Gap Junction Intercellular Communication in the Carcinogenesis Hallmarks: Is This a Phenomenon or Epiphenomenon?

Abstract

If occupational tumors are excluded, cancer causes are largely unknown. Therefore, it appeared useful to work out a theory explaining the complexity of this disease. More than fifty years ago the first demonstration that cells communicate with each other by exchanging ions or small molecules through the participation of connexins (Cxs) forming Gap Junctions (GJs) occurred. Then the involvement of GJ Intercellular Communication (GJIC) in numerous physiological cellular functions, especially in proliferation control, was proven and accounts for the growing attention elicited in the field of carcinogenesis. The aim of the present paper is to verify and discuss the role of Cxs, GJs, and GJIC in cancer hallmarks, pointing on the different involved mechanisms in the context of the multi-step theory of carcinogenesis. Functional GJIC acts both as a tumor suppressor and as a tumor enhancer in the metastatic stage. On the contrary, lost or non-functional GJs allow the uncontrolled proliferation of stem/progenitor initiated cells. Thus, GJIC plays a key role in many biological phenomena or epiphenomena related to cancer. Depending on this complexity, GJIC can be considered a tumor suppressor in controlling cell proliferation or a cancer ally, with possible preventive or therapeutic implications in both cases.

Keywords: angiogenesis; cancer; connexins; hallmark; inflammation; metastasis; microenvironment; stem cells.

Figure 1

Schematic overview of the structural and functional features of connexins (Cxs). The folding of Cx is shown as inferred from the crystallographic structure of the Cx26 gap junction (GJ). The exameric connexons are shown in closed and open conformation, leading in the latter case to the hemichannel activity and GJ intercellular communication (GJIC). Non-GJIC or hemichannel related function of Cxs is also shown as resulting from interaction with cytosolic effectors.

Figure 2

Different roles of GJIC in early and late phases of carcinogenesis involving either stem cells or differentiated cells. Intact (not inhibited) GJIC acts as tumor suppressor in the initial stages of tumorigenesis, it is inhibited in the promoter phase, and it is reactivated (re-opened) during the metastasization stage. In migrating tumor cells, re-expression of Cxs promote tumor metastasis, enabling cell-to-cell communication between tumor cells and cancer-associated fibroblasts, as well as endothelial and stromal cells. The same might happen in the secondary tumor.

Figure 3

Schematic overview of the cancer hallmarks, as defined by Hanahan and Weinberg [66], and the involvement of GJIC in all of the hallmarks discussed in this review.

Figure 4

Involvement of GJIC in the different steps of carcinogenesis. Carcinogenesis is characterized by “initiation,” “promotion,” and “progression” phases. After a stem/progenitor cell is initiated by genotoxic agents, this is followed by promotion of cell growth. If functional GJIC is expressed, the initiated cell will be stopped at first step (Initiation). On the other hand, if these initiated cells are exposed, chronically, to agents that down regulate GJIC, they will lose sensitivity to antigrowth signals and evade apoptosis, giving rise to the so-called “founder” cell. During the progression phase, these cells would proliferate, accumulate, and accrue sufficient genetic/epigenetic changes that will allow them to acquire all the hallmarks of cancer. At the end, a tumor will be a mass of genetically heterogeneous cells. References showing the role of GJIC during all the described phases are indicated in square brackets. GJIC⁺: Gap Junction Intercellular Communication functioning; GJIC^--: Gap Junction Intercellular Communication inhibited.