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)

Numerous studies have demonstrated that overexpression or aberrant expression of the HMGI(Y) family of architectural transcription factors is frequently associated with both neoplastic transformation of cells and metastatic tumor progression. Little is known, however, about the molecular roles played by the HMGI(Y) proteins in these events. Here we report that human breast epithelial cells harboring tetracycline-regulated HMGI(Y) transgenes acquire the ability to form both primary and metastatic tumors in nude mice only when the transgenes are actively expressed. Unexpectedly, the HMG-Y, rather than the HMG-I, isoform of these proteins is the most effective elicitor of both neoplastic transformation and metastatic progression in vivo. Furthermore, expression of either antisense or dominant-negative HMGI(Y) constructs inhibits both the rate of proliferation of tumor cells and their ability to grow anchorage independently in soft agar. Array analysis of transcription profiles demonstrates that the HMG-I and HMG-Y isoform proteins each modulate the expression of distinctive constellations of genes known to be involved in signal transduction, cell proliferation, tumor initiation, invasion, migration, induction of angiogenesis, and colonization. Immunohistochemical analyses of tumors formed in nude mice indicate that many have undergone an epithelial-mesenchymal transition in vivo. Together, these findings demonstrate that overexpression of the HMGI(Y) proteins, more specifically, the HMG-Y isoform protein, is causally associated with both neoplastic transformation and metastatic progression and suggest that induction of integrins and their signaling pathways may play significant molecular roles in these biological events.
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PMID:Architectural transcription factor HMGI(Y) promotes tumor progression and mesenchymal transition of human epithelial cells. 1113 44

A combination of flow cytometry and microsatellite analysis was used to investigate loss of expression of HLA-A and/or HLA-B alleles and concurrent LOH at polymorphic chromosome 6 loci both in freshly isolated lymphocytes (in vivo mutations) and in lymphocytes cultured ex vivo. The fraction of in vivo mutants that showed LOH at 6p appeared to vary from 0%-49% for various donors. During culturing ex vivo, HLA-A(-) cells arose at a high rate and showed simultaneous loss of expression at the linked HLA-B locus. Up to 90% of the ex vivo arisen HLA-A2(-) cell population showed LOH of multiple 6p markers, and 50% had lost heterozygosity at 6q. This ex vivo spectrum resembles that found in HLA-A2 mutants obtained from lymphoblastoid cells. The HLA-A2 mutants present in vivo may reflect only a small fraction of the mutants that can be detected ex vivo. In normal lymphocytes, in vivo only mitotic recombination appears to be sustained, indicating the importance of this mechanism for tumor initiation in normal cells. Although mutations resulting in LOH at both chromosome 6 arms were shown to result in nonviable cells in normal lymphocytes, they have been shown to result in viable mutants in lymphoblastoid cells. We hypothesize that these types of mutations also occur in vivo but only survive in cells that already harbor a mutated genetic background. In light of the high rate at which these types of mutations occur, they may contribute to cancer progression.
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PMID:Intrinsic genetic instability of normal human lymphocytes and its implication for loss of heterozygosity. 1124 85

The molecular pathways and the timing of genetic events during human colorectal carcinogenesis are still not fully understood. We have addressed the intratumor heterogeneity of the mutational status of the k-ras oncogene and of the p53 oncosuppressor gene during the adenoma-carcinoma sequence by investigating 26 human colorectal adenomas containing early cancer. An intratumor comparative analysis was obtained among the adenomatous and carcinomatous component pairs. Additionally, we have analyzed 17 adenomas having cancer in the near vicinity. The adenomatous components of the adenomas containing early cancer and the adenomas having cancer in the near vicinity had comparable frequencies for k-ras mutations (28 and 47%) but different for p53 mutations (52 and 7%, p-value = 0.01). Interestingly, the adenomatous and carcinomatous components of the adenomas containing early cancer were rarely heterogeneous for the k-ras mutational status (only in 13% of the cases) but were characterized by heterogeneity of the p53 status in 59% of the cases (p-value < 0.01). In addition, the mutations of p53 for the adenomatous components of the adenomas containing early cancer were statistically significantly associated with severe dysplasia (p-value = 0.01). Intratumor homogeneity of k-ras status during the human colorectal adenoma-carcinoma sequence suggests that the role of k-ras is more related to tumor initiation than to tumor progression. On the contrary, intratumor heterogeneity of p53 mutations indicates that the type of the p53 mutations may also be relevant for selection and expansion of new subclones leading to tumor progression.
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PMID:Intratumor heterogeneity of k-ras and p53 mutations among human colorectal adenomas containing early cancer. 1131 Jun 41

