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
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.
Mice treated with miR-200 family members delivered in a fatty nanoparticle developed by Sood and Gabriel Lopez, M.D., professor of Experimental Therapeutics, had steep reductions in lung cancer tumor volume, tumor size and the density of small blood vessels compared to controls. Results were repeated with kidney, ovarian and triple-negative breast cancers.
miR-200 nanoparticles stymie metastasis
In mouse models of lung and triple-negative breast cancers prone to spread to other organs, treatment with the miR-200 nanoliposomes significantly reduced the volume of the primary tumor and the number and size of metastases in other organs compared to controls. Similar results were observed in an ovarian cancer model, accompanied by sharp reductions in IL-8 levels and blood vessel formation.
Additional experiments showed that these therapeutic effects were due to blocking of IL-8 levels by miR-200. In tumors that had high amounts of synthetically produced IL-8 (designed so that miR-200 could not block it) the cancer burden was no longer reduced. Circulating IL-8 levels in the blood strongly correlated with tumor burden, Pecot said, suggesting it may serve as a possible biomarker for miR-200 treatment.Treatment of blood vessels cuts metastases by 92 percent
Targeting a second ovarian cancer line with the chitosan nanoparticles also developed by Sood and colleagues, resulted in decreased primary and metastatic tumor burden and reduced blood vessel formation with no apparent toxicity observed in treated mice.
Co-authors with Sood, Pecot and Lopez are Rajesha Rupaimoole, Ph.D., Cristina Ivan, Ph.D., Chunhua Lu, Sherry Wu, Hee-Dong Han, Justin Bottsford-Miller, M.D., Behrouz Zand, M.D., Myrthala Moreno-Smith, Ph.D., Lingegowda Mangala, Ph.D., Ph.D., Morgan Taylor, Ph.D., Healther Dalton, Ph.D.,Yunfei Wen, Ph.D., and Yu Kang, M.D., all of the Gynecologic Oncology; Da Yang, Ph.D., Yuexin Liu, Ph.D., and Wei Zhang, Ph.D., of Pathology; Rehan Akbani, Ph.D., Anna Unruh, and Keith Baggerly, Ph.D., of Bioinformatics and Computational Biology; Maitri Shah, Cristian Rodriguez-Villasana, Ph.D., Vianey Gonzalez-Villasana, Ph.D., and George Calin, M.D., Ph.D., of Experimental Therapeutics; Sang Bae Kim, Vasudha Sehgal, Ph.D., Ju-Seog Lee, Ph.D., Prahlad Ram, Ph.D., and Ana-Maria Gonzalez-Angulo, M.D., of Breast Medical Oncology; Murali Ravoori and Vikas Kundra, M.D., Ph.D., of Experimental Diagnostic Imaging; Li Huang and Xinna Zhang of Cancer Biology; Rouba Ali-Fehmi, M.D., of Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit; and Pierre Massion, M.D., of Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tenn.
Sood, Lopez, Xinna Zhang, Wei Zhang, Calin, Mangala and Ivan are also with MD Anderson's Center for RNA Interference and Non-Coding RNA. Sang Bae Kim and Anna Unruh are students in The University of Texas Graduate School of Biomedical Sciences, a joint operation of MD Anderson and The University of Texas Health Science Center at Houston.
This research was funded by grants from the National Cancer Institute of the National Institutes of Health (CA109298, P50 CA083639, P50 CA098258, CA128797, RC2GM092599, U54 CA151668 and
U24CA143835, CA009666, CA90949, CA143883, T32 CA101642, and U24CA143835); the Cancer Prevention and Research Institute of Texas, the Ovarian Cancer Research Fund, Inc., The U.S. Department of Defense, The Marcus Foundation, Inc., Laura Lee Blanton Ovarian Cancer Endowed Fund, the Vanderbilt SPORE in lung cancer ; the 2011 Conquer Cancer Foundation ASCO Young Investigator Award, MD Anderson's Division of Cancer Medicine Advanced Scholar Program, The Cancer Genome Atlas MD Anderson Data Analysis Center, an MD Anderson Odyssey Fellowship, Diane Denson Tobola Fellowship for Ovarian Cancer Research and the Harold C. and Mary L. Dailey Endowment Fellowships.
Scott Merville | EurekAlert!
Multi-institutional collaboration uncovers how molecular machines assemble
02.12.2016 | Salk Institute
Fertilized egg cells trigger and monitor loss of sperm’s epigenetic memory
02.12.2016 | IMBA - Institut für Molekulare Biotechnologie der Österreichischen Akademie der Wissenschaften GmbH
A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.
Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...
In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.
“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...
The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.
The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...
Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water
In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...
The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.
Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...
16.11.2016 | Event News
01.11.2016 | Event News
14.10.2016 | Event News
02.12.2016 | Medical Engineering
02.12.2016 | Agricultural and Forestry Science
02.12.2016 | Physics and Astronomy