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)

Cancer-associated DNA hypomethylation is as prevalent as cancer-linked hypermethylation, but these two types of epigenetic abnormalities usually seem to affect different DNA sequences. Much more of the genome is generally subject to undermethylation rather than overmethylation. Genomic hypermethylation in cancer has been observed most often in CpG islands in gene regions. In contrast, very frequent hypomethylation is seen in both highly and moderately repeated DNA sequences in cancer, including heterochromatic DNA repeats, dispersed retrotransposons, and endogenous retroviral elements. Also, unique sequences, including transcription control sequences, are often subject to cancer-associated undermethylation. The high frequency of cancer-linked DNA hypomethylation, the nature of the affected sequences, and the absence of associations with DNA hypermethylation are consistent with an independent role for DNA undermethylation in cancer formation or tumor progression. Increased karyotypic instability and activation of tumor-promoting genes by cis or trans effects, that might include altered heterochromatin-euchromatin interactions, may be important consequences of DNA hypomethylation which favor oncogenesis. The relationship of DNA hypomethylation to tumorigenesis is important to be considered in the light of cancer therapies involving decreasing DNA methylation. Inducing DNA hypomethylation may have short-term anticancer effects, but might also help speed tumor progression from cancer cells surviving the DNA demethylation chemotherapy.
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PMID:DNA methylation in cancer: too much, but also too little. 1215 3

Inhibition of matrix metalloproteinases (MMPs), a family of proteolytic enzymes linked to many aspects of cancer progression, has been explored as a therapeutic goal for almost two decades. Thus far, all tested MMP inhibitors (MMPIs) have failed to reach primary end points in Phase III clinical trials, although secondary analyses suggest benefits in particular patient groups. The clinical development of these agents has been hampered by problems related to determination of effective dosages and side effects that necessitate dose lowering or drug holidays. Imaging technologies offer hope as a means to measure enzyme activity and hence effective enzyme inhibition in vivo. Meanwhile, recent results from genetic studies of both mice and man have given some clues to possible causes of musculoskeletal side effects. Future progress in the therapeutic use of MMPIs is dependent on the ability to selectively target cancer-associated MMPs at the correct stage in tumour progression and the development of surrogate markers of in vivo efficacy.
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PMID:Matrix metalloproteinase inhibitors for cancer therapy:the current situation and future prospects. 1278 74

The progression of primary tumors to an invasive phenotype requires dynamic changes in multiple cellular and local tumor microenvironment markers. In this study, we report a genomic approach to assess gene transcriptional changes upon overexpression of ErbB receptors, in vitro and in vivo, focusing on markers involved in the regulation of the tumor microenvironment. ErbB receptors (ErbB-1/epidermal growth factor receptor, ErbB-2, ErbB-3, and ErbB-4) were stably overexpressed in a polyclonal cell population as single or paired combinations using murine and human breast cell models. The overall numbers of known genes that are up- or down-regulated was significantly higher in cells and tumors overexpressing paired combinations of receptors compared with cells and tumors overexpressing single ErbB receptors. Genes encoding components of cell-cell structures, extracellular matrix, coagulation factors, and angiogenesis were predominantly affected by the most active ErbB receptor combinations and were predictive of the aggressive in vivo tumorigenicity, a feature that was not always seen in vitro. Among ErbB-regulated tumor microenvironment markers detected by the genomic analysis, thrombospondin 1, an endogenous inhibitor of angiogenesis, was additionally validated in relation to tumor growth phenotype. Thrombospondin 1 mRNA and protein were down-regulated by specific ErbB receptors, in vitro and in both rodent and human ErbB-induced tumors, consistent with the extent of tumor growth and tumor vascularization associated with specific ErbB receptors. In summary, our genomic results highlight the broad diversity of ErbB-regulated cancer-associated genes and revealed several novel targets that may have potential therapeutic applications for targeting tumor progression involving aberrations of ErbB receptors.
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PMID:Regulation of multiple tumor microenvironment markers by overexpression of single or paired combinations of ErbB receptors. 1283 72

