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  • Through a molecular gain of

    2020-08-03

    Through a molecular gain-of-function approach, we demonstrated that Cx43 overexpression inhibits in vivo ES tumor growth, providing the first experimental evidence indicating that the decrease of Cx43 gene expression is one mechanism through which ES cells can acquire high tumor growth potential. Since the main function of connexins is the formation of intercellular channels, the mechanisms by which connexins modulate cell proliferation and thus tumor growth were firstly proposed to depend on the ability of these channels to promote exchange of molecules that regulate the s3i australia [49]. Over the past 40years, numerous studies have demonstrated a loss or at least a decrease of GJIC between cancer cells or between cancer cells and their surrounding normal cells, supporting the link between gap junction defects and tumor growth [20]. In agreement with this dogma, numerous studies reported that many tumor promoters were indeed inhibitors of GJIC [50] supporting the idea that the inhibition of GJIC during the tumor promoting stage may favor the clonal expansion of initiated cells [20], [51]. It was thus proposed that the recovery of GJIC between cancer cells could inhibit their proliferation and by consequence in vivo tumor growth. In this context, over-expression of connexins in different tumor cells was shown to restore GJIC and therefore inhibit cell proliferation [20], [21], [35]. Although we showed that Cx43 overexpression in ES cells restores GJIC, we cannot exclude that the effect of Cx43 overexpression on cell proliferation and in vivo tumor growth was not associated with the restoration of GJIC. Indeed, numerous studies have provided evidence for a dissociation of GJIC and the ability of connexins to inhibit cell proliferation and tumor growth [21]. Mechanistic studies demonstrated that Cx43 overexpression may inhibit cell proliferation via the inhibition of the expression of S phase kinase associated protein 2 (skp2), the protein that promotes the ubiquitination of cyclin-dependent kinase inhibitor p27kip [49]. With regard to primary bone tumors, a down-regulation of cyclin D1 associated with a blockade of the cell cycle in G0/G1 phase was observed in osteosarcoma after Cx43 overexpression [52]. Supporting this observation, we demonstrated that Cx43 overexpression in ES cells increases p27 levels with an associated marked decrease of Rb phosphorylation, consistent with the observed blockade of the cell cycle in G0/G1 phase. The presence of a “vicious cycle” established between tumor proliferation and paratumor osteolysis plays a crucial role in the development of primary bone tumors [53]. Cancer cells produce soluble factors that activate directly or indirectly via osteoblasts, osteoclast differentiation and maturation [54], [55]. In turn, during bone degradation, osteoclasts release tumor supportive growth factors stocked in the mineralized bone matrix [56]. Studies about the cellular mechanisms underlying the rapid bone resorption in ES indicate that ES cells activate osteoclast activity [4]. According with these findings, we demonstrated that the increase in bone volume observed after Cx43 overexpression in ES cells is due in large part to inhibition of osteoclast activity rather than to stimulation of osteoblast activity. The decrease of TRAP activity at the level of the growth plate, that is, not in direct contact with the tumor, suggests that the overexpression of Cx43 affects the ability of the tumor cells to produce a soluble factor able to regulate osteoclast activity, such as RANKL or M-CSF. This hypothesis is supported by previous reports demonstrating that ES cells support osteoclast formation by a RANKL- and M-CSF-dependent mechanism [4].