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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemical carcinogenesis in mouse skin has been useful in delineating the molecular events that underlie squamous cell carcinoma progression. A late event in this progression, the epithelial-to-mesenchymal transition (EMT), is characterized by the loss of epithelial markers and the presence of mesenchymal markers. One mesenchymal marker associated with this transition is the matrix metalloproteinase stromelysin 1 (Str-1). To examine the molecular mechanisms regulating the expression of Str-1 during the EMT, genetically related mouse skin tumor cell lines representing the epithelial (B9(SQ)) and mesenchymal (A5(SP)) phenotypes were studied. As expected, B9(SQ) cells did not make Str-1, while A5(SP) cells did. B9(SQ)-A5(SP) somatic hybrids did not make Str-1, suggesting that a critical regulatory factor was a B9(SQ)-specific repressor. Str-1 promoter analysis revealed that a canonical AP-1 site was sufficient to maintain differential reporter gene activity. This result correlated with the observed loss of binding of the transcriptionally inactive JunB-Fra-2 AP-1 complex from B9(SQ) cells, being replaced primarily by the more active JunD-Fra-2 complex in A5(SP) cells. The higher level of JunB binding to both DNA and Fra-2 correlated with its hyperphosphorylation by Jun N-terminal kinase, an activity that was significantly higher in B9(SQ) cells. In the somatic hybrids, JunB gene expression was highly upregulated, a condition that also was sufficient to repress the expression of the endogenous Str-1 gene in A5(SP) cells. These data suggested that alterations in JunB activity, by changes in either phosphorylation or gene expression, contributed to the phenotypic differences that occur in this model of the EMT.
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PMID:Loss of JunB activity enhances stromelysin 1 expression in a model of the epithelial-to-mesenchymal transition of mouse skin tumors. 1146 30

We review recent data that support a potential antiangiogenic effect of selenium (Se) in the chemoprevention of cancer and data that contrast two pools of Se metabolites, namely, methylselenol vs. hydrogen selenide, that differentially affect proteins and cellular processes crucial to tumor angiogenesis regulation. With regard to tumor angiogenesis, the chemopreventive effect of increased Se intake on chemically induced mammary carcinogenesis has been associated with reduced intratumoral microvessel density and an inhibition of the expression of vascular endothelial growth factor. The in vitro data show that monomethyl Se potently inhibits cell cycle progression of vascular endothelial cells to the S phase, endothelial expression of matrix metalloproteinase-2, and cancer epithelial expression of vascular endothelial growth factor with concentrations giving half-maximal inhibition that are within the plasma range of Se in US adults. The methyl Se-specific activities may therefore be physiologically pertinent for angiogenic switch regulation in early lesions in vivo in the context of cancer chemoprevention, which aims at retarding and blocking the growth and progression of early lesions. We argue for the antiangiogenic action of Se, especially the methyl Se pool of metabolites, as a primary mechanism for preventing avascular lesion growth. Contrary to the currently held paradigm, we speculate that there is a potential role for selenoproteins in regulating the growth and fate of transformed epithelial cells.
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PMID:Antiangiogenic activity of selenium in cancer chemoprevention: metabolite-specific effects. 1179 26

An important role for beta-catenin pathways in colorectal carcinogenesis was first suggested by the protein's association with adenomatous polyposis coli (APC) protein, and by evidence of dysregulation of beta-catenin protein expression at all stages of the adenoma-carcinoma sequence. Recent studies have, however, shown that yet more components of colorectal carcinogenesis are linked to beta-catenin pathways. Pro-oncogenic factors that also release beta-catenin from the adherens complex and/or encourage translocation to the nucleus include ras, epidermal growth factor (EGF), c-erbB-2, PKC-betaII, MUC1, and PPAR-gamma, whereas anti-oncogenic factors that also inhibit nuclear beta-catenin signaling include transforming growth factor (TGF)-beta, retinoic acid, and vitamin D. Association of nuclear beta-catenin with the T cell factor (TCF)/lymphoid enhancer factor (LEF) family of transcription factors promotes the expression of several compounds that have important roles in the development and progression of colorectal carcinoma, namely: c-myc, cyclin D1, gastrin, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-7, urokinase-type plasminogen activator receptor (aPAR), CD44 proteins, and P-glycoprotein. Finally, genetic aberrations of several components of the beta-catenin pathways, eg, Frizzled (Frz), AXIN, and TCF-4, may potentially contribute to colorectal carcinogenesis. In discussing the above interactions, this review demonstrates that beta-catenin represents a key molecule in the development of colorectal carcinoma.
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PMID:Beta-catenin--a linchpin in colorectal carcinogenesis? 1183 57