About 5% of colon cancer cases correspond to classic hereditary monogenic mendelian transmission involving at least 8 major genes of predisposition to this tumor. Genes with more moderate effects, in association with other genes can contribute to the occurrence of sporadic polygenic forms. These genes confer susceptibility to environmental factors and can play the role of aggravating or protective modifier genes in the different hereditary forms. Foods can interact with these genes and modulate their expression. Moreover sequence variations (polymorphisms) in these genes may also be responsible for slower or more rapid metabolism of nutrients leading to toxic or carcinogenic compounds. If some foods, or "pharmafoods" can have beneficial effects in some individuals with a particular subtype of the disease, others can be inefficient or even detrimental in patients with the same disease but with a different genetic origin or if the genetic background is different. Moreover tumorigenic processes are diverse. Tumor progression depends on genetic and environmental factors different from tumor initiation and on the site of the tumor along the colon tract. Interactions with the gut flora, the lymphoid system and specific features of growth of the colon mucosa are also important parameters. Today with a formidable genetic knowledge arising from the genome project, new epidemiological data integrating the genetic data for multiple markers and a better knowledge of the tumorigenic processes involved, a new discipline is emerging. "Nutrigenetics" which is the study of hereditary basis of individual variations in response to foods opens for the oncoming decade the era of a personalised predictive medecine based on a nutrition adapted to the genetic make up of each of us.
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PMID:[Colon cancer and nutritional genetics: modifier genes]. 1159 47

The malignant phenotype results from multiple genetic alterations, including the activation of oncogenes and inactivation of tumor suppressor genes. Activation of the Ki-ras oncogene has been implicated as an early event in the pathogenesis of lung adenocarcinomas in humans and experimental animal models. Previous studies from this laboratory have shown that, following treatment of pregnant [D2 x B6D2F(1)]F(2) or Balb/c mice with the polycyclic aromatic hydrocarbon, 3-methylcholanthrene (MC), lung tumors from the transplacentally exposed offspring exhibited a high incidence of mutations in the Ki-ras gene. The role of genetic alterations at other oncogenic or tumor suppressor loci that can mediate lung tumor initiation and/or progression have not been well characterized in either human or murine models. Using the transplacental carcinogenesis model, which results in the induction of both lung and liver tumors following in utero exposure to MC, the results of this and our previous studies show that alterations in the Ink4a locus occur in only 15 and 27% of the lung and liver tumors, respectively. Preliminary data also suggests that the type of mutation induced in the Ki-ras gene following the initial exposure to MC may influence lung tumor progression. These results imply that damage to the Ink4a gene is not a frequent pathway to malignant progression in mouse lung and liver tumors following in utero exposure to environmental carcinogens.
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PMID:Alterations at the Ink4a locus in transplacentally induced murine lung tumors. 1159 30

Circulating tumor DNA in plasma and serum has been demonstrated to reflect the biological characteristics of tumors, including the rates of apoptosis and necrosis. Aberrant promoter methylation has increasingly emerged as a fundamental molecular abnormality associated with loss of critical gene functions during carcinogenesis. This epigenetic inheritance has significant biological implications for early tumor initiation and cancer progression or metastasis formation. The promoter-region methylation is crucial in transcriptional silencing of tumor suppressor genes, DNA repair genes, and metastasis inhibitor genes, and is linked to the predisposition of genetic alterations of other cancer-associated genes. Of clinical relevance, epigenetic markers in plasma and serum have recently been established as specific and sensitive biomarkers for early and noninvasive screening, risk assessment, and monitoring of neoplastic diseases. A panel of epigenetic markers may possibly allow the detection of circulating tumor DNA in virtually all patients with different cancer types. Furthermore, the prognostic value of aberrant DNA methylation and therapeutic implications of demethylation of methylated genes could further improve the management of patients with different kinds of cancer.
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PMID:Epigenetic tumor markers in plasma and serum: biology and applications to molecular diagnosis and disease monitoring. 1170 93

Adenocarcinoma of the lung is the most common form of lung cancer, but the cell of origin and the stages of progression of this tumor type are not well understood. We have developed a new model of lung adenocarcinoma in mice harboring a conditionally activatable allele of oncogenic K-ras. Here we show that the use of a recombinant adenovirus expressing Cre recombinase (AdenoCre) to induce K-ras G12D expression in the lungs of mice allows control of the timing and multiplicity of tumor initiation. Through the ability to synchronize tumor initiation in these mice, we have been able to characterize the stages of tumor progression. Of particular significance, this system has led to the identification of a new cell type contributing to the development of pulmonary adenocarcinoma.
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PMID:Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. 1175 30

