10 October 2012

MIT News: Understanding Tumor Metastasis, Cancer, And Cellular Adhesion

A microscopic image of cancer cells adhering to a spot coated with molecules found in the extracellular matrix.
Image: Nathan Reticker-Flynn
Cancer researchers at MIT are focusing their attention on how tumor metastasis occurs. Metastasis is the spread of the tumor to other parts of the body and is the primary reason for ninety percent of all cancer deaths. Their findings are published in the October issue of Nature Communications.

When a tumor metastasize, cancerous cells detach from the primary tumor and spread to other organs through the blood stream. The team of researchers headed by Sangeeta Bhatia, the John and Dorothy Wilson Professor of Health Sciences and Technology and Electrical Engineering and Computer Science, are studying how the anchoring process works within the tumor.

“As cancer cells become more metastatic, there can be a loss of adhesion to normal tissue structures. 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,” says Bhatia, who is also a member of the David H. Koch Institute for Integrative Cancer Research at MIT. “If we can prevent them from growing at these new sites, we may be able to interfere with metastatic disease.”

Cells bind itself to a tissue surface or extracellular matrix because of cell adhesion. The extracellular matrix is a structural support system that holds cells in place and also regulates its behavior. On the surface of the matrix are cell adhesion molecules such as the protein Integrin that anchor the cells in place. Integrins can communicate with the cellular matrix both ways, meaning it can send signals from the matrix environment to the matrix and vice-versa.

The scientists tested eight hundred different protein pairs to find out how the cells will bind to them. They noticed that one pair of extracellular matrix molecules that metastatic tumors stuck to especially well was fibronectin and galectin-3, both made of proteins that contain or bind to sugars. Integrin works especially well with fibronectin.

Video: Head Researcher Sangeeta Bhatia

In an analysis of human tumor samples, both primary and metastatic, the researchers saw similar patterns. Specifically, they found that the more aggressive the metastasis, the more galectin-3 was present.

Previous studies have suggested that tumors first develop an environment that is hospitable to cancer growth before metastasis. By secreting molecules into the system, the body is then gradually preparing itself for an influx of cancer cells. Accumulation of galectin-3 and other molecules that help tumor cells colonize new sites may be part of this process, the researchers say.

Nathan Reticker-Flynn, lead author of the paper and a PhD student in Bhatia’s lab says, “There’s a lot of evidence to suggest that a hospitable niche for the tumor cells is being established prior to the cells even arriving and establishing a home there,”.

The findings offer potential new ways to block metastasis by focusing on a specific protein-protein or protein-sugar interaction, rather than a particular gene mutation, Reticker-Flynn says. “If those changes do confer a lot of metastatic potential, we can start thinking about how you target that interaction specifically,” he says.

The researchers tested this approach by genetically knocking down the amount of an integrin found on the surface of cancer cells, which they had identified as interacting with fibronectin and galectin-3. In those mice, tumor spread was reduced. Other possible therapeutic approaches include blocking binding sites on fibronectin and galectin-3 with antibodies, so tumor cells can’t latch onto them.

To help with efforts to develop such drugs, the research team is now trying to figure out the details of tumor cells’ interactions with galectin-3 and is developing new candidate therapeutics aimed at inhibiting those interactions.

The research was funded by Stand Up to Cancer, the Koch Institute Circulating Tumor Cell Project, the Harvard Stem Cell Institute, the National Cancer Institute, the Howard Hughes Medical Institute and the Ludwig Center at MIT.


How Cancer Cells Break Free From Tumors
Nature Communications
Stand Up to Cancer
Koch Institute
Harvard Stem Cell Institute
National Cancer Institute
Howard Hughes Medical Institute
The Koch Institute: Ludwig Center for Molecular Oncology
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