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)

Human kallikrein 6 (KLK6) was identified based on its transient upregulation in a primary breast tumor and its subsequent silencing in a metastatic tumor from the same patient. The molecular mechanism(s) underlying the deregulated expression of KLK6 during cancer progression are currently unknown. Here, we provide evidence that aberrant expression of KLK6 is regulated at the level of transcription by multiple cooperating mechanisms. KLK6 can be reactivated in non-expressing breast cancer cells by treatment with 5-aza-2'-deoxycytidine (5-aza-dC), a compound causing DNA demethylation. Trichostatin A (TSA), an inhibitor of histone deacetylases, resulted in moderate induction of KLK6 only in MDA-MB-231 cells. However, combined 5-aza-dC/TSA treatment resulted in synergistic activation of KLK6. We show that KLK6 inactivation is associated with hypermethylation of specific CpG dinucleotides located in the KLK6 proximal promoter and overexpression with complete demethylation. These results indicate a causal role of DNA methylation and chromatin structure in cancer-associated loss of KLK6 expression. In some breast cancer cell lines, KLK6 expression could be restored by the vitamin D3 analog EB1089. Our data indicate that transcriptional deregulation of KLK6 in cancer cells during breast cancer progression is complex and certainly not uniform in different tumors, involving epigenetic mechanisms as well as pathways regulated by nuclear receptors. This allows for the pharmacological modulation of KLK6 with potential therapeutic implications.
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PMID:Multiple mechanisms underlie the aberrant expression of the human kallikrein 6 gene in breast cancer. 1680 Jul 39

Chromosomal translocations that join the cellular oncogene Myc (c-myc) with immunoglobulin (Ig) heavy-chain (Igh) or light-chain (Igk, Igl) loci are widely believed to be the crucial initiating oncogenic events in the development of B cell and plasma cell neoplasms in three mammalian species: Burkitt lymphoma (BL) in human beings, plasmacytoma (PCT) in mice, and immunocytoma in rats. Among the Myc-Ig translocations found in these neoplasms, mouse PCT T(12;15)(Igh-Myc) is of special interest because it affords a uniquely useful model system to study the fundamental outstanding questions on the mechanisms, genetics, and biological consequences of Myc translocations. Mouse T(12;15) is the direct counterpart of the human BL t(8;14)(q24;q32) translocation and thus of great relevance for human cancer. Mouse T(12;15) is the only cancer-associated translocation in mice that occurs with high incidence, spontaneity, and cell-type specificity. Due to the development of PCR methods for the detection of the underlying reciprocal Myc-Igh junction fragments, it is now known that mouse T(12;15) can be a dynamic process that begins with the genetic exchange of Myc and the Igh switch mu region (Smu), progresses by class switch recombination (CSR) just 3' of the translocation break site, and then undergoes further clonal diversification by micro-deletions in the junction flanks. The molecular pathway that subverts CSR to mediate trans-chromosomal joining of Myc and Smu (translocation origin) and secondary modification of Myc-Igh junctions (translocation "remodeling") has not been elucidated, but recent evidence indicates that it includes CSR factors, such as the activation-induced cytidine deaminase (AID), that may also be involved in the ongoing neoplastic progression of the translocation-bearing tumor precursor. Transgenic mouse models of T(12;15)/t(8;14), including newly developed "iMyc" gene-insertion mice, will be useful in elucidating the role of these CSR factors in the progression of Myc-induced B cell tumors.
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PMID:Myc translocations in B cell and plasma cell neoplasms. 1681 5

It is not surprising that cancer, a kind of derangement of development, hijacks DNA methylation, which is necessary for normal mammalian embryogenesis. Both decreases and increases in DNA methylation are a frequent characteristic of a wide variety of cancers. There is often more hypomethylation than hypermethylation of DNA during carcinogenesis, leading to a net decrease in the genomic 5-methylcytosine content. Although the exact methylation changes between different cancers of the same type are not the same, there are cancer type-specific differences in the frequency of hypermethylation or hypomethylation of certain genomic sequences. These opposite types of DNA methylation changes appear to be mostly independent of one another, although they may arise because of a similar abnormality leading to long-lasting epigenetic instability in cancers. Both tandem and interspersed DNA repeats often exhibit cancer-associated hypomethylation. However, one of these repeated sequences (NBL2) displayed predominant increases in methylation in some ovarian carcinomas and Wilms tumors and decreases in others. Furthermore, decreases and increases in CpG methylation can be interspersed within a small subregion of the 1.4-kb repeat unit of these tandem arrays. While the transcription-silencing role of DNA hypermethylation at promoters of many tumor-suppressor genes is clear, the biological effects of cancer-linked hypomethylation of genomic DNA are less well understood. Evidence suggests that DNA hypomethylation functions in direct or indirect control of transcription and in destabilizing chromosomal integrity. Recent studies of cancer-linked DNA hypomethylation indicate that changes to DNA methylation during tumorigenesis and tumor progression have a previously underestimated plasticity and dynamic nature.
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PMID:Cancer-linked DNA hypomethylation and its relationship to hypermethylation. 1690 14