The homeodomain-containing transcription factor NKX3.1 is a putative prostate tumor suppressor that is expressed in a largely prostate-specific and androgen-regulated manner. Loss of NKX3.1 protein expression is common in human prostate carcinomas and prostatic intraepithelial neoplasia (PIN) lesions and correlates with tumor progression. Disruption of the murine Nkx3.1 gene results in defects in prostate branching morphogenesis, secretions, and growth. To more closely mimic the pattern of NKX3.1 loss that occurs in human prostate tumors, we have used Cre- and loxP-mediated recombination to delete the Nkx3.1 gene in the prostates of adult transgenic mice. Conditional deletion of one or both alleles of Nkx3.1 leads to the development of preinvasive lesions that resemble PIN. The pattern of expression of several biomarkers (Ki-67, E-cadherin, and high-molecular-weight cytokeratins) in these PIN lesions resembled that observed in human cases of PIN. Furthermore, PIN foci in mice with conditional deletion of a single Nkx3.1 allele lose expression of the wild-type allele. Our results support the role of NKX3.1 as a prostate tumor suppressor and indicate a role for this gene in tumor initiation.
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PMID:Conditional loss of Nkx3.1 in adult mice induces prostatic intraepithelial neoplasia. 1183 15

COX-2, the isoform of cyclooxygenase inducible by cytokines, mitogens, and growth factors, appears to play an important role in inflammation and carcinogenesis. In the colon, COX-2 overexpression results in cell cycle alterations, and NSAIDs have proven effective in cancer chemoprevention. HNPCC (hereditary nonpolyposis colon cancer) is a clinically defined cancer susceptibility syndrome in which women are also at significantly increased risk for the development of endometrial carcinoma. The purpose of this study was to evaluate expression of COX-2 in benign and malignant endometrium in the context of other cell cycle and proliferation markers, including Ki-67, cyclin D1, and the cyclin-dependent kinase inhibitor, p21. Immunostains with COX-2, Ki-67, cyclin D1, and p21 antibodies were performed on formalin-fixed and paraffin-embedded tissue sections from 40 cases: 10 benign (5 atrophic and 5 proliferative) endometria, 6 hyperplasias (complex without atypia), and 24 endometrioid carcinomas (9 well, 4 moderately, and 11 poorly differentiated). Ki-67 was positive in all proliferative and neoplastic endometria. Cyclin D1 and p21 were both overexpressed in endometrial hyperplasia and endometrioid carcinomas. COX-2 was negative in the nonneoplastic endometrium, stained minimally in the well-differentiated endometrioid carcinomas, and stained most strongly in the moderately and poorly differentiated endometrioid carcinomas. Because cyclin D1 may function as an oncogene, its effects may dominate the usual inhibitory effect of a rising p21. Alternatively, it has been shown that p21 can promote cell cycle function by stabilizing cell cycle complexes. The overexpression of COX-2 in poorly differentiated endometrioid carcinoma and lack of expression in hyperplasia and well-differentiated carcinoma suggests that in this form of cancer, COX-2 may play a role in tumor progression rather than tumor initiation.
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PMID:Expression of COX-2, Ki-67, cyclin D1, and P21 in endometrial endometrioid carcinomas. 1191 24

Thyroid follicular neoplasms commonly have aneuploidy, presumably due to chromosomal instability. This property is associated with a greater malignant potential and worse prognosis. Recently, there has been considerable progress in our understanding of mechanisms that may account for chromosomal instability in cancer cells. Many tumors with chromosomal instability have abnormalities in the cell cycle checkpoint that monitors the fidelity of mitosis. Mutations of Bub1 or BubR1, genes coding for kinases involved in mitotic spindle assembly checkpoint signaling, are found in a small subset of aneuploid tumors. Other components of protein complexes responsible for attachment of kinetochores to microtubules, or for cohesion between sister chromatids, may also be subject to alterations during tumor progression. Here, we also discuss the evidence that certain oncogenic events, such as Ras mutations, may predispose cells to chromosomal instability by favoring inappropriate posttranslational changes in mitotic checkpoint components through activation of upstream kinases during tumor initiation or progression.
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PMID:Minireview: branded from the start-distinct oncogenic initiating events may determine tumor fate in the thyroid. 1198 Oct 26


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