Glioblastoma: a pathogenic crosstalk between tumor cells and pericytes

PLoS One. 2014 Jul 17;9(7):e101402. doi: 10.1371/journal.pone.0101402. eCollection 2014.

Abstract

Cancers likely originate in progenitor zones containing stem cells and perivascular stromal cells. Much evidence suggests stromal cells play a central role in tumor initiation and progression. Brain perivascular cells (pericytes) are contractile and function normally to regulate vessel tone and morphology, have stem cell properties, are interconvertible with macrophages and are involved in new vessel formation during angiogenesis. Nevertheless, how pericytes contribute to brain tumor infiltration is not known. In this study we have investigated the underlying mechanism by which the most lethal brain cancer, Glioblastoma Multiforme (GBM) interacts with pre-existing blood vessels (co-option) to promote tumor initiation and progression. Here, using mouse xenografts and laminin-coated silicone substrates, we show that GBM malignancy proceeds via specific and previously unknown interactions of tumor cells with brain pericytes. Two-photon and confocal live imaging revealed that GBM cells employ novel, Cdc42-dependent and actin-based cytoplasmic extensions, that we call flectopodia, to modify the normal contractile activity of pericytes. This results in the co-option of modified pre-existing blood vessels that support the expansion of the tumor margin. Furthermore, our data provide evidence for GBM cell/pericyte fusion-hybrids, some of which are located on abnormally constricted vessels ahead of the tumor and linked to tumor-promoting hypoxia. Remarkably, inhibiting Cdc42 function impairs vessel co-option and converts pericytes to a phagocytic/macrophage-like phenotype, thus favoring an innate immune response against the tumor. Our work, therefore, identifies for the first time a key GBM contact-dependent interaction that switches pericyte function from tumor-suppressor to tumor-promoter, indicating that GBM may harbor the seeds of its own destruction. These data support the development of therapeutic strategies directed against co-option (preventing incorporation and modification of pre-existing blood vessels), possibly in combination with anti-angiogenesis (blocking new vessel formation), which could lead to improved vascular targeting not only in Glioblastoma but also for other cancers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / blood supply*
  • Brain / cytology
  • Brain / pathology
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / pathology*
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Surface Extensions / pathology
  • Glioblastoma / blood supply
  • Glioblastoma / pathology*
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism
  • Mice
  • Mice, Nude
  • Mice, Transgenic
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / pathology
  • Neovascularization, Pathologic / pathology
  • Pericytes / pathology*
  • RNA Interference
  • RNA, Small Interfering
  • Transplantation, Heterologous
  • cdc42 GTP-Binding Protein / genetics*
  • cdc42 GTP-Binding Protein / metabolism

Substances

  • CD44 protein, human
  • Hyaluronan Receptors
  • RNA, Small Interfering
  • cdc42 GTP-Binding Protein

Grants and funding

This work was funded by Spanish Ministry of Science and Innovation: FEDER (BFU-2010-27326) and Consolider (CSD2007-00023); Health Institute Carlos III: Red TERCEL (RD12/0019/0024); P.H.C was also supported by Marie Curie Intra-European Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.