UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
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Gap-junction-mediated intercellular communication (GJIC) is required for completion of embryonic development, tissue homeostasis, and regulation of cell proliferation and death. Although, as emphasized in several reports, defects or disruption of GJIC may be important in carcinogenesis, the potential role of GJIC in the onset and progression of human prostate cancer remains ill-defined. The gap junction channel-forming connexins (Cx) comprise a multigene family of highly conserved proteins that are differentially expressed in a tissue- and development-specific manner; changes in connexin expression are also commonly seen during cellular differentiation. However, when multiple connexins are concurrently expressed, gap junction channels may consist of more than one connexin species. This is important, because only certain pairings give rise to functional channels. In our studies, we investigated GJIC in a panel of both nontumorigenic (RWPE-1) and malignant (RWPE-2, LNCaP, DU-145) human prostate epithelial cells, compared to a normal rat liver epithelial F344 (WB-1) cell line, as it was found to be junctionally proficient. In addition, expression and regulation of Cx43 and Cx32 were also inspected using western blot analysis. The ability of hormones, antihormones, and the antihypertensive drug forskolin to restore GJIC in nontumorigenic and malignant human prostate epithelial cells was examined by the scrape-loading/dye transfer (SL/DT) or fluorescence recovery after photobleaching (FRAP) methods using an Ultima laser cytometer. Results from both assays showed that neither nontumorigenic nor malignant prostate cells have functional GJIC. However, both estrone (E1) and forskolin (FK) induced a significant increase (4.4- and 2.8-fold, respectively) in cell-cell communication only in the RWPE-1 cells. Interestingly, the use of Matrigel, a solubilized basement membrane, as substrate for cell attachment and growth resulted in the rescue of GJIC activity in RWPE-1 cells, as revealed by the SL/DT method. Furthermore, E1 induced a twofold increase in connexin 43 (Cx43), whereas forskolin caused a 50% reduction in Cx32 expression in RWPE-1 cells. These data suggest that agents that increase Cx43:Cx32 ratio may restore GJIC in junctionally deficient cells, providing a basis for the development of new strategies for the prevention and treatment of human prostate cancer.
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PMID:Intercellular communication and human prostate carcinogenesis. 1209 41

Non-genotoxic carcinogens are thought to induce tumour formation by disturbing the balance between cell growth and cell death. Gap junctions (GJ) contribute to the maintenance of tissue homeostasis by allowing the intercellular exchange of growth regulatory signals and potential inhibition of GJ intercellular communication through loss of connexin (Cx) plaques has been shown to be involved in the cancer process. We have investigated the time- and dose-dependent effects of the non-genotoxic hepatocarcinogens Wy-14,643, 2,3,7,8-tetrachlorodibenzo-p-dioxin, methapyrilene and hexachlorobenzene and the male rat kidney carcinogens chloroform, p-dichlorobenzene and d-limonene on gap junction plaque expression in relation to proliferation and apoptosis. With the exception of limonene, all non-genotoxic carcinogens significantly reduced the expression of GJ plaques containing Cx32 in their respective target tissue. No dose-dependent, significant effects were seen in non-target organs. Although alteration of Cx32 expression did not appear to correlate with induction of cell proliferation, out data suggest that the interaction of both processes-interference of GJ coupled with a proliferative stimulus (at the carcinogenic dose)-may be important in non-genotoxic carcinogenesis and provide a potential alert for non-genotoxic carcinogens in short-term toxicity tests.
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PMID:Non-genotoxic carcinogens: early effects on gap junctions, cell proliferation and apoptosis in the rat. 1239 93

