A family of microRNAs (miR-200) blocks cancer progression and metastasis by stifling a tumor's ability to weave new blood vessels to support itself, researchers at The University of Texas MD Anderson Cancer Center report today in Nature Communications.
Patients with lung, ovarian, kidney or triple-negative breast cancers live longer if they have high levels of miR-200 expression, the researchers found.
Subsequent experiments showed for the first time that miR-200 hinders new blood vessel development, or angiogenesis, and does so by targeting cytokines interleukin-8 (IL-8) and CXCL1.
"Nanoparticle delivery of miR-200 blocked new blood vessel development, reduced cancer burden and inhibited metastasis in mouse models of all four cancers," said Anil Sood, M.D., professor of Gynecologic Oncology, senior author of the study.
The team's findings highlight the therapeutic potential of nanoparticle-delivered miR-200 and of IL-8 as a possible biomarker for identifying patients who might benefit from treatment. Sood said safety studies will need to be completed before clinical development can begin.
Micro RNAs do not code for genes like their cousins, the messenger RNAs. They regulate gene activation and expression.
"We initially looked at miR-200 because we have an approach for targeting and delivering these molecules with nanoparticles and miR-200 is known to inhibit EMT, a cellular transition associated with cancer progression and metastasis," said Sood, who also holds the Bettyann Asche Murray Distinguished Professorship in Ovarian Cancer Research.
First author Chad Pecot, M.D., a fellow in Cancer Medicine, said initial research provided a new perspective. "Cautionary tales emerged from the literature about poor outcomes in hormone-positive breast cancer, so we decided to delve more deeply into understanding the mechanisms involved."
miR-200 effect differs by breast cancer type
Sood and colleagues analyzed hundreds of annotated ovarian, renal, breast and non-small cell lung cancer samples from The Cancer Genome Atlas for expression of all five miR-200 family members. Low expression of miR-200 was associated with poor survival in lung, ovarian and renal cancers, but improved survival for breast cancer.
However, they found a striking difference when they analyzed breast cancers by those that are hormone-receptor positive (luminal) and those that lack hormone receptors or the HER2 protein, called triple-negative breast cancer. High expression for miR-200 was associated with improved survival for triple-negative disease, which is more difficult to treat due to its lack of therapeutic targets.
Gene expression analysis of ovarian and lung cancer cell lines pointed to an angiogenesis network involving both IL-8 and CXCL1. By mining public miRNA and messenger RNA databases, the researchers found:
An inverse relationship between expression of four of the five members of the miR-200 family and IL-8.
Lung, ovarian, kidney and triple-negative breast cancer all have elevated IL-8 and CXCL1 expression compared to hormone-positive breast cancers.
Elevated IL-8 associated with poor overall survival in lung, ovarian, renal and triple-negative breast cancer cases.
Treating cancer cell lines with miR-200 decreased levels of IL-8 and CXCL1, and the team also identified binding sites for these genes, meaning they are direct miR-200 targets.