In a breakthrough with important implications for the future of immunotherapy for breast cancer, UC San Francisco scientists have found that blocking the activity of a single enzyme can prevent a common type of breast cancer from spreading to distant organs.
While studying a mouse model that replicates key features of early-stage human breast cancer, the researchers discovered that a ubiquitous enzyme called MMP9 is an essential component of the cancer's metastasis-promoting machinery, helping to create a hospitable environment for itinerant cancer cells to form new metastatic tumors.
New findings might help make metastatic breast cancers susceptible to immunotherapy.
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"Metastasis is the biggest hurdle when it comes to successfully treating breast cancer, and solid tumors in general," said Vicki Plaks, PhD, now an assistant adjunct professor in the Department of Orofacial Sciences at UCSF. "Once a cancer becomes metastatic, there's really no cure, and the only option is to manage it as a chronic disease." Plaks co-led the team that made the discovery when still a postdoctoral fellow in the laboratory of Zena Werb, PhD, a professor of anatomy and associate director for basic science at the UCSF Helen Diller Family Comprehensive Cancer Center.
When they examined lung tissue in their mouse model, the researchers found that MMP9 is involved in remodeling healthy tissue and transforming it into a kind of safe haven for migrating breast cancer cells. When the cancer cells colonize these sites with the help of MMP9, they're able to start growing into new tumors.
The new study, published Nov. 14 in the journal Life Science Alliance, shows that these metastases can be stopped before they are able to lay the foundations for tumor growth. By administering an antibody that specifically targets and disrupts MMP9 activity, the scientists were able to prevent cancer from colonizing the lungs of mice. But interestingly, interfering with MMP9 had no effect on the primary tumor, which suggests that the enzyme's primary role in this scenario is helping existing malignancies metastasize and colonize other organs rather than promoting the growth of established primary tumors.
To further investigate MMP9's role in metastasis, the researchers turned to a unique mouse model of "luminal B" breast cancer, which is among the most frequently diagnosed forms of the disease. "We selected the model because it's one of the few that captures the natural progression of breast cancer, closely mimicking the progression of the disease experienced by patients," Owyong said.
In a key set of experiments, the researchers injected tumor cells into mice that had early stage breast cancer but no discernible metastases. They found that the cells colonized the lungs and formed new tumor growth sites. But when these cells were injected into genetically identical mice without breast cancer, no metastases formed.
When the experiment was repeated in mice with early stage breast cancer whose MMP9 gene had been knocked out, there was a significant reduction in the size of metastatic lung tumors, though there was no effect on the primary breast tissue tumor. These findings suggest that MMP9 is required to promote metastasis, but not essential for continued growth of the primary tumor.
Similar results were seen when the researchers disrupted the activity of MMP9 with a unique antibody that specifically targets the activated form of the enzyme. The researchers injected tumor cells into these mice, followed by injections of the antibody every two days. At the end of the treatment regimen, the researchers inspected the mice and saw a significant reduction in the number and size of lung metastases in mice who received the antibody compared with those that didn't.
The researchers also discovered that interfering with MMP9 activity helped recruit and activate cancer-fighting immune cells to metastatic sites, a result with important implications for treating certain types of metastatic breast cancer with immunotherapy.
"These findings come at an exciting time in cancer immunology, with antibodies targeting MMP9 being actively explored for clinical use within the biotech industry," Plaks said.
MEDICA-tradefair.com; Source: University of California - San Francisco