The development of the most efficacious strategy for the prevention and treatment of cancers is based on understanding the underlying mechanisms of carcinogenesis. This includes the knowledge that the carcinogenic process is a multi-step, multi-mechanism process and that no two cancers are alike, in spite of some apparent universal characteristics, such as their inability to have growth control, to terminally differentiate, to apoptose abnormally and to have an apparent extended or immortalized life span. The multi-step process, involving the "initiation" of a single cell via some irreversible process, with the clonal expansion of this initiated cell by suppressing growth control and inhibiting apoptosis (promotion step), leads to a situation whereby additional genetic and epigenetic events can take place (progression step) to confer the necessary phenotypes of invasiveness, and metasis (neoplastic stage). While it is clear that, in principle, prevention of each of these three steps is possible, in practical terms, while it would make sense to minimize the initiation step, one can never reduce this step to zero. On the other hand, since the promotion step is the rate-limiting step of carcinogenesis, intervening to block this step makes the most sense. Also, by understanding the ultimate biological function that confers growth control, terminal differentiation or apoptosis for cells, there is even some hope of treating some, but not all, malignant cells such that they can regain some ability to perform these vital cellular functions. Gap junctional intercellular communication (GJIC) has been speculated to be a necessary, if not sufficient, biological function of metazoan cells for the regulation of growth control, differentiation and apoptosis of normal progenitor cells. Normal, contact-inhibited fibroblast and epithelial cells have functional GJIC, while most, if not all, tumor cells have dysfunctional homologous or heterologous GJIC. Cancer cells are characterized by the lack of growth control, inability to terminally differentiate or apoptose under normal conditions and have extended or immortalized life spans. Chemical tumor promoters, growth factors and hormones have been shown to inhibit GJIC. Several oncogenes and anti-sense connexin genes have been shown to down-regulate GJIC function. Anti-oncogene drugs, anti-tumor promoting natural and synthetic chemicals, as well as GJIC-deficient neoplastic cells, transfected with various connexin genes, have been shown to re-gain GJIC and growth control with the loss of tumorigenicity. Therefore, the hypothesis for a rational approach to identify anti-tumor promoting chemopreventive drugs and anti-carcinogenic treatments is to use the prevention of the down regulation of GJIC by the tumor promoters and the restoration of GJIC in neoplastic cells. While previous and many current strategies for chemoprevention and therapy have been based on treating specific oncogene products or cell signalling mechanisms, as well as advance molecular modifications of older strategies, none have specifically used the prevention of GJIC by agents during the rate limiting step of carcinogenesis or the restoration of GJIC in neoplastic cells which are deficient in GJIC. Since there are multiple mechanisms by which GJIC is down regulated during the tumor promotion phase and since stable GJIC deficiencies in neoplastic cells can be the result of transcriptional, translational or posttranslational mechanisms, it should be clear there would not be one "golden bullet" approach to resolve either the chemoprevention or therapeutic approach. Even with the hypothesis that GJIC, which depends on the transcription of normal connexin genes, their normal translation, trafficking, assembly and function, it should be clear that cells with normal connexin genes and potentially normal GJIC might not have functional GJIC because of dysfunction of other defects in cancer cells, namely cell-adhesion or cell-matrix problems (both of which are necessary for GJIC to occur). In essence, if dietary or chemopreventive/therapy is to be effective, the strategy must either ameliorate the growth stimulatory effects of exogenous chemicals, growth factors or hormones, that trigger various mitogenic/anti-apoptotic signal transducing systems that inhibit GJIC.
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PMID:Gap junctions as targets for cancer chemoprevention and chemotherapy. 1244 98

Gap junctional communication permits the direct exchange of small molecules and ions and has been implicated in tissue homeostasis/metabolite exchange. The lack of gap junctional intercellular communication (GJIC) plays important roles in the promotion and progression of carcinogenesis. In the present study, we demonstrate that treatment of human hepatoma Hep G2 cells with retinoic acid (RA) results in increased amounts and phosphorylation of connexins, their stabilisation in plasma membrane plaques and enhanced GJIC. In cultured fetal hepatocytes, which represent a non-transformed, proliferating and incompletely differentiated liver system, the effects of RA are limited to the establishment of connexin in areas of cell-cell contact and the improvement of GJIC. This suggests that modulation of cell-cell channel communication by RA occurs differently in these two experimental models: while RA is able to revert cell transformation in Hep G2 cells, in fetal hepatocytes it may induce the expression of a more differentiated phenotype.
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PMID:Retinoic acid modulates gap junctional intercellular communication in hepatocytes and hepatoma cells. 1247 86