Patients with metastatic cancer commonly have increased serum galectin-3 concentrations, but it is not known whether this has any functional implications for cancer progression. We report that MUC1, a large transmembrane mucin protein that is overexpressed and aberrantly glycosylated in epithelial cancer, is a natural ligand for galectin-3. Recombinant galectin-3 at concentrations (0.2-1.0 microg/ml) similar to those found in the sera of patients with metastatic cancer increased adhesion of MUC1-expressing human breast (ZR-75-1) and colon (HT29-5F7) cancer cells to human umbilical vein endothelial cells (HUVEC) by 111% (111 +/- 21%, mean +/- S.D.) and 93% (93 +/- 17%), respectively. Recombinant galectin-3 also increased adhesion to HUVEC of MUC1 transfected HCA1.7+ human breast epithelial cells that express MUC1 bearing the oncofetal Thomsen-Friedenreich antigen (Galbeta1,3 GalNAc-alpha (TF)) but did not affect adhesion of MUC1-negative HCA1.7-cells. MUC1-transfected, Ras-transformed, canine kidney epithelial-like (MDE9.2+) cells, bearing MUC1 that predominantly carries sialyl-TF, only demonstrated an adhesive response to galectin-3 after sialidase pretreatment. Furthermore, galectin-3-mediated adhesion of HCA1.7+ to HUVEC was reduced by O-glycanase pretreatment of the cells to remove TF. Recombinant galectin-3 caused focal disappearance of cell surface MUC1 in HCA1.7+ cells, suggesting clustering of MUC1. Co-incubation with antibodies against E-Selectin or CD44H, but not integrin-beta1, ICAM-1 or VCAM-1, largely abolished the epithelial cell adhesion to HUVEC induced by galectin-3. Thus, galectin-3, by interacting with cancer-associated MUC1 via TF, promotes cancer cell adhesion to endothelium by revealing epithelial adhesion molecules that are otherwise concealed by MUC1. This suggests a critical role for circulating galectin-3 in cancer metastasis and highlights the functional importance of altered cell surface glycosylation in cancer progression.
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PMID:Galectin-3 interaction with Thomsen-Friedenreich disaccharide on cancer-associated MUC1 causes increased cancer cell endothelial adhesion. 1709 May 43

We examined the proteomic background of esophageal cancer. We used laser microdissection to obtain tumor tissues from 72 esophageal squamous cell carcinoma cases and adjacent normal tissues in 57 of these cases. The 2D-DIGE generated quantitative expression profiles with 1730 protein spots. Based on the intensity of the protein spots, unsupervised classification distinguished the tumor tissues from their normal counterparts, and subdivided the tumor tissues according to their histological differentiation. We identified 498 protein spots with altered intensity in the tumor tissues, which protein identification by LC-MS/MS showed to correspond to 217 gene products. We also found 41 protein spots that were associated with nodal metastasis, and identified 33 proteins corresponding to the spots, including cancer-associated proteins such as alpha-actinin 4, hnRNP K, periplakin, squamous cell carcinoma antigen 1 and NudC. The identified cancer-associated proteins have been previously reported to be individually involved in a range of cancer types, and our study observed them collectively in a single type of malignancy, esophageal cancer. As the identified proteins are involved in important biological processes such as cytoskeletal/structural organization, transportation, chaperon, oxidoreduction, transcription and signal transduction, they may function in a coordinate manner in carcinogenesis and tumor progression of esophageal cancer.
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PMID:Protein clusters associated with carcinogenesis, histological differentiation and nodal metastasis in esophageal cancer. 1713 71

Every year, renal cell carcinoma (RCC) is responsible for the highest proportion of cancer-associated deaths in relation to all other malignant urological diseases. Initially called carcinosarcoma, the sarcomatoid differentiation confers higher aggressiveness on any of the different subtypes of RCC, with a frequency of ca. 1%. The presence of a sarcomatoid component makes the disease locally aggressive, which typically presents an advanced grade that is associated with fast progression and fatal outcome in a vast proportion of cases, with median survival lower than 1 year. This is important for predicting the outcome for patients undergoing nephrectomy due to RCC, since chemotherapy in a certain group of patients with progressive disease can be a reasonable alternative to the failure of immunotherapy in sarcomatoid renal carcinoma. We report our experience with sarcomatoid RCC in four patients with extensive tumor progression in comparison to the literature.
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PMID:[Sarcomatoid renal cell carcinoma. A rare and aggressive variation of primary renal cell carcinoma]. 1716 Jun 66