Mutations in the beta-catenin gene (CTNNB 1) with abnormal nuclear accumulation of beta-catenin have recently been identified in endometrial carcinoma (EC). Their relationship with microsatellite instability (MI) is unclear. It has been suggested that matrix metalloproteinase-7 (MMP-7) and cyclin D1 (cD) genes are targets for beta-catenin activation. DNA from 73 patients with EC was obtained from tumor and normal tissue (59 endometrioid and 14 nonendometrioid). CTNNB 1 mutations in exon 3 were assessed by single-strand conformation polymorphism and DNA sequencing. The results were correlated with immunostaining for beta-catenin, MMP-7, and cD. Three (CA)n repeats and mononucleotide tracts BAT 25 and BAT 26 had been previously used for MI analysis. CTNNB1 mutations were identified in 15 ECs (20.5%), all of them endometrioid carcinomas (15 of 59; 25.4%). They occurred in 6 of 19 MI-positive ECs (31.5%) and in 9 of 54 MI-negative ECs (16.6%). Eleven of the 15 CTNNB 1-mutated ECs showed beta-catenin nuclear immunostaining (P <.05). MMP-7 expression (>50% cells) was observed in 23 ECs, with 7 of these showing CTNNB 1 mutations. Significant expression of cD (>50% cells) was detected in 8 ECs, with 5 of these exhibiting CTNNB 1 mutations (P <.05). The results confirm that beta-catenin plays a role in endometrial carcinogenesis, particularly in endometrioid carcinomas. The results also suggest that MMP-7 and particularly cD may be targets of beta-catenin activation in ECs.
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PMID:CTNNB1 mutations and beta-catenin expression in endometrial carcinomas. 1195 46

Proprotein convertases (PCs) have been implicated in tumor cell invasion by processing a variety of substrates including matrix metalloproteinases (MMPs). PACE4, a member of the family of PCs was shown to enhance mouse skin carcinoma progression by increasing tumor cell invasiveness. However, the effects of PACE4 on malignant conversion have not been investigated. In the present study we address the possible role of PACE4 as a trigger of malignant conversion by transfecting with a full-length PACE4 cDNA, three keratinocyte cell lines with no or little tumorigenic potential, i.e. non-tumorigenic BALB/MK-2 cells, tumorigenic non-invasive MT1/2 cells and tumorigenic moderately invasive p117 mouse skin keratinocytes. Overexpression of PACE4 led to a significant increase in the processing of stromelysin-3, a well-characterized substrate of this PC. When assayed for invasive ability, the PACE4-transfected cells were invasive both in vitro and in vivo, whereas their control counterparts were not. In addition, an enhanced processing ability of MT2-MMP a known substrate of PCs was detected in the PACE4-transfected cells. This was accompanied by MMP-2 and MMP-9 activation in PACE4 transfectants. Invasion and MMP processing were remarkably reduced when PACE4 was inhibited with a specific antibody. By triggering the processing of crucial invasion-related proteases, PACE4 is not only able to enhance the invasive ability of malignant cells as demonstrated previously, but also played a significant role in converting non-invasive keratinocytes into malignant cells.
Carcinogenesis 2002 Apr
PMID:Malignant conversion of non-tumorigenic murine skin keratinocytes overexpressing PACE4. 1196 Sep 7

