Small Molecules Found to Play Complex Roles in Cancer Metastasis

Research indicates that a family of tiny molecules called microRNAs could potentially play a large role in the process of cancer metastasis, or the spread of cancer from one area of the body to another. A team of researchers from The Cancer Institute of New Jersey (CINJ) and Princeton University, along with European colleagues, have revealed that miR-200s play a paradoxical role in the development of metastatic cancer. On the one hand, these microRNAs slow down the initial escape of cells from the primary breast tumor into blood circulation, impeding the spread of cancer at that point in the process. However when tumor cells do escape and then seek to colonize new organs such as the lungs, the same miR-200s facilitate that process. The study is described in the online edition of Nature Medicine that is out today. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.

The miR-200 family of microRNAs, which are molecules essential for laying out the body plan of developing embryos, has previously been shown to play a role in hindering metastasis in its early stages. Their surprising ability to promote metastasis in the later stages of the process by altering the social communication between the tumor cells and host tissues is identified for the first time in the current research.

Most cancers arise from epithelial tissue, a class of tissue which lines the surface of most organs. High levels of the molecule E-cadherin in epithelial cells provide the intercellular adhesion required to maintain the structure and function of these tissues. However, in the first step of metastasis, tumor cells reduce E-cadherin levels, compromising their ability to physically interact with neighboring epithelial tumor cells. That process allows them to spread from the main tumor as part of a process called epithelial-mesenchymal transition (EMT). EMT typically occurs during normal embryonic development as a means to provide the plan for an embryo''s developing body. In normal adult tissue, EMT only occurs in rare instances, such as during wound healing. In the case of cancer metastasis, tumor cells adopt this unusual feature of embryonic cells and use it to spread to distant vital organs. In this study, investigators have discovered the complex role miR-200s play in regulating EMT as it relates to metastasis.

CINJ member Yibin Kang, PhD, an associate professor of molecular biology at Princeton University, is the senior author of the study. Previous research from his lab and others showed that miR-200s enforce the production of E-cadherin, thereby blocking the process of EMT and tumor cell migration. Because of this, miR-200s have been considered to be potential therapeutic agents to reduce metastasis. However, given the potential harm caused by miR-200s when tumor cells attack secondary organs, Dr. Kang and colleagues now have reason to believe that such agents may actually increase metastasis in certain situations.

Using experimental models of breast cancer metastasis, investigators found that miR-200s were over-produced in highly metastatic cells. They also found that human breast cancers with elevated levels of miR-200s have a significantly higher risk of metastatic relapse. Looking more closely at lung metastasis samples, the team found elevated levels of miR-200s compared to those in primary breast tumors of the same patients.

"Once escaped tumor cells reach a distant organ, miR-200s allow them to regain their original adhesive trait. By reestablishing a tight cell-to-cell connection, tumor cells then have the ability to facilitate the survival and growth of secondary tumors," noted Kang, who is a member of CINJ''s Genomic Instability and Tumor Progression Program. "In essence, the flexibility to freely transition between the epithelial and mesenchymal (middle layer) states allows tumor cells to cope with different challenges they face during the multi-step process of metastasis."

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In addition to this finding, the team also discovered that miR-200s block a protein transport pathway that compromises the ability of tumor cells to secrete proteins such as IGFBP4 and TINAGL1 which can suppress metastasis. The study therefore provides evidence supporting the new concept that the influence of EMT on tumor metastasis is beyond the intrinsic control of tumor cell behaviors such as mobility, but additionally involves the alteration of the tumor cells'' communication with their neighbors.

"On the one hand, miR-200s hinder early steps of migration and invasion, and on the other, they promote late steps of metastatic colonization. Because of this dichotomous nature, therapeutic targeting of miR-200 must consider these opposing effects in order to reduce unexpected risk to patients," noted Manav Korpal, the lead author of the study who recently graduated from the PhD program in molecular biology at Princeton. "It is conceivable instead that the metastasis suppressive proteins IGFBP4 or TINAGL1 can be utilized as therapeutic proteins to prevent or reduce the spread of disease without the risk of increasing migration and invasion of primary tumors."

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The study has been recognized as a paradigm-shifting discovery in the field of metastasis research. Dr. Erik Thompson, Professor of Surgery at the St. Vincent''s Institute and University of Melbourne and President of the International Metastasis Research Society, wrote in an accompanying commentary in Nature Medicine that "this work takes several anomalies in our current understanding of EMT, builds a clinical context around them and provides a new paradigm that the miR-200 status in the original primary tumor, in a manner which exceeds E-cadherin expression and EMT status, predisposes the cancer to successful metastasis."

Even though miR-200s and the suppression of the protein transport pathway may represent new therapeutic opportunities for metastatic cancer, the authors note that their dual functions "warrant careful assessment of potential therapeutic benefits and adverse side effects when treatments are applied at different stages of disease."

Along with Kang and Korpal, the author team consists of Brian J. Ell, Princeton University; Francesca M. Buffa, University of Oxford; Toni Ibrahim, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori; Mario A. Blanco, Princeton University; Toni Celia-Terrassa, Princeton University and Institut de Biologia Molecular de Barcelona; Laura Mercatali, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori; Zia Khan, Princeton University; Hani Goodarzi, Princeton University; Yuling Hua, Princeton University; Yong Wei, Princeton University; Guohong Hu, Princeton University; Benjamin A. Garcia, Princeton University; Jiannis Ragoussis, University of Oxford; Dino Amadori, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori; and Adrian L. Harris, University of Oxford.

The research was supported by grants from the National Institutes of Health (1R01-CA141062), The Department of Defense, the Champalimaud Foundation, the Brewster Foundation, Cancer Research U.K., Oxford NHS Biomedical Research Centre and Friends of Kennington Cancer Fund.

About The Cancer Institute of New Jersey
The Cancer Institute of New Jersey (www.cinj.org) is the state''s first and only National Cancer Institute-designated Comprehensive Cancer Center dedicated to improving the detection, treatment and care of patients with cancer, and serving as an education resource for cancer prevention. CINJ''s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. To make a tax-deductible gift to support CINJ, call 732-235-8614 or visit www.cinjfoundation.org. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School. Follow us on Facebook at www.facebook.com/TheCINJ.

The CINJ Network is comprised of hospitals throughout the state and provides the highest quality cancer care and rapid dissemination of important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. System Partner: Meridian Health (Jersey Shore University Medical Center, Ocean Medical Center, Riverview Medical Center, Southern Ocean Medical Center, and Bayshore Community Hospital). Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Medical Center, Carol G. Simon Cancer Center at Overlook Medical Center, and Cooper University Hospital. Affiliate Hospitals: CentraState Healthcare System, JFK Medical Center, Mountainside Hospital, Robert Wood Johnson University Hospital Hamilton (CINJ Hamilton), Somerset Medical Center, The University Hospital/UMDNJ-New Jersey Medical School*, and University Medical Center at Princeton. *Academic Affiliate



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