Cholangiocarcinoma Stem-like Subset Shapes Tumor-initiating Niche by Educating Associated Macrophages
| العنوان: | Cholangiocarcinoma Stem-like Subset Shapes Tumor-initiating Niche by Educating Associated Macrophages |
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| المؤلفون: | Jesper B. Andersen, Cédric Coulouarn, Massimo Roncalli, Elisa Forti, Annarita Destro, Margherita Correnti, Chiara Raggi, Luca Di Tommaso, Giovanna Chiorino, Jesus M. Banales, Francesca Sozio, Vincenzo Cardinale, Domenico Alvaro, Antonio Sica, Guido Torzilli, Shannon Glaser, Gianfranco Alpini, Luis Bujanda, Pietro Invernizzi |
| المساهمون: | Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Cancer Genomics Laboratory, Fondazione 'Edo ed Elvo Tempia Valenta', Texas AandM Health Science Center, Hospital Donostia. CIBERehd, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), The study was supported partly by the Italian Foundation of Cancer Research award (MFGA17588) to Dr. Raggi, partly by the Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Scott & White, a VA Research Career Scientist Award, VA Merit award (5I01BX000574) to Dr. Alpini and a VA Merit award (5I01BX002192) to Dr. Glaser. Dr. Raggi was supported by U. Veronesi Foundation Post-Doctoral fellowship., University of Copenhagen = Københavns Universitet (KU), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Raggi, C, Correnti, M, Sica, A, Andersen, J, Cardinale, V, Alvaro, D, Chiorino, G, Forti, E, Glaser, S, Alpini, G, Destro, A, Sozio, F, Di Tommaso, L, Roncalli, M, Banales, J, Coulouarn, C, Bujanda, L, Torzilli, G, Invernizzi, P |
| المصدر: | Web of Science Journal of Hepatology Journal of Hepatology, 2017, 66 (1), pp.102-115. ⟨10.1016/j.jhep.2016.08.012⟩ Publons Journal of Hepatology, Elsevier, 2017, 66 (1), pp.102-115. ⟨10.1016/j.jhep.2016.08.012⟩ |
| مصطلحات موضوعية: | 0301 basic medicine, Stromal cell, Carcinogenesis, CD14, information science, [SDV.CAN]Life Sciences [q-bio]/Cancer, Tumor initiation, Biology, medicine.disease_cause, Article, Cholangiocarcinoma, 03 medical and health sciences, Mice, Tumor-associated macrophage, Cancer stem cell, Antigens, CD, parasitic diseases, medicine, Animals, Humans, cardiovascular diseases, Innate immune system, Membrane Glycoproteins, Hepatology, Cluster of differentiation, Cancer stem cells, Tumor-associated macrophages, Interleukins, Macrophages, fungi, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Embryonic stem cell, 3. Good health, 030104 developmental biology, Bile Duct Neoplasms, Immunology, Cancer research, cardiovascular system, Carcinogens, Neoplastic Stem Cells |
| الوصف: | Background & Aims A therapeutically challenging subset of cells, termed cancer stem cells (CSCs) are responsible for cholangiocarcinoma (CCA) clinical severity. Presence of tumor-associated macrophages (TAMs) has prognostic significance in CCA and other malignancies. Thus, we hypothesized that CSCs may actively shape their tumor-supportive immune niche. Methods CCA cells were cultured in 3D conditions to generate spheres. CCA sphere analysis of in vivo tumorigenic-engraftment in immune-deficient mice and molecular characterization was performed. The in vitro and in vivo effect of CCA spheres on macrophage precursors was tested after culturing healthy donor cluster of differentiation (CD)14 + with CCA-sphere conditioned medium. Results CCA spheres engrafted in 100% of transplanted mice and revealed a significant 20.3-fold increase in tumor-initiating fraction ( p =0.0011) and a sustained tumorigenic potential through diverse xenograft-generations. Moreover, CCA spheres were highly enriched for CSC, liver cancer and embryonic stem cell markers both at gene and protein levels. Next, fluorescence-activated cell sorting analysis showed that in the presence of CCA sphere conditioned medium, CD14 + macrophages expressed key markers (CD68, CD115, human leukocyte antigen-D related, CD206) indicating that CCA sphere conditioned medium was a strong macrophage-activator. Gene expression profile of CCA sphere activated macrophages revealed unique molecular TAM-like features confirmed by high invasion capacity. Also, freshly isolated macrophages from CCA resections recapitulated a similar molecular phenotype of in vitro -educated macrophages. Consistent with invasive features, the largest CD163 + set was found in the tumor front of human CCA specimens (n=23) and correlated with a high level of serum cancer antigen 19.9 (n=17). Among mediators released by CCA spheres, only interleukin (IL)13, IL34 and osteoactivin were detected and further confirmed in CCA patient sera (n=12). Surprisingly, a significant association of IL13, IL34 and osteoactivin with sphere stem-like genes was provided by a CCA database (n=104). In vitro combination of IL13, IL34, osteoactivin was responsible for macrophage-differentiation and invasion, as well as for in vivo tumor-promoting effect. Conclusion CCA-CSCs molded a specific subset of stem-like associated macrophages thus providing a rationale for a synergistic therapeutic strategy for CCA-disease. Lay summary Immune plasticity represents an important hallmark of tumor outcome. Since cancer stem cells are able to manipulate stromal cells to their needs, a better definition of the key dysregulated immune subtypes responsible for cooperating in supporting tumor initiation may facilitate the development of new therapeutic approaches. Considering that human cholangiocarcinoma represents a clinical emergency, it is essential to move to predictive models in order to understand the adaptive process of macrophage component (imprinting, polarization and maintenance) engaged by tumor stem-like compartment. |
| تدمد: | 0168-8278 1600-0641 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0e6380039cd611f6d060188c9c51ebb5 https://publons.com/wos-op/publon/27014994/ |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0e6380039cd611f6d060188c9c51ebb5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 01688278 16000641 |
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