Connective tissue growth factor (CTGF) is known to be a potent angiogenic factor. Here we investigated how CTGF and matrix metalloproteinases (MMPs) are involved in the early stage of hypoxia-induced angiogenesis using human breast cancer cell line, MDA231, and vascular endothelial cells. Hypoxic stimulation (5% O(2)) of MDA231 cells increased their steady-state level of ctgf mRNA by approximately 2-fold within 1.5 h, and the levels remained at a plateau up to 6 h, and then decreased by 12 h as compared with the cells cultured under the normoxic condition. Membrane-type 1 MMP (MT1-MMP) mRNA levels was also increased within a few hours of the exposure to hypoxia. Indeed, ELISA revealed that the CTGF protein/cell in medium conditioned by MDA231 cells exposed to hypoxia was maximally greater at 24 h than in the medium from normoxic cultures and that the secretion rate (supernatant CTGF/cell layer CTGF) increased in a time-dependent manner from 24 to 72 h of hypoxic exposure. Hypoxic induction of CTGF was also confirmed by immunohistochemical analyses. Furthermore, zymogram analysis revealed that the production of active MMP-9 was also induced in MDA231 cells incubated under hypoxic conditions. Finally, we found that recombinant CTGF also increased the expression of a number of metalloproteinases that play a role in the vascular invasive processes and decreased the expression of tissue inhibitors of metalloproteinases by vascular endothelial cells. These findings suggest that hypoxia stimulates MDA231 cells to release CTGF as an angiogenic modulator, which initiates the invasive angiogenesis cascade by modulating the balance of extracellular matrix synthesis and degradation via MMPs secreted by endothelial cells in response to CTGF. This cascade may play critical roles in the hypoxia-induced neovascularization that accompanies tumor invasion in vivo.
Carcinogenesis 2002 May
PMID:Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases. 1201 49

STAT3, a member of signal transducers and activators of transcription (STATs) originally discovered as mediators in cytokine signaling pathways, plays an active role in oncogenesis. However, the function of STAT3 in signaling multistage carcinogenesis, especially in transformation of tumor-promotion sensitive epithelial cells has not been elucidated. The present study demonstrates that STAT3 is activated in interleukin-6 induced transformation in mouse skin epithelial cells. DNA binding and transcriptional activities of STAT3 were significantly increased by interleukin-6. This induced anchorage-independent transformation in tumor-promotion sensitive JB6 mouse skin P+ cells but not in the resistant variant P- cells. Two forms of dominant negative STAT3 (mutant of transcriptional domain, mF, or DNA-binding domain, mD) were stably transfected into P+ cells. Activation of STAT3 was abolished and importantly, interleukin-6 induced anchorage-independent growth was absent in both mutant STAT3 transfectants. To determine the genes targeted by STAT3, three matrix metalloproteinase proteins linked with carcinogenesis of epithelial cells were analysed. Both basal and interleukin-6 induced expression of collagenase I and stromelysin I, but not gelatinase A, were inhibited in the mutant STAT3 transfectants. Furthermore, transfection of a wild type STAT3 restored STAT3 transactivation and response to interleukin-6 induced transformation in mutant STAT3 transfectants, which up-regulated collagenase I and stromelysin I as well. Together, these results provide the first evidence that STAT3 activation is required in the progression of multistage carcinogenesis of mouse skin epithelial cells, and matrix metalloproteinases are actively involved in STAT3-mediated cell transformation.
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PMID:STAT3 activation is required for interleukin-6 induced transformation in tumor-promotion sensitive mouse skin epithelial cells. 1203 77

Although ovarian mechanisms of ovulation have been a subject of investigation for more than a century, essential regulatory pathways remain uncertain. A role for the ovarian surface epithelium in ovulation has recently been demonstrated. Ovarian surface epithelial cells in close contact with the apical wall of preovulatory ovine follicles secrete a urokinase-type plasminogen activator in response to surge concentrations of (locally delivered) gonadotrophins. Urokinase activates latent collagenases and stimulates release of tumour necrosis factor alpha from thecal endothelium. Tumour necrosis factor alpha progressively induces matrix metalloproteinase gene expression, apoptosis and inflammatory necrosis. Collagenolysis and cellular death are a prelude to stigma formation and ovarian rupture. Epithelium exfoliated from the dome of ovulatory follicles is replenished by generative stem cell replication and migration from the wound edges. Common epithelial ovarian cancer has been related to successive bouts of ovulation and mitosis. The integrity of the DNA of surface cells circumjacent to the ovarian rupture site is compromised during the ovulatory process. Clonal expansion of an epithelial cell with damaged (unrepaired) DNA is a putative factor in carcinogenesis. Ovarian cancer is a deadly insidious disease because typically it is asymptomatic until the malignancy has reached beyond the ovaries.
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PMID:Roles of the ovarian surface epithelium in ovulation and carcinogenesis. 1205 28

