Crosstalk between glial and glioblastoma cells triggers the “go-or-grow” phenotype of tumor cells

Abstract

BackgroundGlioblastoma (GBM), the most malignant primary brain tumor, leads to poor and unpredictable clinical outcomes. Recent studies showed the tumor microenvironment has a critical role in regulating tumor growth by establishing a complex network of interactions with tumor cells. In this context, we investigated how GBM cells modulate resident glial cells, particularly their paracrine activity, and how this modulation can influence back on the malignant phenotype of GBM cells.MethodsConditioned media (CM) of primary mouse glial cultures unexposed (unprimed) or exposed (primed) to the secretome of GL261 GBM cells were analyzed by proteomic analysis. Additionally, these CM were used in GBM cells to evaluate their impact in glioma cell viability, migration capacity and activation of tumor-related intracellular pathways.ResultsThe proteomic analysis revealed that the pre-exposure of glial cells to CM from GBM cells led to the upregulation of several proteins related to inflammatory response, cell adhesion and extracellular structure organization within the secretome of primed glial cells. At the functional levels, CM derived from unprimed glial cells favored an increase in GBM cell migration capacity, while CM from primed glial cells promoted cells viability. These effects on GBM cells were accompanied by activation of particular intracellular cancer-related pathways, mainly the MAPK/ERK pathway, which is a known regulator of cell proliferation.ConclusionsTogether, our results suggest that glial cells can impact on the pathophysiology of GBM tumors, and that the secretome of GBM cells is able to modulate the secretome of neighboring glial cells, in a way that regulates the “go-or-grow” phenotypic switch of GBM cells.Electronic supplementary materialThe online version of this article (10.1186/s12964-017-0194-x) contains supplementary material, which is available to authorized users.

Alterations in Cell Motility, Proliferation, and Metabolism in Novel Models of Acquired Temozolomide Resistant Glioblastoma

“…These divergent alterations in basal growth rate and migratory capacity provide two unique models – one adapting the “go” (8MGBA-TMZres) and the other the “grow” (42MBGA-TMZres) strategy of TMZ resistance 13 . There have been many hypotheses as to what determines the switch between “go or grow”, including mutational status, hypoxia, and influences of the surrounding cell secretome 13 , 32 , 33 . Activation of the FAK and MAPK/ERK pathways have been shown to be differentially regulated between a “go” and “grow” phenotype 32 , 33 , respectively.…”

“…There have been many hypotheses as to what determines the switch between “go or grow”, including mutational status, hypoxia, and influences of the surrounding cell secretome 13 , 32 , 33 . Activation of the FAK and MAPK/ERK pathways have been shown to be differentially regulated between a “go” and “grow” phenotype 32 , 33 , respectively. Others have also hypothesized that remaining cells from the “go” population lead to recurrence of GBM 13 .…”

“…While there are always potential limitations to studying metabolism in an in vitro setting, Oliveira et al . showed that the in vitro secretome can affect the “go or grow” phenotype of murine GBM cells 32 . Therefore is it important to identify potential in vitro mechanisms that can be further extrapolated to in vivo models in the future.…”

Oncogenic MSH6-CXCR4-TGFB1 Feedback Loop: A Novel Therapeutic Target of Photothermal Therapy in Glioblastoma Multiforme

“…On the basis of the above results, we propose a triangular relationship among MSH6, CXCR4 and TGFB1 as the MSH6-CXCR4-TGFB1 feedback loop. For tumor cells, the theory of “grow-or-go” illustrated that proliferation and invasion are mutually exclusive behaviors 45. In the MSH6-CXCR4-TGFB1 feedback loop, TGFB1 is more inclined to promote GBM cell invasion, while MSH6 is more inclined to boost proliferation 46, 47.…”

Liver fluke granulin promotes exosome-mediated crosstalk and cellular microenvironment conducive to cholangiocarcinoma

“…Crosstalk between malignant and neighboring cells contributes to tumor growth (34)(35)(36)(37). To investigate crosstalk among cholangiocytes during liver fluke infection, here we focused on exosome-mediated transfer of mRNAs from cultured cholangiocytes following exposure to liver fluke granulin.…”