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.
Highlights
Cancer is a multifactorial disease [1,2]
A scenario has been proposed that highlights that both autocrine and paracrine loops are at work: Extracellular adenosine triphosphate (ATP) released by tumor cells interacts with P2X7R expressed by the same cells or adjacent tumor cells and drives tumor cell proliferation [165]
The role of cytokines cannot be omitted in the crosstalk between stromal cells and cancer cells, because as noted above, cancer cells derive their fate by the tumor microenvironment (TME)
Summary
Cancer is a multifactorial disease [1,2]. Cell–cell communication plays a fundamental role in maintaining tissue homeostasis and responding to both external and internal stimuli. We might name all these interactions “metagenetic factors” using an ancient Greek prefix that means “beyond” In this regard, we verified the scientific literature, focusing on the GJIC between cancer cells and endothelial cells (ECs), such communication allowing cancer cells to use ECs to achieve two different useful results: (1) Gaining needed nutrients by the blood supply in order to thrive; and (2) obtaining a possible way out from the tissue where tumor cells arise, the latter permitting cancer cells to colonize other organs during the metastatization process. ECs and cancer cells interact with the IS cells, and in this respect, such communication appears decisive to determine cell fate as the evolution or worsening of the disease depends on such interplay In this context, cytokines play an essential role as capable of shaping an inflammatory or alternatively an anti-inflammatory state. Understanding exactly how it operates will be increasingly relevant to counteract cancer in a preventive/therapeutic context
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