Stromal fibroblasts induce metastatic tumor cell clusters via epithelial–mesenchymal plasticity
| Autor: | Yoshihiro Mezawa, Satoru Shimizu, Yuko Matsumura, Takumi Itoh, Akira Orimo, Masayuki Ozawa, Atsushi Takano, Michiaki Hamada, Yasuhiko Ito, Kaidiliayi Sulidan, Masaaki Abe, Okio Hino, Nadila Wali, Kazuyoshi Takeda, Kaoru Mogushi, Harumi Saeki, Satoru Takeda, Yohei Miyagi, Yataro Daigo, Hiromu Suzuki, Ko Okumura, Yasuhisa Terao, Tomoyuki Yokose, Sonoko Habu, Toru Hiraga |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Epithelial-Mesenchymal Transition Lung Neoplasms Stromal cell Health Toxicology and Mutagenesis Cell Plasticity Cell Breast Neoplasms Plant Science GPI-Linked Proteins Biochemistry Genetics and Molecular Biology (miscellaneous) Metastasis Mice 03 medical and health sciences 0302 clinical medicine Antigens CD medicine Animals Humans Neoplasm Invasiveness Epithelial–mesenchymal transition Research Articles Cells Cultured Ecology Cell adhesion molecule Chemistry Mesenchymal stem cell Zinc Finger E-box-Binding Homeobox 1 Fibroblasts Cadherins medicine.disease Carcinoembryonic Antigen 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis Cancer cell MCF-7 Cells Cancer research Female Cell Adhesion Molecules Neoplasm Transplantation Research Article |
| Zdroj: | Life Science Alliance |
| ISSN: | 2575-1077 |
| Popis: | This study highlights the cellular and molecular mechanisms by which stromal fibroblasts enable human breast cancer cells to form tumor cell clusters and acquire highly invasive and metastatic traits. Emerging evidence supports the hypothesis that multicellular tumor clusters invade and seed metastasis. However, whether tumor-associated stroma induces epithelial–mesenchymal plasticity in tumor cell clusters, to promote invasion and metastasis, remains unknown. We demonstrate herein that carcinoma-associated fibroblasts (CAFs) frequently present in tumor stroma drive the formation of tumor cell clusters composed of two distinct cancer cell populations, one in a highly epithelial (E-cadherinhiZEB1lo/neg: Ehi) state and another in a hybrid epithelial/mesenchymal (E-cadherinloZEB1hi: E/M) state. The Ehi cells highly express oncogenic cell–cell adhesion molecules, such as carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 that associate with E-cadherin, resulting in increased tumor cell cluster formation and metastatic seeding. The E/M cells also retain associations with Ehi cells, which follow the E/M cells leading to collective invasion. CAF-produced stromal cell-derived factor 1 and transforming growth factor-β confer the Ehi and E/M states as well as invasive and metastatic traits via Src activation in apposed human breast tumor cells. Taken together, these findings indicate that invasive and metastatic tumor cell clusters are induced by CAFs via epithelial–mesenchymal plasticity. |
| Databáze: | OpenAIRE |
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