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The function of intercellular communication in the development of a tumor stem cell character

 

When cells cease to communicate via "gap junctions" (GJs), stem cell characteristics and autonomous behavior are created. Inactive GJs prevent contact inhibition, programmed cell death and terminal differentiation, which makes the cell autonomous; that means it no longer responds to cellular regulatory mechanisms or chemotherapy. GJs are channels in the outer membrane through which small molecules and ions are passively transported, and which thus enable direct communication of adjacent cells. Also gemcitabine, and other chemotherapeutic agents diffuse from cell to cell through GJs. The resulting "bystander effect" causes a higher therapeutic efficiency. GJs are composed of a family containing more than 20 different connexin proteins. We have found that a lacking connexin 43 (Cx43) protein is a mediator of defective GJs and a broken "Gap Junctional Intercellular Communication" (GJIC) in advanced pancreatic cancer. This was associated with resistance to gemcitabine and occurred only in cells with CSC properties. Sulforaphane however caused a restoration of the Cx43 protein and resulted in functional GJs and GJIC. This prevented ultimately tumor progression. Data from the literature and our own preliminary results support the hypothesis that microRNAs (miRNAs) are involved in the inhibition of Cx43 expression and the sulforaphane-induced recovery in advanced pancreatic cancer. The aim of our current study is therefore to investigate the role of miRNA signals in the regulation of Cx43 expression and GJIC in normal, low malignant and highly malignant pancreatic cells.

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