Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To elucidate what changes in the expression of gap junction proteins (connexins) occur at what stages during multistage mouse skin carcinogenesis in vivo, we immunohistochemically and morphometrically analyzed the expression of connexin 26 (Cx26) and connexin 43 (Cx43) in papillomas, well-, moderately- and poorly-differentiated squamous cell carcinomas, as well as in squamous cell carcinomas at invasion sites and those metastasized into lymph nodes in female CD-1 mice as a result of treatment with dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. In papillomas, no clear reduction of the two connexins was observed; however, Cx26 and Cx43 were frequently co-localized in the same gap junction plaques, whereas the two kinds of Cxs were differentially expressed in normal and surrounding non-tumorous epidermis. In squamous cell carcinomas, the expression of both Cx26 and Cx43 significantly decreased compared with surrounding non-tumorous epidermis and papillomas. The Western blot analysis confirmed that both Cx26 and Cx43 proteins were reduced in squamous cell carcinomas compared with papillomas. Furthermore, the expression of Cx26 was reduced as cancer cells became morphologically less differentiated, while that of Cx43 did not change. Squamous cell carcinomas at invasive sites showed clear reduction of Cx26 and Cx43. In squamous cell carcinomas metastasized into lymph nodes, Cx26 was expressed, but few carcinoma cells expressed Cx43. The localization of E-cadherin on the plasma membrane between cancer cells was maintained even at invasive and metastatic sites. Our data suggest that quantitative and qualitative changes in connexin expression are associated with tumor progression, including the loss of differentiation, and invasion and metastasis, during multistage mouse skin carcinogenesis.
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PMID:Aberrant expression of gap junction proteins (connexins) is associated with tumor progression during multistage mouse skin carcinogenesis in vivo. 778 45

Poor gap junctional intercellular communication (GJIC) has been associated with uncontrolled cell growth and neoplasia. We have successfully propagated normal first trimester invasive extravillous trophoblast (EVT) cells, and have produced premalignant EVT lines after SV40 Tag transformation: RSVT-2 is an uncloned line that is long-lived; RSVT2/C is a clonal line that is immortal. Both are hyperproliferative, hyperinvasive and variably refractory to the anti-proliferative and anti-invasive effects of transforming growth factor beta (TGFbeta). Possible changes in gap junctions during the transition of normal invasive EVT cells to the premalignant stage were examined by comparing expression of connexin proteins (by immunolabeling for Cx26, Cx32, Cx40, Cx43), and mRNA (by Northern blot with cDNA probes for Cx26, Cx32, Cx43), and functional GJIC (by dye transfer using the preloading method) in normal parental EVT cells and their SV40 Tag transformants. Results from immunofluorescence and Northern blot analysis revealed that, of the panel of connexins examined, only Cx43 was variably expressed in these cell lines in vitro. Expression of Cx43 protein and mRNA was abundant in normal EVT cell line HTR8, reduced in long-lived RSVT-2 cells and undetectable in immortalized RSVT2/C cells. GJIC, as measured by dye transfer between donor and recipient cells, was also similarly reduced in recipient RSVT-2 cells, and drastically reduced in RSVT2/C cells, irrespective of whether the dye donor was of the same cell type (homocellular coupling) or HTR8 cells (heterocellular coupling). Treatment with TGFbeta reduced Cx43 mRNA expression as well as GJIC in normal EVT cells, but not in the SV40 Tag transformants. Our findings suggest that downregulation of connexins with the resultant impairment in GJIC is an early event in tumor progression, as observed in the premalignant SV40 Tag transformants.
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PMID:SV40 Tag transformation of the normal invasive trophoblast results in a premalignant phenotype. II. Changes in gap junctional intercellular communication. 966 8

Loss of gap junctional intercellular communication (GJIC) has been linked to aberrant proliferation and an enhanced neoplastic phenotype. Many human tumors, including the cervical carcinoma line HeLa, have been reported to be deficient in expression of the gap junction protein connexin43 (Cx43) and GJIC. To determine if this is an early event in carcinogenesis, we utilized immunohistochemistry to screen a series of cervical biopsy samples and demonstrated a major reduction in Cx43 expression in dysplastic regions compared to normal epithelia. To determine whether this loss influences the neoplastic behavior of cervical carcinoma cells, we have constructed HeLa cell lines in which Cx43 expression can be induced in response to doxycycline. This approach allows for the discrimination of Cx43-mediated effects from those due to pre-existing clonal heterogeneity. Cx43 induction in these cells led to assembly of functional junctions but did not alter growth control in vitro as measured by logarithmic growth, saturation density or focus formation when in co-culture with growth-controlled fibroblasts. However, Cx43 induction decreased two indices of neoplasia: it reduced anchorage-independent growth and attenuated the growth rate of tumor xenografts. These results indicate that established HeLa cell lines are unresponsive to Cx43-mediated signals which are thought to mediate growth control of non-transformed cells, however, Cx43 expression can still reduce aspects of the neoplastic phenotype of these cells, indicating that loss of connexin signaling in dysplastic cells may contribute to their neoplastic progression.
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PMID:Reduced levels of connexin43 in cervical dysplasia: inducible expression in a cervical carcinoma cell line decreases neoplastic potential with implications for tumor progression. 1083 96

