Cancer Prevention and Therapy of Two Types of Gap Junctional Intercellular Communication–Deficient “Cancer Stem Cell”

Abstract

Early observations showed a lack of growth control and terminal differentiation with a lack of gap junctional intercellular communication (GJIC). Subsequent observations showed that epigenetic tumor promoters and activated oncogenes, which block gap junction function, provide insights into the multi-stage, multi-mechanism carcinogenic process. With the isolation of embryonic induced pluri-potent stem cells and organ-specific adult stem cells, gap junctions were linked to early development. While tumors and tumor cell lines are a heterogeneous mixture of “cancer stem cells” and “cancer non-stem cells”, the cancer stem cells seem to be of two types, namely, they express (a) no connexin genes or (b) connexin genes, but do not have functional GJIC. These observations suggest that these “cancer stem cells” originate from normal adult stem cells or from the de-differentiation or re-programming of somatic differentiated cells. This “Concept Paper” provides a hypothesis that “cancer stem cells” either originate from (a) organ-specific adult stem cells before the expression of the connexin genes or (b) organ-specific adult stem cells that just express gap junction genes but that the connexin proteins are rendered dysfunctional by activated oncogenes. Therefore, cancer prevention and therapeutic strategies must account for these two different types of “cancer stem cell”.

Facets of Communication: Gap Junction Ultrastructure and Function in Cancer Stem Cells and Tumor Cells

“…The impact of non-communicating Cx26 on the malignant potential of BCSCs allows the expansion of the classical view on connexin function in CSCs. This is in line with a recent review by Trosko, which provides the characterization of cancer stem cells in view of connexin expression: He states that expression of the transcription factor OCT4A, which has been associated with the pluripotency of stem cells [118], is also a characteristic of CSCs, and that those pluripotent CSCs expressing OCT4A do not express connexins and do not form functional gap junctions [112]. In contrast, in those CSCs expressing connexin proteins, these do not form functional gap junctions but serve a communication-independent purpose—which is supported by the data on Cx26 in breast cancer CSCs as outlined above.…”

“…When referring to CSCs in terms of a tumor-transmitting cell with self-renewal capacity, irrespective of their pluripotency, the expression of connexins has been demonstrated by many studies and was shown to have a functional impact—despite the connexins themselves possibly being dysfunctional [112]. In general, CSCs depend on intercellular communication, (a) via paracrine secretion of, for example, interleukins, cytokines or pro-angiogenic factors [113,114,115] and (b) via gap junctional intercellular communication.…”

Pro-Apoptotic Effect of Grape Seed Extract on MCF-7 Involves Transient Increase of Gap Junction Intercellular Communication and Cx43 Up-Regulation: A Mechanism of Chemoprevention

“…These kinds of studies must now be put into the context of knowing all tumours are a mixture of “cancer stem cells” and “cancer non-stem cells”. It is the “cancer stem cells” that must be targeted in order to prevent them from sustaining the growth of the tumour [28].…”

“…Several phytochemicals are able to induce apoptosis in cancer cells by enhancing gap-junctional intercellular communication (GJIC) [30,31,32,33,34]. Cancer cells usually exhibit dysfunctional GJIC, due generally to the lack of expression of connexin genes or the aberrant localization of connexin proteins [28,35], the structural components of the hexameric hemichannels that, when juxtaposed on adjacent cells, build up intercellular gap junctions [36]. As the tumour promoter agents exert their action by affecting cell-cell communication [37,38], several natural compounds, such as phytochemicals able to restore or enhance GJIC, although transiently, are able to allow cell-cell coupling and induce apoptosis through the passage of chemical signals [30,39,40,41,42,43].…”

Connexins and Gap Junctions in Cancer of the Urinary Tract

“…Gap junctions facilitate intercellular communication and regulate proliferation and differentiation [1]. Since gap junctional intercellular communication (GJIC) is necessary to mediate contact inhibition in growing cells and tissues, inhibited GJIC might reduce growth control and differentiation [2] and is a hallmark of epithelial-derived cancer cells [3]. James Trosko stated that epigenetic tumor promoters and activated oncogenes can block gap junction function and yield insights into the complex [2].…”