How Cells Communicate with Each Other in the Tumor Microenvironment: Suggestions to Design Novel Therapeutic Strategies in Cancer Disease

Abstract

Connexin- and pannexin (Panx)-formed hemichannels (HCs) and gap junctions (GJs) operate an interaction with the extracellular matrix and GJ intercellular communication (GJIC), and on account of this they are involved in cancer onset and progression towards invasiveness and metastatization. When we deal with cancer, it is not correct to omit the immune system, as well as neglecting its role in resisting or succumbing to formation and progression of incipient neoplasia until the formation of micrometastasis, nevertheless what really occurs in the tumor microenvironment (TME), which are the main players and which are the tumor or body allies, is still unclear. The goal of this article is to discuss how the pivotal players act, which can enhance or contrast cancer progression during two important process: "Activating Invasion and Metastasis" and the "Avoiding Immune Destruction", with a particular emphasis on the interplay among GJIC, Panx-HCs, and the purinergic system in the TME without disregarding the inflammasome and cytokines thereof derived. In particular, the complex and contrasting roles of Panx1/P2X7R signalosome in tumor facilitation and/or inhibition is discussed in regard to the early/late phases of the carcinogenesis. Finally, considering this complex interplay in the TME between cancer cells, stromal cells, immune cells, and focusing on their means of communication, we should be capable of revealing harmful messages that help the cancer growth and transform them in body allies, thus designing novel therapeutic strategies to fight cancer in a personalized manner.

Keywords: connexin; cytokines; epithelial-mesenchymal transition; gap junction intercellular communication; hemichannels; immune system; inflammasome; pannexin; purinergic system; tumor microenvironment.

Figure 1

The assembly of connexins and pannexins into hemichannels and gap junctions. The upper panel shows the structure of connexin 43 and pannexin 1 subunits. The lower panel (on the right hand) illustrates how connexins and pannexins assemble into hexamers, called connexon and pannexon, respectively, to form a hemichannel. Docking of two hemichannels from two neighboring cells form a gap junction (on the left hand). They permit the cells to exchange ions and small low molecular weight (MW) molecules with <1.2 kDa, that is intercellular communication. The shown protein structures of connexin 43 and pannexin 1 were taken from the RCSB-protein data bank (http://www.rcsb.org/ access date: 31 January 21).

Figure 2

The Panx/purinergic system role in cancer facilitation. ATP is released into the extracellular space via different modalities, among which relevant to this review, Panx1-HCs, or P2XR7, amplifying the signal derived from ATP. P2XR7 is activated by extracellular ATP, that, in turn, activates P2X7R to trigger K+ efflux. Released ATP is hydrolyzed to ADP and AMP by ectonucleotidase such as CD39. AMP is further degraded to adenosine (ADO) by CD73 and activate adenosine receptors (AR). CD39 and CD73 are expressed not only by tumor stromal cells (such as endothelial cells or tumor-associated regulatory T cells) but also by certain cancer cells. Adenosine exerts its immunosuppressive effects by activating AR expressed by tumors cells, endothelial cells (EC), or immune cells, then acting in paracrine and autocrine way. Due to the activation of A2A adenosine receptors, an inhibition of IFN-γ production and cytotoxic killing by CD8+ T cells and promotion of CD4+ cells differentiation into T-regulatory cells occur. ADO also acts on the tumor-surrounding endothelium repressing T-cell homing to tumors via downmodulation of adhesion proteins such as ICAM-1, VCAM-1, or P-selectin on EC.

Figure 3

The Panx1/PR signalosome in anti-cancer innate immunity. When a pathogen-associated molecular pattern (PAMP), such as lipopolysaccharide (LPS), binds to innate immunity receptors of phagocytic and dendritic cells (e.g., toll-like receptors, not shown), the activation of the NF-κB signaling cascade ensues (not shown), which upregulates the expression of the inflammasome component NLRP3, pro-IL-1β and TNF-α, and the whole complex associates with P2X7R. DAMPs, either shed from dying cancer cells and acting at the plasma membrane or in the cytosol, including ATP, and PAMPs, may cause Panx1 opening and ATP release, which activates P2X7R, allowing calcium flow into the cells and K+ efflux. Lower intracellular K⁺ provokes inflammasome assembly, bringing NLRP3 and pro-caspase 1 together with the adaptor protein ASC. The inflammasome activates pro-caspase 1, that will cleave the pro-peptide from IL-1β, which is then secreted from the cell along with TNF-α (not shown). Both cytokines increase CD4+ and CD8+ T cells, mediating antitumor responses.