Gap junctions, or connexons, are formed by connexin proteins and connect most cells in the body to form water-filled channels directly linking the cytoplasm. Among the molecules known to be transferred via junctions are cAMP, ATP, IP3 and glucose. Tumor cells are in general deficient in functional gap junctions either as a result of gene silencing, or failure to correctly process and assemble connexons. Tumor promoters inhibit function whereas certain cancer preventive agents increase junctional communication. When connexin expression in tumor cells is forced by introduction of exogenous genes or is increased by pharmacological agents, connexin expression reduces growth in suspension and growth as xenografts in nude mice. It is as yet unclear if in tumor cells these actions depend on junctional transfer of signal molecules or reflect some other function of these genes. Restoration of connexin function offers an exciting opportunity to delay tumor progression and inhibit metastasis.
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PMID:Cancer chemoprevention by connexins. 1254 61

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

Loss of connexin expression/gap junction intercellular communication (GJIC) has been correlated with decreased growth control and increased tumorigenesis. Studies utilizing Connexin32 (Cx32)-deficient knockout mice have demonstrated that loss of Cx32 increases susceptibility to chemically induced liver tumorigenesis. Here, in addition to dramatically increased liver tumorigenesis, we show that tumor induction utilizing X-ray radiation resulted in a statistically significant increase in overall tumor burden in Cx32-deficient mice compared with wild-type mice due to tumorigenesis in several other tissues (lung, adrenal, lymph and small intestine) even when excluding prevalent liver tumors. Irradiated Cx32-deficient mice were particularly sensitive to liver tumorigenesis (46% incidence compared with 18% in wild-type mice, P = 0.007) demonstrating that Cx32 functions as a hepatic tumor suppressor in response to radiation-associated mutation events. Cx32-deficient mice also exhibited increased lung tumorigenesis (bronchioloalveolar) with an increased progression to carcinoma when compared with wild-type mice. Two Cx32-deficient mice developed an uncommon, invasive medullary adrenal tumor type (pheochromocytoma) not observed in irradiated wild-type mice. Immunohistochemical analysis revealed increased levels of activated mitogen-activated protein kinase (MAPK) (p44/Erk1, p42/Erk2) in Cx32-deficient mouse liver tumors (P = 0.006), lung tumors (P = 0.056) and adrenal tumors (primary and metastases) compared with wild-type counterparts implicating elevated activation of MAPK-interacting pathways in Cx32-deficient tumorigenesis. Interestingly, lung tumors from Cx32-deficient mice also demonstrated decreased p27Kip1 levels compared with wild-type lung tumors (P = 0.05). This study demonstrates that loss of Cx32/GJIC plays a significant role in radiation-induced tumorigenesis of the liver and importantly that Cx32 may also play a role in tumor suppression and/or tumor progression in other tissue types such as lung and adrenal gland. Additionally, this mouse model suggests that MAPK-related pathways may be preferentially activated or conversely that tumors harboring activated MAPK pathways may selectively progress towards more advanced tumor states in the absence of Cx32-mediated GJIC.
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PMID:Mice deficient for the gap junction protein Connexin32 exhibit increased radiation-induced tumorigenesis associated with elevated mitogen-activated protein kinase (p44/Erk1, p42/Erk2) activation. 1474 25

Stimulation of the endometrium by estrogens without the differentiating effect of progestins is the primary etiological factor associated with the development of endometrial hyperplasia and adenocarcinoma. However, the correlation between sex steroids and gap junctional intercellular communication (GJIC), which is considered to play an important role in the control of cell growth and differentiation, is not well known in endometrial carcinoma. In this study, we focused on the influence of estrogen and its receptor in connexin (Cx) expression and GJIC in endometrial carcinoma cells, established stable clone IK-ER1 overexpressing ER-alpha to transfect the expression vector and analysed them in various hormonal conditions. The growth of IK-ER1 was accelerated by 17beta-estradiol and the acceleration of the 5-bromo-25-deoxyuridine labeling index was observed. GJIC was assayed by scoring the number of dye-coupled cells after microinjection of single cells with Lucifer-Yellow, and subcellular localization of Cx26 and Cx32 was analysed by immunocytochemistry. In the presence of estradiol, dye-coupled cells of IK-ER1 were significantly reduced compared to those without estradiol and the reduction was completely inhibited by adding ICI182.780, a pure antiestrogen substrate. Cxs were detected as only small spots by immunocytochemistry, and Western blotting showed that the expression was decreased. These results suggest that activation of ER-alpha by estrogen results in tumor progression by stimulating cell growth and suppressing GJIC via suppression of the expression of Cxs in endometrial carcinogenesis.
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PMID:Overexpression of estrogen receptor-alpha gene suppresses gap junctional intercellular communication in endometrial carcinoma cells. 1476 40

