Tumor Microenvironment Impacts Cancer Subtype Progression

Scientists at Cold Spring Harbor Laboratory (CSHL) report that two different mouse models of breast cancer progressed differently based on characteristics of the tumor microenvironment, which is the area of tissue in which the tumor is embedded. The team published its study (“Presence of Insulin-Like Growth Factor Binding Proteins Correlates With Tumor-Promoting Effects of Matrix Metalloproteinase 9 in Breast Cancer”) in Neoplasia.

The tumor microenvironment includes cells and extracellular molecules that support the tumor’s growth. Mikala Egeblad, Ph.D., associate professor, and her team looked at two types of breast cancer driven by different mutations, and found different microenvironments. One common factor was the presence of extracellular protein matrix metalloproteinase 9 (MMP9). It was expressed at similar levels in tumors from both breast cancer mouse models.

MMP9 previously has been linked to the progression of many types of cancers. When the researchers deleted the Mmp9 gene, they found that the absence of the MMP9 protein delayed tumor onset only in one mouse model, and had no effect in the other model.

Dr. Egeblad and her team found that whether MMP9 promoted cancer or not depended on the tumor microenvironment. Specifically, on the presence of another molecule that MMP9 is known to act on, i.e., insulin-like growth factor binding protein 1 (IGFBP-1).

“MMP9 has different effects on breast cancer progression depending on whether IGFBPs are expressed,” wrote the investigators.

“If IGFBP-1 is not there, MMP9 didn’t really have an effect, but if it’s there, then MMP9 has a role,” says Dr. Egeblad. This suggests that IGFBP-1 interacts with MMP9 to promote tumor formation.

IGFBP-1 binds insulin-like growth factors (IGFs), which play a role in promoting cancer proliferation. “IGFBP-1 keeps the growth factors sequestered so they can’t act on the cancer cells and can’t make them proliferate,” continues Dr. Egeblad. “But if MMP9 is present, it degrades these IGFBPs and releases the growth factors.” The release of the IGFs then accelerates cancer progression.

Dr. Egeblad and her team looked in human cancer databases to see if the interaction between MMP9 and IGFBPs predicted breast cancer prognosis in humans. “We found that IGF-binding proteins are associated with a good prognosis, but if MMP9 is also present, there’s no longer good association with survival,” she explains.

The study’s results have implications for anti-cancer drugs that target MMPs, and may explain why previous clinical trials using MMP inhibitors have failed, according to Dr. Egeblad. “Maybe you can actually think about using these inhibitors if you better understand their biology.”

The new study suggests that trials of MMP inhibitors could focus on patients whose tumor microenvironment contains IGFBPs. More broadly, the research suggests that it may not be enough to see if a particular drug target is present in a certain type of cancer; researchers may also need to look for the presence of the molecules that the drug target acts upon. “It complicates things, but I think biologically it makes a lot of sense. You really need to dig deep and understand mechanistically what the target does,” says Dr. Egeblad.

The lab’s next goal is to look more generally at the differences in microenvironments in different types of cancer. “What we’re starting to learn now is that the microenvironments are different in different tumors, and that there is really a very intricate interplay between what’s driving the mutations in cancer cells and the type of microenvironment they build around themselves,” points out Dr. Egeblad.