Extracellular Matrix Proteins Modulate Metastatic Tumor Cell Adhesion Behaviors
The team found “that metastatic cells selectively associate with fibronectin when in combination with galectin-3, galectin-8 or laminin,” they reported – molecules that “correlate with human disease,” reported PhD student Nathan Reticker-Flynn, MD, of the David H Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts, and colleagues.
Cell-surface integrins facing the extracellular matrix provide structural support and anchor cells in place within both healthy tissue and nonmetastatic tumor tissue, the team noted. But metastasis involves aberrant patterns of cellular adhesion, they confirmed.
“As cancer cells become more metastatic, there can be a loss of adhesion to normal tissue structures,” noted senior study author Sangeeta Bhatia, PhD, John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science at MIT. “Then, as they become more aggressive, they gain the ability to stick to, and grow on, molecules that are not normally found in healthy tissues but are found in sites of tumor metastases. If we can prevent them from growing at these new sites, we may be able to interfere with metastatic disease.”
Using genetically-engineered mice that develop primary lung tumors that metastasize to regional lymph nodes, those that metastasize to distant organs like the liver, and lung tumors that do not metastasize, the team found that metastatic tumors and primary, non- or premetastatic tumors differ markedly in their adhesion to two extracellular matrix proteins: fibronectin and galectin-3.
In a subsequent analysis of human tumor tissues, the team confirmed that galectin-3 levels were higher in more-aggressive metastases.
The team developed a novel microarray screening platform for the research, to measure cellular phenotypic responses to different combinations of extracellular matrix proteins; tumor cells were exposed to 800 pairs of extracellular-matrix molecules, and cell surface binding patterns were measured for each pair.
The new platform “allowed us to interrogate interactions between metastatic cells and their microenvironments, and identified extracellular matrix and integrin interactions that could serve as therapeutic targets,” the authors wrote.
An estimated 90% of cancer deaths are caused by metastatic tumors, the team noted.