Understanding the process of carcinogenesis will involve both the accumulation of many scientific facts derived from molecular, biochemical, cellular, physiological, whole animal experiments and epidemiological studies, as well as from conceptual understanding as to how to order and integrate those facts. From decades of cancer research, a number of the "hallmarks of cancer" have been identified, as well as their attendant concepts, including oncogenes, tumor suppressor genes, cell cycle biochemistry, hypotheses of metastasis, angiogenesis, etc. While all these "hallmarks" are well known, two important concepts, with their associated scientific observations, have been generally ignored by many in the cancer research field. The objective of the short review is to highlight the concept of the role of human adult pluri-potent stem cells as "target cells" for the carcinogenic process and the concept of the role of gap junctional intercellular communication in the multi-stage, multi-mechanism process of carcinogenesis. With these two concepts, an attempt has been made to integrate the other well-known concepts, such as the multi-stage, multimechanisn or the "initiation/promotion/progression" hypothesis; the stem cell theory of carcinogenesis; the oncogene/tumor suppression theory and the mutation/epigenetic theories of carcinogenesis. This new "integrative" theory tries to explain the well-known "hallmarks" of cancers, including the observation that cancer cells lack either heterologous or homologous gap junctional intercellular communication whereas normal human adult stem cells do not have expressed or functional gap junctional intercellular communication. On the other hand, their normal differentiated, non-stem cell derivatives do express connexins and express gap junctional intercellular communication during their differentiation. Examination of the roles of chemical tumor promoters, oncogenes, connexin knock-out mice and roles of genetically-engineered tumor and normal cells with connexin and anti-sense connexin genes, respectively, seems to provide evidence which is consistent with the roles of both stem cells and gap junctional communication playing a major role in carcinogenesis. The integrative hypothesis provides new strategies for chemoprevention and chemotherapy which focuses on modulating connexin gene expression or gap junctional intercellular communication in the premalignant and malignant cells, respectively.
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PMID:The role of stem cells and gap junctional intercellular communication in carcinogenesis. 1254 74

While many theories have been proposed for the aging process, and many debates on the matter of aging and the diseases of aging being either the result of the same or independent processes, most have not considered humans as a hierarchical system made up of cybernetically interacting levels of organization. To understand the aging process and the diseases of aging, one must view the human as the result of the total genomic DNA in the single fertilized egg that proliferates, differentiates and develops into an individual of about 100 trillion cells, organized by different cell types (pluri-potent stem cells, progenitor stem cells, terminally differentiated cells) into multiple tissue, organ and organ systems which interact with each other via endogenous factors and with exogenous factors. Our hypothesis is that both aging and diseases of aging are dependent of the normal functioning of the pluri-potent stem cell pool. Specifically, the concept involves the cybernetic feedback between the 'quantity' of the stem cell pool in each tissue niche with the 'quality' of the stem cells in the pool. The process of gap junctional inter-cellular communication (GJIC), which has been implicated in the evolution from the single cell organism to the multi-cellular organisms, requiring growth control, differentiation, apoptosis, adaptive response capability of differentiated cells and senescence, is speculated to be a shared mechanism in stem cell biology and in many chronic disease processes (teratogenesis; carcinogenesis, atherogenesis, diabetigenesis, etc.). Specifically, stem cells are assumed to be 'immortal' until induced to express their connexin genes and have functional GJIC, at which time they can differentiate and become 'mortal'. As long as the stem cells are communicating with their differentiated daughters via some extra-cellular soluble negative growth factor, the homeostatic control of their growth and differentiation is maintained for the organism. However, if the stem cell pool is depleted by any process, replacement of tissue due to wear and tear is diminished. The dependence of this tissue/organ to maintain homeostatic control of other organ systems then diminishes, leading to 'systems failure'. In addition, if the stem cells in the pool have been exposed to agents that prevent the normal terminal differentiation of that cell, but whereby these 'initiated' stem cells can be expanded in any tissue, clones of partially differentiated and non-functional appear in the tissue. This diminishes the efficacy of that tissue to function properly and, thereby, also contributes to 'system failure' by contributing to the breakdown of homeostatic organ system control. One clear example, that of carcinogenesis, illustrates this point.
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PMID:Human stem cells as targets for the aging and diseases of aging processes. 1258 26

Both reproductive and therapeutic cloning of human stem cells have been made possible with recent technological advances in the isolation of embryonic stem cells and of pluripotent stem cells from adult tissues. We have isolated normal human kidney and human breast epithelial stem cells, as well as having characterized "immortalized" cells from human neuronal and human pancreatic tissue (Trosko et al., Methods 20:245-264, 2000). The isolation was motivated by the stem cell theory of carcinogenesis. Based on the assumption that stem cells would not express connexin genes, nor have functional gap junctional intercellular communication (GJIC), we have demonstrated that the human kidney, breast, neuronal, and pancreatic stem cells can divide either symmetrically or asymmetrically, depending on whether they are grown in microenvironmental conditions that suppress GJIC (the undifferentiated, proliferative state) or induce GJIC (the differentiated state). Normal breast epithelial stem cells appear to be intrinsically "immortal" until induced to express GJIC, at which time, with appropriate substrate and microenvironmental nutrients, they can form three-dimensional "organoids." expressing markers associated with the mature mammary tissue and forming a physical structure very similar to the in vivo budding, ductal structures. The breast stem cells can be prevented from "mortalizing" and can be converted to neoplastic cells, which maintain many phenotypes of the stem cells.
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PMID:Isolation and characterization of normal adult human epithelial pluripotent stem cells. 1272 25

