Cx43 in Neural Progenitors Promotes Glioma Invasion in a 3D Culture System.

Kanika Khosla,Christian C Naus,Wun Chey Sin

doi:10.3390/ijms21155216

Kanika Khosla, Christian C Naus + Show 1 more

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https://doi.org/10.3390/ijms21155216

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Abstract

The environment that envelops the cancer cells intimately affects the malignancy of human cancers. In the case of glioma, an aggressive adult brain cancer, its high rate of recurrence after total resection is responsible for a poor prognosis. Connexin43 (Cx43) is a gap junction protein with a prominent presence in glioma-associated normal brain cells, specifically in the reactive astrocytes. We previously demonstrated that elimination of Cx43 in these astrocytes reduces glioma invasion in a syngeneic mouse model. To further our investigation in human glioma cells, we developed a scaffold-free 3D platform that takes into account both the tumor and its interaction with the surrounding tissue. Using cell-tracking dyes and 3D laser scanning confocal microscopy, we now report that the elimination of Cx43 protein in neural progenitor spheroids reduced the invasiveness of human brain tumor-initiating cells, confirming our earlier observation in an intact mouse brain. By investigating the glioma invasion in a defined multicellular system with a tumor boundary that mimics the intact brain environment, our findings strengthen Cx43 as a candidate target for glioma control.

Highlights

Cancer research has mostly focused on understanding and reversing the deleterious effect due to aberrant expression of mutated proteins in tumor cells
The smallest Cx43 band detected in GBM4 was absent in GBM8 but present in GL261, a mouse glioma cell line that was used in our intracranial mouse glioma model [15]
The tissue environment that envelops the glioma cells affects the dissemination of cancer cells, but it influences the susceptibility of cancer cells to therapeutic intervention [24]

Summary

Introduction

Cancer research has mostly focused on understanding and reversing the deleterious effect due to aberrant expression of mutated proteins in tumor cells. In this aspect, the gene of the ubiquitously expressed Cx43 (Gja1) is not usually altered in human cancers, based on a finding from a large cancer genome atlas (TCGA: https://www.cancer.gov/tcga). A TCGA query revealed preferential upregulation of Cx43 in malignant glioma [1], the most common brain cancer in adults, with very poor prognosis due to the high chance of recurrence, even after a successful total resection [2]. There is strong evidence to suggest that Cx43 has a pivotal role in cancer of the central nervous system [12] and a promising therapeutic target for gliomas [13]

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