Ling Li1, Klaus Piontek1, Masaharu Ishida1,2, Michel Fausther3, Jonathan A Dranoff3, Rongdang Fu1, Esteban Mezey1, Stephen J Gould4, Francis K Fordjour4, Stephen J Meltzer1, Alphonse E Sirica5, Florin M Selaru1,6,7. 1. Division of Gastroenterology and Hepatology, School of Medicine, The Johns Hopkins University, Baltimore, MD. 2. Department of Surgery, Tohoku University, Sendai, Japan. 3. Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, AR. 4. Department of Biological Chemistry, The Johns Hopkins University School of Medicine, Baltimore, MD. 5. Division of Cellular and Molecular Pathogenesis, Department of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA. 6. Sidney Kimmel Cancer Center, The Johns Hopkins University, Baltimore, MD. 7. The Institute for Nanobiotechnology, The Johns Hopkins University, Baltimore, MD.
Abstract
The cancer microenvironment plays a central role in cancer development, growth, and homeostasis. This paradigm suggests that cancer fibroblasts support cancers, probably in response to stimuli received from the cancer cells. We aimed at investigating whether extracellular vesicles (EVs) can shuttle microRNA (miR) species between cancer-associated fibroblasts (CAFs) and cancer cells. To this end, we extracted EVs according to published protocols. EVs were studied for their miR content by quantitative reverse-transcription polymerase chain reaction. EVs were transfected with select miR species and utilized in vitro as well as in vivo in a rat model of cholangiocarcinoma (CCA). We found that miR-195 is down-regulated in CCA cells, as well as in adjoining fibroblasts. Furthermore, we report that EVs shuttle miR-195 from fibroblasts to cancer cells. Last, we show that fibroblast-derived EVs, loaded with miR-195, can be administered in a rat model of CCA, concentrate within the tumor, decrease the size of cancers, and improve survival of treated rats. CONCLUSION: EVs play a salient role in trafficking miR species between cancer cells and CAFs in human CCA. Understanding of these mechanisms may allow devising of novel therapeutics. (Hepatology 2017;65:501-514).
The cancer microenvironment plays a central role in cancer development, growth, and homeostasis. This paradigm suggests that cancer fibroblasts support cancers, probably in response to stimuli received from the cancer cells. We aimed at investigating whether extracellular vesicles (EVs) can shuttle microRNA (miR) species between cancer-associated fibroblasts (CAFs) and cancer cells. To this end, we extracted EVs according to published protocols. EVs were studied for their miR content by quantitative reverse-transcription polymerase chain reaction. EVs were transfected with select miR species and utilized in vitro as well as in vivo in a rat model of cholangiocarcinoma (CCA). We found that miR-195 is down-regulated in CCA cells, as well as in adjoining fibroblasts. Furthermore, we report that EVs shuttle miR-195 from fibroblasts to cancer cells. Last, we show that fibroblast-derived EVs, loaded with miR-195, can be administered in a rat model of CCA, concentrate within the tumor, decrease the size of cancers, and improve survival of treated rats. CONCLUSION: EVs play a salient role in trafficking miR species between cancer cells and CAFs in human CCA. Understanding of these mechanisms may allow devising of novel therapeutics. (Hepatology 2017;65:501-514).
Authors: S Saijyo; T Kudo; M Suzuki; Y Katayose; M Shinoda; T Muto; K Fukuhara; T Suzuki; S Matsuno Journal: Tohoku J Exp Med Date: 1995-09 Impact factor: 1.848
Authors: Alphonse E Sirica; Catherine I Dumur; Deanna J W Campbell; Jorge A Almenara; Olorunseun O Ogunwobi; Jennifer L Dewitt Journal: Clin Gastroenterol Hepatol Date: 2009-11 Impact factor: 11.382