Mutations in the tumour suppressor gene adenomatous polyposis coli (Apc) are early and critical events in the development of colon cancer. In the absence of functional Apc, beta-catenin is not degraded in the cytoplasm and can be transported to the nucleus and turn on transcription of several genes, including the gap junction protein connexin43. Apc also stabilizes microtubules and regulates microtubule polymerization. Changes in Wnt signalling and microtubule function are reported to affect the connexin level. To study the effect of heterozygous Apc mutation we examined gap junctional intercellular communication (GJIC) in IMCE (Immorto-Min colonic epithelium) cells with one mutated Apc allele and in YAMC (Young adult mouse colon) cells with normal Apc function. IMCE cells had only half the GJIC level compared with YAMC cells. RT-PCR showed that both YAMC and IMCE cells express a common complement of seven connexin genes (Cx26, Cx31, Cx39, Cx40, Cx43, Cx45 and Cx50), with an additional Cx29 gene expression in YAMC cells. We found that the Cx43 level was correspondingly lower in IMCE cells as detected by western blotting and immunofluorescence. There were no differences in the level or localization of beta-catenin and the downstream gene E-cadherin between the cells, indicating no activation of the Wnt-signalling pathway in cells with one mutated Apc allele. We also examined the microtubule polymerization rate, and IMCE cells had markedly slower microtubule polymerization than YAMC cells. Hence, it appears that mutation in one Apc allele is sufficient to affect microtubule function, while inactivation of both wild-type Apc alleles may be necessary for activation of Wnt signalling. Reduction in GJIC and Cx43 level in IMCE cells may be caused by reduced Cx43 transport as a result of alterations in microtubule function.
Carcinogenesis 2003 Apr
PMID:Cells heterozygous for the ApcMin mutation have decreased gap junctional intercellular communication and connexin43 level, and reduced microtubule polymerization. 1272 91

Gap junctional intercellular communication (GJIC) is essential in the maintenance of tissue homeostasis and has been implicated in tumor suppression. Recent studies have indicated that GJIC is also involved in cellular stress responses to low dose ionizing radiation, UV light and hydrogen peroxide. However, the contribution of GJIC to the heat stress response has not yet been elucidated. We here demonstrate a potential link between GJIC and the heat stress response. First, we investigated whether the abolition of GJIC by lindane affects heat sensitivity in normal human cells. Lindane potentiated cell killing by heat shock at 43 degrees C, whereas little or no cytotoxicity was observed at 37 degrees C. Nuclear translocation of heat shock protein 72 (HSP72) was interrupted by lindane, although its induction was not affected. These results indicate that lindane exacerbates hyperthermic lethality via disrupted nuclear translocation of HSP72 protein. Second, we assessed whether heat shock alters GJIC and phosphorylation of gap junction connexin (Cx) proteins in normal human cells. Persistent heat treatment augmented Cx43 phosphorylation in a heat- and time-dependent fashion and this phosphorylation was recovered after heat shock. GJIC was also disturbed by heat shock. These results indicate that heat shock augments Cx43 phosphorylation leading to GJIC abrogation. Our present results imply that GJIC contributes to protection against heat stress and that loss of GJIC function during carcinogenesis exacerbates hyperthermic lethality.
Carcinogenesis 2003 Nov
PMID:Gap junctional intercellular communication and cellular response to heat stress. 1291 56

Ionizing radiation (IR) is a known human breast carcinogen. Although the mutagenic capacity of IR is widely acknowledged as the basis for its action as a carcinogen, we and others have shown that IR can also induce growth factors and extracellular matrix remodeling. As a consequence, we have proposed that an additional factor contributing to IR carcinogenesis is the potential disruption of critical constraints that are imposed by normal cell interactions. To test this hypothesis, we asked whether IR affected the ability of nonmalignant human mammary epithelial cells (HMEC) to undergo tissue-specific morphogenesis in culture by using confocal microscopy and imaging bioinformatics. We found that irradiated single HMEC gave rise to colonies exhibiting decreased localization of E-cadherin, beta-catenin, and connexin-43, proteins necessary for the establishment of polarity and communication. Severely compromised acinar organization was manifested by the majority of irradiated HMEC progeny as quantified by image analysis. Disrupted cell-cell communication, aberrant cell-extracellular matrix interactions, and loss of tissue-specific architecture observed in the daughters of irradiated HMEC are characteristic of neoplastic progression. These data point to a heritable, nonmutational mechanism whereby IR compromises cell polarity and multicellular organization.
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PMID:Ionizing radiation induces heritable disruption of epithelial cell interactions. 1296 Mar 93

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