DDNEWS Cancer Research News Exclusive: Connecting collagen and cancer
ST. LOUIS—Women with denser breasts live with the knowledge that they are at a higher risk of developing breast cancer, and within that group, those diagnosed with breast cancer are more prone to developing aggressive tumors with a tendency to metastasize. The greater density results from an excess of collagen, and new research from the Washington University School of Medicine in St. Louis has shed some light on why an overabundance of this natural protein predisposes this group to cancer and metastasis.
Researchers worked with mouse models of breast cancer as well as tumor samples from patients and discovered that there is a protein, DDR2, found on the surface of tumor cells. This protein binds to collagen and activates a pathway that encourages the spread of tumor cells. This sequence contains another protein, SNAIL1, at the other end of the pathway, that is known to play a role in cancer metastasis. Gregory D. Longmore, M.D., professor of medicine at Washington University School of Medicine in St. Louis, and his colleagues found that DDR2 is one of the biological factors responsible for keeping levels of SNAIL1 high inside tumor cell nuclei, thereby priming them to spread. It is not the only protein responsible for maintaining SNAIL1 levels, according to Longmore, but it might represent the most viable target.
"We have shown how increased collagen in the breasts could increase the chances of breast tumors spreading and becoming more invasive," said Longmore in a press release. "It doesn't explain why women with dense breasts get cancer in the first place. But once they do, the pathway that we describe is relevant in causing their cancers to be more aggressive and more likely to spread."
To keep SNAIL levels high, DDR2 must be constantly binding with collagen. If that signaling is blocked, the cell, while still cancerous, is no longer invasive, which means that a drug capable of inhibiting DDR2 from binding to collagen could reduce metastasis.
More studies need to be done on this protein, but it 's possible that DDR2 might control metastasis as a result of the alignment of collagen fibers. If the fibers are parallel to the tumor's surface, it is less likely to spread, but fibers that are perpendicular to the tumor encourage metastasis. Tumors that lack DDR2 or SNAIL1 evince that the parallel collagen fiber alignment is protective against the spread of tumors.
Longmore noted that DDR2's functions aren't well understood, and that up to this point, it has not been implicated in cancer. Given its reaction with collagen and its relationship with SNAIL1, however, DDR2 could represent an attractive new target, as the protein is found on the surface of the cells and the edge of tumors, said Longmore, a physician at Siteman Cancer Center at Washington University and Barnes-Jewish Hospital and co-director of the Section of Molecular Oncology.
"The collagen receptor is an unusual candidate for regulating tumor cell migration, and the extent to which it did so was also surprising," says Longmore. "Most receptors of this nature are activated by growth factors or cytokines, not by structural proteins. Moreover, the location where this receptor is activated makes perfect sense to explain where the SNAIL protein is stabilized in tumors."
And while many cancer subtypes are the result of genetic mutations, Longmore noted that while 70 percent of invasive ductal breast cancers present with DDR2, in 95 percent of those tumors, all the genes in the pathway have no mutations.
"If you did genomic sequencing, all of these particular genes would be normal," said Longmore. "You have to be careful not to just focus on mutations in cancer. This is an example of normal genes put together in an aberrant situation. The change in the environment — the tumor and its surroundings — causes the abnormal expression of these proteins. It is abnormal, but it's not caused by a gene mutation."
Longmore expects this discovery to result in new answers and benefits, noting that it will hopefully lead to "understanding how tumor cells alter the organization of collagen fibers to facilitate their exit from primary tumors and metastasize," and that DDR2 "could be an important new target for the development of therapeutics to treat or prevent metastatic breast cancer."
The researchers will be pursuing research into DDR2 in several directions, including its role in the metastasis of other cancers. Longmore says they have "an early interest in pancreatic cancer and head and neck cancers, including esophageal cancer, in particular." In addition, Longmore says they will also seek to understand more about DDR2, specifically how the receptor signals and how it is regulated, and whether it contributes to other tumors. They will work on developing drugs that can block DDR2's activity specifically, and explore the function of mutations in this protein found in sequencing studies of other tumors, such as those from lung or esophageal cancers.
While Longmore has noted that there are currently no inhibitors specific to DDR2, he added that work is underway at Washington University and elsewhere for their development.
"We are currently working to discover molecules that inhibit the binding of DDR2 to collagen," says Longmore. "Many of the existing receptor tyrosine kinase drugs (e.g., imatinib) already in the clinic will inhibit the kinase activity of DDR2 as well."