Proteolysis-a characteristic of tumor-initiating cells in murine metastatic breast cancer

Autor: Jochen Hochrein, Larissa E. Hillebrand, Julia Bender, Melanie Boerries, Thomas Reinheckel, Jan Hülsdünker, Marie Follo, Hauke Busch, Fee Bengsch
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Pathology
Carcinogenesis
Cell Culture Techniques
Cell Separation
Mice
0302 clinical medicine
Neoplasm Metastasis
education.field_of_study
Proteolytic enzymes
Flow Cytometry
Metastatic breast cancer
Cell Transformation
Neoplastic
Oncology
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Female
Research Paper
Signal Transduction
medicine.medical_specialty
proteolysis
matrix metalloproteinase
Population
Mammary Neoplasms
Animal
Mice
Transgenic
03 medical and health sciences
Breast cancer
breast cancer
mental disorders
medicine
Matrix Metalloproteinase 14
Animals
CD90
degradome
education
Cell Proliferation
business.industry
Sequence Analysis
RNA
Cancer
CD24 Antigen
medicine.disease
Molecular medicine
030104 developmental biology
Gene Expression Regulation
Cancer cell
Cancer research
Leukocyte Common Antigens
Thy-1 Antigens
business
Transcriptome
Peptide Hydrolases
Zdroj: Oncotarget
ISSN: 1949-2553
Popis: // Larissa E. Hillebrand 1, 2, 3 , Fee Bengsch 1 , Jochen Hochrein 1, 4, 5 , Jan Hulsdunker 1 , Julia Bender 1 , Marie Follo 6 , Hauke Busch 1, 4, 5, 7 , Melanie Boerries 1, 4, 5, 7 , Thomas Reinheckel 1, 3, 5, 7 1 Institute of Molecular Medicine and Cell Research, Medical Faculty, Albert-Ludwigs-University Freiburg, Freiburg, Germany 2 Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany 3 BIOSS Centre for Biological Signalling Studies, Freiburg, Germany 4 Systems Biology of the Cellular Microenvironment Group, Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany 5 Comprehensive Cancer Center Freiburg, Freiburg, Germany 6 Department of Hematology/Oncology, Core Facility, University Medical Center, Freiburg, Germany 7 German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany Correspondence to: Thomas Reinheckel, email: thomas.reinheckel@uniklinik-freiburg.de Keywords: breast cancer, degradome, matrix metalloproteinase, proteolysis Received: February 18, 2016 Accepted: July 27, 2016 Published: August 16, 2016 ABSTRACT Tumor initiating cells (TICs) have been identified and functionally characterized in hematological malignancies as well as in solid tumors such as breast cancer. In addition to their high tumor-initiating potential, TICs are founder cells for metastasis formation and are involved in chemotherapy resistance. In this study we explored molecular pathways which enable this tumor initiating potential for a cancer cell subset of the transgenic MMTV-PyMT mouse model for metastasizing breast cancer. The cell population, characterized by the marker profile CD24 + CD90 + CD45 − , showed a high tumorigenicity compared to non-CD24 + CD90 + CD45 − cancer cells in colony formation assays, as well as upon orthotopic transplantation into the mammary fat pad of mice. In addition, these orthotopically grown CD24 + CD90 + CD45 − TICs metastasized to the lungs. The transcriptome of TICs freshly isolated from primary tumors by cell sorting was compared with that of sorted non-CD24 + CD90 + CD45 − cancer cells by RNA-seq. In addition to more established TIC signatures, such as epithelial-to-mesenchymal transition or mitogen signaling, an upregulated gene set comprising several classes of proteolytic enzymes was uncovered in the TICs. Accordingly, TICs showed high intra- and extracellular proteolytic activity. Application of a broad range of protease inhibitors to TICs in a colony formation assay reduced anchorage independent growth and had an impact on colony morphology in 3D cell culture assays. We conclude that CD24 + CD90 + CD45 - cells of the MMTV- PyMT mouse model possess an upregulated proteolytic signature which could very well represent a functional hallmark of metastatic TICs from mammary carcinomas.
Databáze: OpenAIRE
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