An osteosarcoma zebrafish model implicates Mmp-19 and Ets-1 as well as reduced host immune response in angiogenesis and migration

J Pathol. 2012 Jun;227(2):245-53. doi: 10.1002/path.3998. Epub 2012 Mar 19.

Abstract

About 40% of osteosarcoma patients die of metastases. Novel strategies to improve treatment of metastatic patients require a better understanding of the processes involved, like angiogenesis, migration, and the immune response. However, the rarity of osteosarcoma and its heterogeneity make this neoplasm difficult to study. Recently we reported malignant transformation of mouse mesenchymal stem cells (MSCs) which formed osteosarcoma upon transplantation into mice. Here we studied these cells in zebrafish embryos and found that transformed MSCs induced angiogenesis and migrated through the bodies of the embryos, but this was never observed with non-transformed normal MSCs (progenitors of the transformed MSCs). Whole genome expression analysis of both the cells and the host showed that angiogenesis and migration-related genes matrix metalloproteinase 19 (Mmp-19) and erythroblastosis virus E26 oncogene homologue 1 (Ets-1) were overexpressed in transformed MSCs compared to normal MSCs. Investigating the host response, embryos injected with transformed MSCs showed decreased expression of immune response-related genes, especially major histocompatibility complex class 1 (mhc1ze), as compared to embryos injected with normal MSCs. These findings contribute to the identification of genetic events involved in angiogenesis, migration, and host response providing targets as well as an appropriate model for high-throughput drug screens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Bone Neoplasms / blood supply
  • Bone Neoplasms / enzymology*
  • Bone Neoplasms / genetics
  • Bone Neoplasms / immunology
  • Bone Neoplasms / pathology
  • Carbocyanines / metabolism
  • Cell Movement*
  • Cell Transformation, Neoplastic / immunology
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Cells, Cultured
  • Fluorescent Dyes / metabolism
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Luminescent Proteins / biosynthesis
  • Luminescent Proteins / genetics
  • Matrix Metalloproteinases, Secreted / genetics
  • Matrix Metalloproteinases, Secreted / metabolism*
  • Mesenchymal Stem Cell Transplantation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neoplasm Invasiveness
  • Neovascularization, Pathologic / enzymology*
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / immunology
  • Neovascularization, Pathologic / pathology
  • Oligonucleotide Array Sequence Analysis
  • Osteosarcoma / blood supply
  • Osteosarcoma / enzymology*
  • Osteosarcoma / genetics
  • Osteosarcoma / immunology
  • Osteosarcoma / secondary
  • Proto-Oncogene Protein c-ets-1 / genetics
  • Proto-Oncogene Protein c-ets-1 / metabolism*
  • Time Factors
  • Tumor Escape*
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism
  • Zebrafish* / embryology
  • Zebrafish* / genetics
  • Zebrafish* / metabolism

Substances

  • CM-DiI
  • Carbocyanines
  • Ets1 protein, mouse
  • Fluorescent Dyes
  • Luminescent Proteins
  • Proto-Oncogene Protein c-ets-1
  • Zebrafish Proteins
  • red fluorescent protein
  • Matrix Metalloproteinases, Secreted
  • matrix metalloproteinase 19