Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The matrix-degrading metalloproteinases (MMPs) have been implicated in tumor invasion and metastasis. Recently it has become clear that the expression of MMPs in tumors is frequently localized to stromal cells surrounding malignant tumor cells. In the mouse skin model of multi-stage carcinogenesis, the MMP stromelysin is expressed in stromal fibroblast-like cells surrounding benign and malignant squamous cell carcinomas. Conversion of these tumors to highly invasive and metastatic spindle-cell tumors is however, associated with the expression of stromelysin-1 mRNA in the tumor cells themselves. The analysis of MMPs in human colon adenocarcinomas at different stages of tumor progression revealed that matrilysin was the only MMP expressed in the tumor cells, while stromelysin-1 and stromelysin-3 mRNA was detected in stromal cells surrounding malignant tumor cells. Matrilysin mRNA is detected in benign tumors as well as malignant tumor cells, and the relative level and percent of tumors expressing matrilysin correlates with the stage of tumor progression. These results suggest that both stromal and tumor cell metalloproteinases may contribute to tumor invasion and metastasis, and also suggests that MMPs may play a role in earlier events in the tumor progression pathway. A potential role for MMPs in tumor growth is illustrated by results which suggest that the expression of matrilysin in human colon cancer-derived cells increases tumorigenicity following injection into the cecum, and that transgenic mice expressing matrilysin mRNA show a marked proliferative response. MMPs may therefore play multiple roles in tumor progression.
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PMID:Matrix-degrading metalloproteinases in tumor progression. 898 72

Matrix metalloproteinases are believed to play an important role in tumor progression, invasion and metastasis. In order to investigate if the expression of stromelysin-3 (ST3) mRNA could add prognostic information concerning invasive laryngeal cancer and/or be indicative of a high risk for tumor progression in laryngeal dysplasias ST3 expression was analyzed by in situ hybridisation of formalin fixed paraffin embedded laryngeal specimens. Furthermore, all specimens underwent image cytometry (ICM) DNA analysis, and, p53 immunostaining. Invasive epithelial cancer, both localized (T1, T2) cancers, cured, as well as not cured, by radiotherapy, and cases with regional lymph node metastases were studied. Furthermore, high grade and low grade dysplasias, selected for rapid, slow and non-progression, as well as non-neoplastic inflammatory lesions were investigated. Expression of the ST3 gene was found in 9 out of 14 (64%) invasive cancer lesions, and in 3 out of 10 (30%) dysplasias, thus indicating that ST3 expression correlates to tumor progression. The ST3 positive laryngeal cancer lesions displayed a higher degree of DNA aberration than the ST3 negative lesions thus suggesting that ST3 positivity could indicate highly malignant tumors. Of the three ST3 positive dysplasias, the first progressed rapidly to cancer in situ with suspected microinvasion. The second ST3 positive dysplasia progressed to invasive cancer within five months. The third ST3 positive dysplasia had been radically excised and hereby cured. All but one of the dysplastic lesions showed p53 immunoreactivity, and all dysplasias exhibited aneuploid cells. ST3 expression appears to be a late event in the multistage process of carcinogenesis and could prove useful as an indicator of dysplasias with imminent risk for progression to invasive cancer.
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PMID:Stromelysin-3 mRNA expression in dysplasias and invasive epithelial cancer of the larynx. 949 47

