific journal.

The spread of cancer is one example of what can happen when things go awry with the cytoskeleton, a meshwork created by the assembly of multiple copies of a cellular protein called actin, Rivera said.

The actin cytoskeleton determines a cell's shape and its ability to stick to other cells or to tissue. The cytoskeleton is constantly being reshaped in response to external clues sensed by cells. Through a complex process of "signal transduction" cells translate external clues into specific behaviors. They may grow rapidly. They may alter their functions. Or they may migrate to others parts of the body.

Cells respond to signals from the environment by several ways. Among the most critical are the changes in lipids called phosphoinositides as well as in tyrosine phosphorylation, the addition of a phosphate group to specific cellular proteins.

"The long-term goal of our research is to define how signals that alter the cytoskeletal architecture promote cancer initiation and progression, as well as migration of vascular cells, "Rivera said. "Our recent article published in Molecular Cell addresses the important question of how signal transduction mechanisms set in motion by external clues result in remodeling of the actin cytoskeleton."

Using a unique combination of experimental approaches, including molecular genetics, proteomics, and high resolution optical microscopy, Rivera and his co-investigators uncovered a novel molecular mechanism in the regulation of N-WASp, a protein critically involved in rearrangements of the actin cytoskeleton.

N-WASp is a direct cousin of WASp (Wiskott-Aldrich Syndrome protein), a protein named after the physicians that first reported a rare inherited disorder characterized by low level of blood platelets, eczema, recurrent infections, and a high risk of leukemia or lymph node tumors in boys.

"Specifically, we demonstrated that a cross-talk between signals that alter tyrosine phosphorylation and the metabolism of phosphoinositides is critical in the regulation of N-WASp activity and the reshaping of the actin meshwork," Rivera said. "Importantly, our work shows that an 'adaptor protein' termed Nck is essential in the coupling of phosphotyrosine- and phosphoinositide-dependent signals that drive cytoskeletal rearrangements through the N-WASp pathway."

Experimental evidence suggests that reducing Nck levels in malignant tumor cells drastically diminishes their ability to migrate in an artificial environment, Rivera explained.

"One could speculate that targeting the intracellular machinery that modulates actin remodeling, and particularly the N-WASp signaling hub, may open new avenues for the treatment of invasive carcinomas," Rivera said. "We are currently determining the role of this signaling pathway in cytoskeletal changes linked to tumor formation and metastatic growth."
The article, "Reciprocal Interdependence between Nck and PI(4,5)P2 Promotes Localized N-WASp-Mediated Actin Polymerization in Living Cells," can be found in the Nov. 13, 2009, issue of Molecular Cell.

Texas A&M University

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