Research News
How Cancer Cells Break Free From Tumors
Although tumor metastasis causes about 90 percent of cancer deaths, the mechanisms that allow cancer cells to spread from one part of the body to another are not well understood. One key question is how tumor cells detach from the structural elements that normally hold tissues in place and then reattach themselves in a new site. A new study from investigators at the Massachusetts Institute of Technology (MIT) reveals some of the cellular adhesion molecules that are critical to this process.
The findings, published in the journal Nature Communications, offer potential new cancer drug targets, says Sangeeta Bhatia, leader of the research team that included Tyler Jacks, senior scientific investigator of the MIT Physical Sciences-Oncology Center. “As cancer cells become 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,” said Dr. Bhatia. “If we can prevent them from growing at these new sites, we may be able to interfere with metastatic disease.”
Cells inside the human body are usually tethered to a structural support system known as the extracellular matrix. Cues from this scaffold help regulate cellular behavior. Proteins called integrins, located on the cell surface, form the anchors that hold them in place. When cancer cells metastasize, these anchors let go.
In this study, the researchers compared the adhesion properties of four types of cancer cells taken from mice genetically engineered to develop lung cancer: primary lung tumors that later metastasized, primary lung tumors that did not metastasize, metastatic tumors that migrated from the lungs to nearby lymph nodes, and metastatic tumors that travelled to more distant locations such as the liver. The investigators used technology they developed that allowed them to systematically expose each type of cell to about 800 different pairs of molecules found in the extracellular matrix.
The researchers found that the adhesion tendencies of metastatic cells from different primary tumors were much more similar to each other than to those of the primary tumor from which they originally came. One pair of glycoproteins that metastatic tumors stuck to especially well were fibronectin and galectin-3, which normally coordinate extracellular matrix interactions during development and would healing.
Although metastatic tumor cells share adhesion traits, they may take different pathways to get there. Some tumor cells alter the combination of integrins that they express, while others vary the types of sugars found on their surfaces. All of these changes can result in higher or lower affinities for certain molecules found in the extracellular matrix of different tissues. 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 pave the way for metastasis by secreting molecules that promote the development of environments hospitable to new cancer growth. Accumulation of galectin-3 and other molecules that help tumor cells colonize new sites may be part of this process, the researchers say. 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.
The MIT team 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.
This work is detailed in a paper titled, “A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis. An abstract of this paper is available at the journal's Web site.
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