Chapter 5 │ Page 169 tumor vascularization in which cancer cells utilize pre-existing blood vessels instead of inducing new blood vessel formation [81]. Taken together, these results suggest an important pro-tumoral role of Cxs in advanced cancer stages, and more specifically points at GJ formation between cancer and normal cells as an important facilitator of cancer cells growth, tumor progression and metastasis. In addition to cancer stage, Aasen et al., dictate the importance of Cx isotype and histological tumor subtypes for pro-tumorigenic properties of GJs and patient prognosis [82]. The team compared the mRNA expression levels of di erent Cxs between healthy lung tissue and lung tumors, and found that Cx26, Cx30.3, and Cx30 proteins were upregulated in lung adenocarcinoma (LUAD) and lung SCC. However, Cx32 proteins were slightly upregulated in LUAD and downregulated in lung SCC, thus highlighting the importance of Cx isotype and cancer subtypespecific [82]. Yamasaki et al. also observed that in many tumor cells, Cxs were normally expressed but aberrantly localized, possibly due to a lack of an appropriate cell-cell recognition apparatus, and phosphorylation of Cxs [83]. Cx phosphorylation is described to influence GJs formation, connexon function, and GJs/Cxs degradation [84]. Thus, the pro-tumorigenic properties of Cxs do not only depend on the pathological overexpression of specific Cx isotypes and cancer stage, but also on tumor subtype and Cxs delocalization and phosphorylation. It is critical to acknowledge that the role of Cxs and GJs in cancer development and progression is highly complex, nuanced, and far from being fully understood. A comprehensive view must be taken to develop strategies that modulate GJs during cancer metastasis, and in-depth studies are required to reveal under which conditions Cxs and GJs may act as tumor promoter. 4. ANTI-TUMORIGENIC PROPERTIES OF Cxs AND GJs Apart from the pro-tumorigenic properties, studies have demonstrated that Cxs and GJs can also have anti-tumorigenic properties in specific structural and
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