Sarcomatoid carcinoma of the esophagus is an unusual type of squamous cell carcinoma (SCC) with a variable component of sarcomatoid spindle cells (SA). The loss of heterozygosity (LOH) involving multiple cancer-associated chromosomal arms has been reported to have a concerted, rather than an individual, effect on tumor progression. In order to delineate the role of LOH in the evolution of a biphasic tumor, the carcinoma in situ (CIS), invasive squamous cell carcinoma (ISCC), and SA components from a sarcomatoid carcinoma of the esophagus were compared for their clonality and extent of LOH. Forty microsatellite markers on the cancer-associated chromosomes, 3p, 4p, 5q, 8p, 9p, 13q, 17p, and 18q, were used for the polymerase chain reaction-based LOH analysis. All eight sarcomatoid carcinomas tested revealed extensive LOHs, involving an average of seven chromosomal arms. All CIS, ISCC, and SA components carried not only a high-level primary LOH (mean chromosomal involvement, 5.3) in common but also a low-level secondary LOH (mean chromosomal involvement, 1.8) in disparity. Interestingly, more secondary LOHs were always burdened in the CIS (four cases) rather than the matched ISCC. SA had a greater (four cases), equal (one case), or fewer (one case) number of secondary LOHs than ISCC. Given that excessive chromosomal losses may confer a disadvantage for tumor growth or a benefit for a metaplastic transformation, these results suggest that the multidirectional differentiation of a SCC precursor is stimulated by extensive and divergent LOHs acquired at the initial or early stages, and a precursor burdened with excessive LOH either remains in CIS or expands as a SA component.
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PMID:Extensive and divergent chromosomal losses in squamous and spindle-cell components of esophageal sarcomatoid carcinoma. 1292 97

Carbonic anhydrase IX (CA IX) is a cancer-associated transmembrane isoform of zinc metalloenzymes that catalyse interconversion between carbon dioxide and bicarbonate. CA IX is strongly induced by tumor hypoxia and has been proposed to participate in acidification of tumor microenvironment and in cell adhesion. To elucidate the cell adhesion-related role of CA IX, we investigated its subcellular localization and relationship to E-cadherin, a key adhesion molecule whose loss or destabilization is linked to tumor invasion. For this purpose, we generated MDCK cells with constitutive expression of human CA IX protein. During the monolayer formation, CA IX was localized to cell-cell contacts and its distribution in lateral membranes overlapped with E-cadherin. Calcium switch-triggered disruption and reconstitution of cell contacts resulted in relocalization of both CA IX and E-cadherin to cytoplasm and back to plasma membrane. A similar phenomenon was observed in hypoxia-treated and reoxygenated cells. Moreover, CA IX-expressing MDCK cells exhibited reduced cell adhesion capacity and lower levels of Triton-insoluble E-cadherin. Finally, CA IX was found to coprecipitate with beta-catenin. We conclude that CA IX has a capacity to modulate E-cadherin-mediated cell adhesion via interaction with beta-catenin, which could be of potential significance in hypoxia-induced tumor progression.
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PMID:Carbonic anhydrase IX reduces E-cadherin-mediated adhesion of MDCK cells via interaction with beta-catenin. 1456 91

Extensive scientific literature data point to reciprocal interactions between prostate stromal cells and prostate cancer cells that likely regulate tumor progression. To investigate whether these intratumoral-reactive stromal cells in human prostate cancer are predictive of survival, tumor stroma volume and specific stroma markers were quantitated by using tissue microarrays (index tumors of 847 patients), and the results were analyzed relative to the recurrence-free survival data set for these patients. Tumor tissue was evaluated with Masson's trichrome stains and by immunohistochemistry with antibody probes to smooth muscle alpha-actin, desmin, vimentin, pro-collagen type I, and calponin. The relative volume of intratumor stroma (5% stroma, grade 0; 5-15%, grade 1; 15-50%, grade 2; >50%, grade 3) and the expression index of stromal marker (staining intensity grade x percentage of positive cells per field) were quantitated and analyzed. Interpretable data were obtained from 545 patients. Statistical analysis of the survival data set showed that the volume of reactive stroma in the tumor was a significant predictor of disease-free survival. Stroma volume was most optimal as an independent predictor in tumors containing stroma, defined as Gleason 7 and lower grades. Of interest, tumors with either little to no stroma or tumors with abundant stroma each showed reduced recurrence-free survival. For specific stromal markers, reduced desmin and smooth muscle alpha-actin were hallmarks of cancer-associated reactive stroma relative to normal fibromuscular stroma. Quantitative analysis of desmin and smooth muscle alpha-actin expression showed both to be significant and independent predictors of recurrence-free survival. This is the first study to demonstrate that nonepithelial-reactive stroma elements in prostate cancer tumors can be used as prognostic indicators. These data also add to the concept that tumors are not purely epithelial and the tumor-reactive stroma must be considered an important biological component of the cancer.
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PMID:Reactive stroma as a predictor of biochemical-free recurrence in prostate cancer. 1458 50

Vertebrate gastrulation is a critical step in the establishment of body plan. During gastrulation, epithelial-mesenchymal transition (EMT) occurs. EMT is one of the central events of embryonic development, organ and tissue regeneration, and cancer metastasis. Signal transducers and activators of transcription (STATs) mediate biological actions such as cell proliferation, differentiation and survival in response to cytokines and growth factors, in a variety of biological processes. STATs are also important in EMT during gastrulation, organogenesis, wound healing and cancer progression. We previously showed that STAT3 is activated in the organizer during zebrafish gastrulation and its activity is essential for gastrulation movements. The requirement for STAT3 is cell-autonomous for the anterior migration of gastrula organizer cells, and non-cell-autonomous for the convergence of neighbouring cells. The molecular mechanisms of STAT's action in EMT, however, are unknown. Here we identify LIV1, a breast-cancer-associated zinc transporter protein, as a downstream target of STAT3 that is essential and sufficient for STAT3's cell-autonomous role in the EMT of zebrafish gastrula organizer cells. Furthermore, we demonstrate that LIV1 is essential for the nuclear localization of zinc-finger protein Snail, a master regulator of EMT. These results establish a molecular link between STAT3, LIV1 and Snail in EMT.
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PMID:Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. 1512 96

