Pericyte-secreted IGF2 promotes breast cancer brain metastasis formation

Kinga Molnár, Ádám Mészáros, Csilla Fazakas, Mihály Kozma, Fanni Győri, Zita Reisz, László Tiszlavicz, Attila E. Farkas, Ádám Nyúl-Tóth, János Haskó, István A. Krizbai, Imola Wilhelm

Research output: Contribution to journalArticle

Abstract

Brain metastases are life-threatening complications of triple-negative breast cancer, melanoma, and a few other tumor types. Poor outcome of cerebral secondary tumors largely depends on the microenvironment formed by cells of the neurovascular unit, among which pericytes are the least characterized. By using in vivo and in vitro techniques and human samples, here we show that pericytes play crucial role in the development of metastatic brain tumors by directly influencing key steps of the development of the disease. Brain pericytes had a prompt chemoattractant effect on breast cancer cells and established direct contacts with them. By secreting high amounts of extracellular matrix proteins, pericytes enhanced adhesion of both melanoma and triple-negative cancer cells, which might be particularly important in the exclusive perivascular growth of these tumor cells. In addition, pericytes secreted insulin-like growth factor 2 (IGF2), which had a very significant pro-proliferative effect on mammary carcinoma, but not on melanoma cells. By inhibiting IGF2 signaling using silencing or picropodophyllin (PPP), we could block the proliferation-increasing effect of pericytes on breast cancer cells. Administration of PPP (a blood–brain barrier-permeable substance) significantly decreased the size of brain tumors in mice inoculated with triple-negative breast cancer cells. Taken together, our results indicate that brain pericytes have significant pro-metastatic features, especially in breast cancer. Our study underlines the importance of targeting pericytes and the IGF axis as potential strategies in brain metastatic diseases.

Original languageEnglish
Pages (from-to)2040-2057
Number of pages18
JournalMolecular Oncology
Volume14
Issue number9
DOIs
Publication statusPublished - Sep 1 2020

Keywords

  • brain metastasis
  • cerebral pericyte
  • insulin-like growth factor 2
  • picropodophyllin
  • triple-negative breast cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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  • Cite this

    Molnár, K., Mészáros, Á., Fazakas, C., Kozma, M., Győri, F., Reisz, Z., Tiszlavicz, L., Farkas, A. E., Nyúl-Tóth, Á., Haskó, J., Krizbai, I. A., & Wilhelm, I. (2020). Pericyte-secreted IGF2 promotes breast cancer brain metastasis formation. Molecular Oncology, 14(9), 2040-2057. https://doi.org/10.1002/1878-0261.12752