Molecular markers can improve staging and predict aggressive clinical behavior in esophageal cancer, thus helping to define appropriate therapeutic protocols and to identify patients who will benefit from surgery. We therefore characterized, by Northern blot and/or immunohistochemistry, the relative expression of three effectors involved in the invasion, angiogenesis, and dissemination of tumor cells in esophageal cancer versus nontumoral mucosae: (a) stromelysin-3 (ST3), a member of the metalloproteinase family; (b) basement membrane 40/secreted protein acidic and rich in cysteine (BM-40/SPARC), an extracellular matrix-associated protein involved in angiogenesis; and (c) the hepatocyte growth factor receptor MET, which triggers the scattering of epithelial cells. Results were analyzed in relation to clinicopathological parameters (cpTNE) including tumor size (T), lymph node status (N), periesophageal tissue invasion (E), disease recurrence, and overall survival. The ST3, BM-40/SPARC, and MET genes were found to be overexpressed in tumor samples compared to control mucosa. BM-40/SPARC and MET mRNA levels were not linked to any one of the cpTNE, indicating that this overexpression occurs at an early stage of neoplastic progression. In contrast, ST3 expression, identified by immunohistochemistry in fibroblastic cells surrounding neoplastic islets, correlated with tumor size and periesophageal tissue invasion. Of the 36 patients studied, those with high ST3 levels had shorter disease-free survival than those with low levels, but there was no relationship between the cpTNE and disease recurrence or survival. Our study demonstrates that ST3, BM-40/SPARC, and MET are involved in different steps of esophageal carcinogenesis and that ST3 overexpression is a marker of aggressive clinical behavior. We conclude that in esophageal cancer, ST3 might help to assess survival and the risk of recurrence after surgical resection.
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PMID:Overexpression of stromelysin-3, BM-40/SPARC, and MET genes in human esophageal carcinoma: implications for prognosis. 962 53

Activator protein-1 (AP-1) is a transcription factor that consists of either a Jun-Jun homodimer or a Jun-Fos heterodimer. Transactivation of AP-1 is required for tumor promoter-induced transformation in mouse epidermal JB6 cells and for progression in mouse and human keratinocytes. Until now, the question of whether AP-1 transactivation is required for carcinogenesis in vivo has remained unanswered, as has the issue of functionally significant target genes. To address these issues we have generated a transgenic mouse in which transactivation mutant c-jun (TAM67), under the control of the human keratin-14 promoter, is expressed specifically in the basal cells of the epidermis where tumor induction is initiated. The keratin-14-TAM67 transgene was expressed in the epidermis, tongue, and cervix, with no apparent abnormalities in any tissue or organ. TAM67 expression blocked 12-O-tetradecanoylphorbol 13-acetate (TPA, phorbol 12-tetradecanoate 13-acetate) induction of the AP-1-regulated luciferase in AP-1 luciferase/TAM67 mice, but did not inhibit induction of candidate AP-1 target genes, collagenase-1 or stromelysin-3. More interestingly, TAM67 expression did not inhibit TPA-induced hyperproliferation. In two-stage skin carcinogenesis experiments, the transgenic animals showed a dramatic inhibition of papilloma induction. We conclude that transactivation of a subset of AP-1-dependent genes is required for tumor promotion and may be targeted for cancer prevention.
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PMID:Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. 1044 79

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

The purpose of the present study was to examine the pathobiological properties of a matrix metalloproteinase, MMP-11 (also known as stromelysin-3), in the carcinogenesis of lobular carcinoma of the breast. Immunohistochemical staining demonstrated immunoreactivity with specific antibody to MMP-11 in 16 of 30 lobular carcinoma cells, but not in the non-cancerous terminal duct lobular unit. In positive cases, both noninvasive and invasive cancer cells exhibited immunoreactivity with anti-MMP-11 antibody; however, the staining patterns in noninvasive and invasive foci were distinct. In the noninvasive foci, immunoreactivity was observed in the cytoplasm beneath the plasma membrane, whereas immunoreactivity was found in all of the cytoplasm of infiltrating lobular carcinoma cells. Enforced expression of MMP-11 in the cultured lobular carcinoma MDA-MB-330 cells did not affect cell growth or Matrigel invasion activity. By contrast, overexpression of MMP-11 significantly increased resistance to anoikis, a programmed cell death triggered by a lack of proper cell matrix interaction, as evidenced by decrease in annexin V-positive cells and apoptotic DNA ladders. The present findings indicate that MMP-11 is overexpressed in many lobular carcinoma cells and that it may play a role in lobular carcinogenesis through increasing resistance to anoikis.
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PMID:Matrix metalloproteinase-11 overexpressed in lobular carcinoma cells of the breast promotes anoikis resistance. 2177 55