Consensus micro RNAs governing the switch of dormant tumors to the fast-growing angiogenic phenotype

PLoS One. 2012;7(8):e44001. doi: 10.1371/journal.pone.0044001. Epub 2012 Aug 31.

Abstract

Tumor dormancy refers to a critical stage in cancer development in which tumor cells remain occult for a prolonged period of time until they eventually progress and become clinically apparent. We previously showed that the switch of dormant tumors to fast-growth is angiogenesis dependent and requires a stable transcriptional reprogramming in tumor cells. Considering microRNAs (miRs) as master regulators of transcriptome, we sought to investigate their role in the control of tumor dormancy. We report here the identification of a consensus set of 19 miRs that govern the phenotypic switch of human dormant breast carcinoma, glioblastoma, osteosarcoma, and liposarcoma tumors to fast-growth. Loss of expression of dormancy-associated miRs (DmiRs, 16/19) was the prevailing regulation pattern correlating with the switch of dormant tumors to fast-growth. The expression pattern of two DmiRs (miR-580 and 190) was confirmed to correlate with disease stage in human glioma specimens. Reconstitution of a single DmiR (miR-580, 588 or 190) led to phenotypic reversal of fast-growing angiogenic tumors towards prolonged tumor dormancy. Of note, 60% of angiogenic glioblastoma and 100% of angiogenic osteosarcoma over-expressing miR190 remained dormant during the entire observation period of ∼ 120 days. Next, the ability of DmiRs to regulate angiogenesis and dormancy-associated genes was evaluated. Transcriptional reprogramming of tumors via DmiR-580, 588 or 190 over-expression resulted in downregulation of pro-angiogenic factors such as TIMP-3, bFGF and TGFalpha. In addition, a G-CSF independent downregulation of Bv8 was found as a common target of all three DmiRs and correlated with decreased tumor recruitment of bone marrow-derived CD11b+ Gr-1+ myeloid cells. In contrast, antiangiogenic and dormancy promoting pathways such as EphA5 and Angiomotin were upregulated in DmiR over-expressing tumors. This work suggests novel means to reverse the malignant tumor phenotype into an asymptomatic dormant state and may provide promising targets for early detection or prevention of cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biomarkers, Tumor / metabolism
  • CD11b Antigen / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Disease Progression
  • Down-Regulation
  • Gastrointestinal Hormones / metabolism
  • Humans
  • Male
  • Mice
  • MicroRNAs / genetics*
  • Myeloid Cells / metabolism
  • Myeloid Cells / pathology
  • Neoplasm Staging
  • Neoplasms / blood supply*
  • Neoplasms / genetics
  • Neoplasms / pathology*
  • Neovascularization, Pathologic*
  • Neuropeptides / metabolism
  • Phenotype*
  • Transcriptome*
  • Tumor Microenvironment / genetics

Substances

  • Biomarkers, Tumor
  • CD11b Antigen
  • Gastrointestinal Hormones
  • MicroRNAs
  • Neuropeptides
  • PROK2 protein, human

Grant support

This material is based upon work supported by the National Aeronautics and Space Administration Specialized Center of Research (NSCOR, grant no. NNJ06HA28G) issued through the Human Research Program. It was also supported in part by the German Krebshilfe (Deutsche Krebshilfe, Max-Eder 108876), German Research Foundation National Priority Research Program: the Tumor-Vessel Interface “SPP1190”, Intramural Grants of the National Center for Tumor diseases (Heidelberg, Germany) and the German Federal Ministry of Research and Technology (Bundesministerium für Bildung und Forschung – BMBF 03NUK004C). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.