Hopes and Disillusions in Therapeutic Targeting of Intercellular Communication in Cancer.

Abstract

Although they tend to develop some independence upon malignant transformation, tumor cells and tumors remain“social” moieties. In many steps during tumor progression, tumor cells’ interaction with each other and with their microenvironment is an essential element in their survival, growth and progression. This dependence on cell-cell interactions provides an opportunity for therapeutic interventions. In addition to long range interactions through growth factors, cytokines and other released molecules, the cells use various structures to interact directly, including gap junctions (GJ), tight junctions, adherens junctions and desmosomes. Gap junction intercellular communication (GJIC), is a process involved in the transfer of second messengers such as cAMP, cGMP, glutamate, NAD+, IP3, glutathione, and Ca++ ions, between cells, through channel structures called gap junctions (GJ). It is involved in various biological functions including regulation of cell growth, cell differentiation, and maintenance of tissue homeostasis (Wei et al. 2004). Structurally, gap junctions are formed by two head-to-head opposing hexameric transmembrane channels called connexons or hemichannels contributed by two interacting cells (Yeager and Harris 2007). The building units of connexons are the connexin proteins (Cxs), which are tetraspan integral membrane proteins (Nakagawa et al. 2010). Expression and functional analysis of connexins and GJIC revealed that, in general, they are lost in cancer (Kandouz and Batist 2010) and their restoration has tumor inhibitory effects, which led to the concept that this type of intercellular communication plays a tumor suppressor role. Consequently, it early became clear that restoring GJIC and connexin expression, using different chemical treatments or by gene transfer, can be used to inhibit tumor cell growth (Fernstrom et al. 2002). GJIC and Cxs have also been suggested to be involved during metastasis, although this role is still largely unclear. For example, on one hand connexin43 (Cx43) affects angiogenesis in vitro and in vivo, via an effect on proteins such as the Monocyte chemotactic protein-1 (MCP­ 1) and Interleukin-6 (McLachlan et al. 2006) , although this effect seems GJIC-independent (McLachlan et al. 2006) . On the other hand, Cx43-mediated GJIC facilitates metastatic homing to the lung via increased adhesion to endothelial cells (Elzarrad et al. 2008). GJIC as