Colonic epithelial cell migration is required for normal differentiated cell function. This migratory phenotype is dependent upon wild-type adenomatous polyposis coli (Apc) expression. Non-tumorigenic murine colon epithelial cell lines with distinct Apc genotypes, i.e. young adult mouse colon (YAMC; Apc(+/+)) and immortomouse/Min colon epithelial (IMCE; Apc(Min/+) cells) were used to assess the association between the Apc genotype, cell motility and matrix metalloproteinase (MMP) activity. Cells were treated with epidermal growth factor (EGF; 1, 10 and 25 ng/ml), hepatocyte growth factor (HGF; 1, 10 and 25 ng/ml) and/or curcumin (0.1-100 microM). EGF (25 ng/ml) and HGF (25 ng/ml) induced a greater migratory response in YAMC compared with IMCE cells after 24 h (P < 0.05). Treatment with curcumin induced a greater or equivalent migratory response in IMCE than YAMC cells. When migrating cells were treated with Ilomastat (MMP inhibitor), migration was inhibited in both cell types. High concentrations of Ilomastat (25 and 50 microM) inhibited migration in both cell types, while low concentrations (10 microM) inhibited HGF-induced IMCE migration. Curcumin-induced migration was inhibited in both cell types at the highest concentration of Ilomastat (50 microM). Immuno-localization analysis of membrane type-1 (MT1)-MMP indicated that migration is associated with the redistribution of this protein from the endoplasmic reticulum to the plasma membrane. Addition of neutralizing polyclonal antibodies against MT1-MMP or a mixture of MT1, 2- and 3-MMPs demonstrated partial or complete inhibition of cell migration in both cell types, respectively. The data provide the first evidence that migration in non-tumorigenic murine colon epithelial cells is: (i) inducible by EGF and HGF in an Apc genotype-dependent manner, (ii) dependent on MT-MMP activity and (iii) inducible by curcumin in an Apc genotype-independent manner. The data suggest a potential mechanism by which curcumin may induce cells heterozygous for Apc to overcome defective cell migration, a phenotype associated with cell differentiation and apoptosis.
Carcinogenesis 2002 Jun
PMID:Membrane-type matrix metalloproteinases mediate curcumin-induced cell migration in non-tumorigenic colon epithelial cells differing in Apc genotype. 1208 30

Both antigen-specific and non-specific mechanisms may be involved in the pathogenesis of oral lichen planus (OLP). Antigen-specific mechanisms in OLP include antigen presentation by basal keratinocytes and antigen-specific keratinocyte killing by CD8(+) cytotoxic T-cells. Non-specific mechanisms include mast cell degranulation and matrix metalloproteinase (MMP) activation in OLP lesions. These mechanisms may combine to cause T-cell accumulation in the superficial lamina propria, basement membrane disruption, intra-epithelial T-cell migration, and keratinocyte apoptosis in OLP. OLP chronicity may be due, in part, to deficient antigen-specific TGF-beta1-mediated immunosuppression. The normal oral mucosa may be an immune privileged site (similar to the eye, testis, and placenta), and breakdown of immune privilege could result in OLP and possibly other autoimmune oral mucosal diseases. Recent findings in mucocutaneous graft-versus-host disease, a clinical and histological correlate of lichen planus, suggest the involvement of TNF-alpha, CD40, Fas, MMPs, and mast cell degranulation in disease pathogenesis. Potential roles for oral Langerhans cells and the regional lymphatics in OLP lesion formation and chronicity are discussed. Carcinogenesis in OLP may be regulated by the integrated signal from various tumor inhibitors (TGF-beta 1, TNF-alpha, IFN-gamma, IL-12) and promoters (MIF, MMP-9). We present our recent data implicating antigen-specific and non-specific mechanisms in the pathogenesis of OLP and propose a unifying hypothesis suggesting that both may be involved in lesion development. The initial event in OLP lesion formation and the factors that determine OLP susceptibility are unknown.
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PMID:The pathogenesis of oral lichen planus. 1219 61


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