Cancer is an increasingly recognized problem associated with immunosuppression. Recent reports, however, suggest that the immunosuppressive agent rapamycin has anti-cancer properties that could address this problem. Thus far, rapamycin's effects on immunity and cancer have been studied separately. Here we tested the effects of rapamycin, versus cyclosporine A (CsA), on established tumors in mice simultaneously bearing a heart allograft. In one tumor-transplant model, BALB/c mice received subcutaneous syngenic CT26 colon adenocarcinoma cells 7 days before C3H ear-heart transplantation. Rapamycin or CsA treatment was initiated with transplantation. In a second model system, a B16 melanoma was established in C57BL/6 mice that received a primary vascularized C3H heart allograft. In vitro angiogenic effects of rapamycin and CsA were tested in an aortic ring assay. Results show that CT26 tumors grew for 2 weeks before tumor complications occurred. However, rapamycin protected allografts, inhibited tumor growth, and permitted animal survival. In contrast, CsA-treated mice succumbed to advancing tumors, albeit with a functioning allograft. Rapamycin's antitumor effect also functioned in severe combined immunodeficient BALB/c mice. Similar effects of the drugs occurred with B16 melanomas and primary vascularized C3H allografts in C57BL/6 mice. Furthermore, in this model, rapamycin inhibited the tumor growth-enhancing effects of CsA. Moreover, in vitro experiments showed that CsA promotes angiogenesis by a transforming growth factor-beta-related mechanism, and that this effect is abrogated by rapamycin. This study demonstrates that rapamycin simultaneously protects allografts from rejection and attacks tumors in a complex transplant-tumor situation. Notably, CsA protects allografts from rejection, but cancer progression is promoted in transplant recipients.
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PMID:Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice. 1516 84

Inherited and acquired changes in pre-mRNA splicing have been documented to play a significant role in human disease development and many cancer-associated genes are regulated by alternative splicing. Loss of fidelity, variation of the splicing process, even controlled switching to specific splicing alternatives may occur during tumor progression and could play a major role in carcinogenesis. Splice variants that are found predominantly in tumors have clear diagnostic value and may provide potential drug targets. Moreover, understanding the process of aberrant splicing and the detailed characterization of the splice variants may prove crucial to our understanding of malignant transformation. This review discusses the basic mechanism of alternative splicing, alternative splicing in cancer-associated genes, tools to identify splice variants, and the development of clinical tests based on alternatively spliced biomarkers.
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PMID:Splice variants as cancer biomarkers. 1523 40

Due to the high prevalence of cancer-associated types of human papillomavirus (HPV) and the poorly reproducible histologic classification of low-grade lesions, identifying infected women at highest risk for cancer prior to neoplastic progression remains a challenge. We therefore explored the utility of p16INK4a immunostaining as a potential diagnostic and prognostic biomarker for cervical neoplasia using paraffin-embedded tissue blocks (punch biopsies and loop electrosurgical excision procedures) obtained from women referred to colposcopy during the enrollment phase of the Guanacaste Project (1993 to 1994). All blocks from 292 women selected by HPV status (HPV negative, nononcogenic HPV positive, or oncogenic HPV positive) and representing the diagnostic spectrum of the population [normal to precancer: cervical intraepithelial neoplasia (CIN) 3] were immunostained for p16INK4a using the p16INK4a research kit based on the monoclonal antibody clone E6H4 (MTM Laboratories, Heidelberg, Germany). For CIN3, the sensitivity of diffuse p16INK4a immunostaining was 100% and the specificity was 95%. For CIN2, the sensitivity and specificity for diffuse staining were 81.1% and 95.4%, respectively. Generalized to the 10,000-woman cohort, this translated to positive predictive value and negative predictive value of 13.9% and 100% for CIN3, respectively, and 20.4% and 99.7% for CIN2 or CIN3, respectively. Of women with an initial diagnosis of less than CIN2 for whom follow-up data for up to 5 to 7 years were available, 44% with diffuse staining developed persistent infection (CIN2 or CIN3). Whereas our data support the diagnostic potential for p16INK4a, further prospective studies with detailed follow-up determining the prognostic capacity of this marker are needed.
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PMID:Validation of p16INK4a as a marker of oncogenic human papillomavirus infection in cervical biopsies from a population-based cohort in Costa Rica. 1529 58


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