HOUSTON—Some of the latest research from The University of Texas MD Anderson Cancer Center has turned up a family of microRNAs—miR-200—that can hamper cancer progression and metastasis by blocking tumor angiogenesis. The researchers found that miR-200 blocks the growth of new blood vessels by targeting interleukin-8 and CXCL1, two cytokines associated with the process of angiogenesis.
The team investigated the potential of miR-200 in mouse models of lung, ovarian, kidney and triple-negative breast cancers. They examined annotated cancer samples of the four cancer types from The Cancer Genome Atlas for expression of the five miR-200 family members, and discovered that while low expression of miR-200 generally linked to poor survival in the cases of lung, ovarian and renal cancers, it was linked to improved survival in breast cancer.
Lung, ovarian, kidney and triple-negative breast cancer were all found to have elevated expression of IL-8 and CXCL1 compared to hormone-positive breast cancers, and of the four cancer types the researchers investigated, all demonstrated that elevated IL-8 levels were associated with poor overall survival. Treating the cancer cells with miR-200, however, proved capable of decreasing levels of both cytokines, which were found to be direct miR-200 targets. Chad Pecot, M.D., first author of the study and a fellow in Cancer Medicine, noted that there was a strong correlation between circulating IL-8 levels in the blood and tumor burden, which may earmark it as a biomarker for miR-200 treatment.
When the researchers treated mice with members of the miR-200 family delivered via a fatty nanoparticle—which was developed by Anil Sood, M.D., professor of Gynecologic Oncology and senior author of the study, and Gabriel Lopez, M.D., professor of Experimental Therapeutics—the mice presented with significant reductions in the size of their lung cancer tumors, the volume and the density of small blood vessels. When the team treated mouse models of metastasis-prone lung and triple-negative breast cancer with miR-200 nanoliposomes, the models demonstrated a reduction in primary tumor volume as well as the number and size of metastases in other organs, with ovarian cancer models also displaying noticeable reductions in levels of IL-8 and angiogenesis.
Sood says that while there may be other cancer types beyond lung, ovarian, kidney and triple-negative breast cancers in which miR-200 would have therapeutic benefit, they haven’t tested any others biologically. Their focus, he explains, was to look for instances in which miR-200 and key angiogenesis factors are related. Sood notes that while “the in-vivo results were really quite robust in terms of the tumors that had a link with angiogenesis and miR-200,” tumor types without those kinds of relationships aren’t likely to see such significant therapeutic benefit.
The researchers also tested the efficacy of using a chitosan nanoparticle to deliver miR-200 directly to blood vessels and found that combination delivery of two types of miR-200 caused a 92-percent reduction in ovarian cancer metastases, with a second ovarian cancer line displaying decreased primary and metastatic tumors and blood vessel formation with no apparent toxicity issues.
Sood says they are in the process of moving some of their nanoparticle platforms toward clinical trials, though additional safety testing needs to be done as well. He says he would also like to investigate the effectiveness of this approach when combined with “conventional modalities such as chemotherapy or other conventional approaches.”
“Until we have clinical data, it’s difficult to know if we could achieve therapeutically relevant levels in a human context, but that’s certainly our goal,” says Sood. “And we do think this kind of approach holds promise in terms of being able to achieve levels within human tumors that would be relevant for therapy.”
The study, “Tumor angiogenesis regulation by the miR-200 family,” appeared in Nature Communications in September.
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