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 discuss how these abnormalities will support tumor survival via the actions of gap junctions (GJs) and hemichannels (HCs) which are composed of hexamer of connexin43 (Cx43) protein. In particular, we 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 on what permeates through GJs, when it is active, and to which cells. The nature of GJs, which has been ambiguous in brain tumor progression, needs to be revisited and understood together with new findings on Cx proteins and HC activities.
Highlights
The gap junction (GJ) protein connexin (Cx) 43 forms intercellular channels permitting the passage of small ions and signaling molecules between adjacent cells [1,2]
Another mechanism by which astrocytic GJs promote brain metastasis was elucidated by Chen et al who revealed that cyclic dinucleotide cyclic GMP-AMP is transmitted via GJs from brain metastatic breast and lung cancer cells to astrocytes, which promotes cancer cell growth [31] (Figure 1, Pathway 1)
It is clear that GJ or HC composed of Cx43 are involved in many steps in the progression of brain cancer
Summary
The gap junction (GJ) protein connexin (Cx) 43 forms intercellular channels permitting the passage of small ions and signaling molecules between adjacent cells [1,2]. Increasing level of Cx43 in malignant mesothelioma cell enhances sensitivity against cisplatin and sunitinib treatment GJ between Cx43- overexpressed BMSCs and leukemic cells induced apoptosis in leukemic cells due to caspase 3/7 activation miR-145-5b from HMEC is transferred to glioblastoma (U87 cells) which decrease cancer proliferation miR-145-5b from HMEC is permitted to be transferred to cancer cells (SW480 cells) and up-regulated Cx43 expression, which inhibits proangiogenic effect of cancer cells. Bcl2-associated protein X, Bax; BMSCs, bone mallow stroma cells; cGAMP, 2 3 -cyclic GMP-AMP; CNS, central nervous system; DC, dendritic cells; GJ, gap junction; HCs, hemichannels; HMEC, human micro vascular cerebral endothelial cells; Interleukin 1 beta, IL-1β; JNK, c-Jun N-terminal kinase; Src, Proto-oncogene tyrosine-protein kinase Src; TNF-α, Tumor necrosis factor alpha
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