Preprint Review Version 1 This version is not peer-reviewed

Conflicting Roles of Connexin43 in Tumor-Induced Inflammation and Cancer Pathology

Version 1 : Received: 9 March 2018 / Approved: 12 March 2018 / Online: 12 March 2018 (04:20:03 CET)

A peer-reviewed article of this Preprint also exists.

Uzu, M.; Sin, W.C.; Shimizu, A.; Sato, H. Conflicting Roles of Connexin43 in Tumor Invasion and Growth in the Central Nervous System. Int. J. Mol. Sci. 2018, 19, 1159. Uzu, M.; Sin, W.C.; Shimizu, A.; Sato, H. Conflicting Roles of Connexin43 in Tumor Invasion and Growth in the Central Nervous System. Int. J. Mol. Sci. 2018, 19, 1159.

Journal reference: Int. J. Mol. Sci. 2018, 19, 1159
DOI: 10.3390/ijms19041159

Abstract

The tumor microenvironment is known to have increased levels of cytokines and metabolites, such as glutamate, due to their release from the surrounding cells. A normal cell around the tumor that responds to the inflammatory environment is likely to be subsequently altered. We will discuss how these abnormalities will support tumor survival via the actions of gap junctions (GJs) and hemichannels (HCs) which are composed of hexamer of connexin 43 (Cx43) protein. In particular, we will discuss how GJ intercellular communication (GJIC) in glioma cells, the primary brain tumor, is a regulatory factor and its attenuation leads to tumor invasion. In contrast, the astrocytes, which are normal cells around the glioma, are "hijacked" by tumor cells, either by receiving the transmission of malignant substances from the cancer cells via GJIC, or perhaps via astrocytic HC activity through the paracrine signaling which enable the delivery of these substances to the distal astrocytes. This astrocytic signaling would promote tumor expansion in the brain. In addition, brain metastasis from peripheral tissues has also been known to be facilitated by GJs formed between cerebral vascular endothelial cells and cancer cells. Astrocytes and microglia are generally thought to eliminate cancer cells at the blood brain barrier. In contrast, some reports suggest they facilitate tumor progression as tumor cells take advantage of the normal functions of astrocytes that support the survival of the neurons by exchanging nutrients and metabolites. In summary, GJIC is essential for the normal physiological function of growth and allowing the diffusion of physiological substances. Therefore, whether GJIC is cancer promoting or suppressing may be dependent by what permeates through GJs, when it is active, and to which cells. The nature of GJs, which has been ambiguous in brain tumor progression, will need to be re-visited and understood together with new findings on Cx proteins and HC activities.

Subject Areas

connexin43; central nervous system; glioma; astrocyte; blood brain barrier; neurovascular unit

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