Even the most potent cancer drug faces a daunting task once it arrives at its destination, namely, cutting through the thick and thorny extracellular matrix that surrounds tumors and their blood vessels. Researchers have been looking for ways to break down this thicket, especially its tough collagen fibers. One approach is to mimic fibroblasts, cells dedicated to building up and breaking down collagen. But there’s a problem: remodeling takes a period of days and, until recently, no one had been able to observe the process unfold in a living animal.
Jean Parentes, Trevor McKee, Yves Boucher, Rakesh Jain, and colleagues have recently caught fibroblasts in the process of doing just that—to dramatic effect. They observed fibroblasts actually pushing collagen fibers around for days until finally the fibers broke down. “We saw fibroblasts could drag the fibers and collapse them,” said Boucher, HMS associate professor of radiation oncology at Massachusetts General Hospital. The findings appear in the February Nature Methods.
The seeds of the study were planted in 2003 when researchers found they could observe collagen fiber breakdown in vivo by joining together multiphoton laser scanning microscopy and a newer technique called second harmonic generation, which focuses laser light onto a sample in such a way that there is no need for artificial labeling. Boucher and Jain, the A. Werk Cook professor of radiation oncology (tumor biology) at MGH and HMS, who has a longstanding interest in drug delivery, along with Parentes and McKee, then postdoctoral fellows, and colleagues applied the paired method to visualize what was going on inside tumors growing on the backs of mice. The tumors, visible through little windows, had been treated with the hormone relaxin, which is known to induce remodeling of the extracellular matrix.
After seeing the collagen collapse, the researchers set out to understand how the fibroblasts might be causing that to happen. They suspected that the cells might be interacting with the collagen by means of a class of adhesion molecules, the beta integrins. They also thought the fibroblasts might bring about collagen collapse by upregulating a well-known class of enzymes, the matrix metalloproteinases (MMPs). They treated some tumors with an inhibitor of MMP and others with a beta-1 integrin inhibitor. Both of the proteins were essential for collagen remodeling.
The findings raise intriguing possibilities. “We’re interested in how collagen in tumors impedes transport. These findings suggest another way for us to modify the matrix. For example, knowing beta-1 integrin plays a role, we can look for agents that activate beta-1 integrin,” said Boucher.
Students may contact Yves Boucher at yves@steele.mgh.harvard.edu for more information.
Conflict Disclosure: The authors report no conflicts of interest.
Funding Sources: The National Cancer Institute and Swiss National Funding for young scientists