We previously reported that normal human keratinocytes controlled neoplastic progression of tumor cells at an early stage of transformation in stratified squamous epithelium. We now studied if cells at a more advanced stage of transformation were also subject to such microenvironmental control. To accomplish this, 3D human tissues that mimic intraepithelial neoplasia were fabricated by mixing genetically marked (beta-gal), early-stage (II-4 cells) or advanced-stage (SCC13) transformed keratinocytes with normal keratinocytes, and tumor cell fate and phenotype were monitored in organotypic culture and after surface transplantation to nude mice. In vivo, SCC13 cells evaded local growth suppression to undergo connective tissue invasion at significantly lower tumor cell volumes (12:1, 50:1 normal:tumor cells) than II-4 cells. This behavior was explained by the growth suppression of II-4 cells, while advanced-stage tumor cells escaped this control and continued to undergo clonal expansion in mixed cultures to form large, intraepithelial tumor clusters. These communities of tumor cells underwent autonomous growth that was associated with altered expression of markers of differentiation (keratin 1) and cell-cell communication (connexin-43). Furthermore, significantly greater numbers of SCC13 cells expanded into a basal position after low-calcium stripping of suprabasal cells of mixed cultures compared to II-4 cells, suggesting that expansion of these cells enabled tumor cell invasion after transplantation. These findings demonstrated that early tumor development in human stratified squamous epithelium required escape from microenvironmental growth control that was dependent on the transformation stage of intraepithelial tumor cells during the premalignant stage of cancer progression.
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PMID:Escape from microenvironmental control and progression of intraepithelial neoplasia. 1585 57

Studies performed to identify early events of ovarian cancer and to establish molecular markers to support of early detection and the development of chemopreventive regimens have been hindered by a lack of adequate cell models. Taking advantage of the spontaneous transformation of mouse ovarian surface epithelial (MOSE) cells in culture, we isolated and characterized distinct transitional stages of ovarian cancer as the cells progressed from a premalignant nontumorigenic phenotype to a highly aggressive malignant phenotype. Transitional stages were concurrent with progressive increases in proliferation, anchorage-independent growth capacity, in vivo tumor formation, and aneuploidy. During neoplastic progression, our ovarian cancer model underwent distinct remodeling of the actin cytoskeleton and focal adhesion complexes, concomitant with downregulation and/or aberrant subcellular localization of two tumor-suppressor proteins E-cadherin and connexin-43. In addition, we demonstrate that epigenetic silencing of E-cadherin through promoter methylation is associated with neoplastic progression of our ovarian cancer model. These results establish critical interactions between cellular cytoskeletal remodeling and epigenetic silencing events in the progression of ovarian cancer. Thus, our MOSE model provides an excellent tool to identify both cellular and molecular changes in the early and late stages of ovarian cancer, to evaluate their regulation, and to determine their significance in an immunocompetent in vivo environment.
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PMID:Sequential molecular and cellular events during neoplastic progression: a mouse syngeneic ovarian cancer model. 1624 77

Gap junctions are membrane structures made of intercellular channels which permit the diffusion from cytoplasm to cytoplasm of small hydrophilic molecules. Nearly 40 years ago, the loss of functional gap junctions has been described in cancer cells and led to the hypothesis that such type of intercellular communication is involved in the carcinogenesis process. From this time, a lot of data has been accumulated confirming that gap junctions are frequently decreased or absent in cancer cells whatever their tissue and species origins. Here, we review such data by insisting on the possible links existing between altered gap-junctional intercellular communication capacity (or the altered expression of their constitutive proteins, the connexins) and the stages of cancer progression in various cancer models. Then, we analyse particular aspects of the disturbance of connexin-mediated communication in cancer such as the cytoplasmic localization of connexins, the lack of heterologous communication between cancer cells and normal cells, the role of connexin gene mutations in cancer. In a separate part of the review, we also analyse the disturbance of gap-junctional intercellular communication during the late stages of cancer (invasion and metastasis processes).
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PMID:Defective gap junctional intercellular communication in the carcinogenic process. 1635 43


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