The PTEN tumor suppressor is frequently affected in cancer cells, and inherited PTEN mutation causes cancer-susceptibility conditions such as Cowden syndrome. PTEN acts as a plasma-membrane lipid-phosphatase antagonizing the phosphoinositide 3-kinase/AKT cell survival pathway. However, PTEN is also found in cell nuclei, but mechanism, function, and relevance of nuclear localization remain unclear. We show that nuclear PTEN is essential for tumor suppression and that PTEN nuclear import is mediated by its monoubiquitination. A lysine mutant of PTEN, K289E associated with Cowden syndrome, retains catalytic activity but fails to accumulate in nuclei of patient tissue due to an import defect. We identify this and another lysine residue as major monoubiquitination sites essential for PTEN import. While nuclear PTEN is stable, polyubiquitination leads to its degradation in the cytoplasm. Thus, we identify cancer-associated mutations of PTEN that target its posttranslational modification and demonstrate how a discrete molecular mechanism dictates tumor progression by differentiating between degradation and protection of PTEN.
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PMID:Ubiquitination regulates PTEN nuclear import and tumor suppression. 1721 52

Missense variants are commonly identified in genomic sequence but only a small fraction directly contribute to oncogenesis. The ability to distinguish those missense changes that contribute to cancer progression from those that do not is a difficult problem usually only accomplished through functional in vivo analyses. Using two computational algorithms, Sorting Intolerant from Tolerant (SIFT) and the Pfam-based LogR.E-value method, we have identified features that distinguish cancer-associated missense mutations from other classes of missense change. Our data reveal that cancer mutants behave similarly to Mendelian disease mutations, but are clearly distinct from either complex disease mutations or common single-nucleotide polymorphisms. We show that both activating and inactivating oncogenic mutations are predicted to be deleterious, although activating changes are likely to increase protein activity. Using the Gene Ontology and data from the SIFT and LogR.E-value metrics, a classifier was built that predicts cancer-associated missense mutations with a very low false-positive rate. The classifier does remarkably well in a number of different experiments designed to distinguish polymorphisms from true cancer-associated mutations. We also show that recurrently observed mutations are much more likely to be predicted to be cancer-associated than rare mutations, suggesting that our classifier will be useful in distinguishing causal from passenger mutations. In addition, from an expressed sequence tag-based screen, we identified a previously unknown germ line change (P1104A) in tumor tissues that is predicted to disrupt the function of the TYK2 protein. The data presented here show that this novel bioinformatics approach to classifying cancer-associated variants is robust and can be used for large-scale analyses.
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PMID:Distinguishing cancer-associated missense mutations from common polymorphisms. 1723 53

Human sodium iodide symporter (hNIS) is a transmembrane protein that actively transports iodide ions into thyroid cells. hNIS is over-expressed in some cases of the thyroid cancers compared with the surrounding normal tissues and has been considered to be an attractive target for immunotherapy. The aim of this study is to determine the feasibility of utilizing the hNIS antigenic protein in enhanced-antigen-associated immunotherapy using image analysis with a gamma counter. To accomplish this, minimalistic immunogenically defined gene expression (MIDGE), either plain or coupled to a nuclear localization signal (NLS) peptide, was used as a vector system. Vaccination with MIDGE/hNIS, MIDGE/hNIS-NLS and pcDNA3.1/hNIS produced a significant increase in the number of hNIS-associated IFN-gamma-secreting CD8(+) T cells, with MIDGE/hNIS having the strongest effect. In addition, immunization with the hNIS encoding vectors induced antigen-mediated antitumor activity against NIS-expressing CT26 tumors in vivo, with the highest tumor free rate (100%) and lowest tumor growth being observed up to 40 days after the CT26/NIS tumor challenge with MIDGE/hNIS than those resulting from other immunization groups. Tumor progression could be followed noninvasively and repetitively by monitoring levels of hNIS gene expression in the tumors using scintigraphic image analysis. Overall, hNIS has a potential use as an antigen for immunization approaches, and vaccination with MIDGE/hNIS vectors is an effective means of generating hNIS-associated immune responses in mice.
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PMID:MIDGE/hNIS vaccination generates antigen-associated CD8+IFN-gamma+ T cells and enhances protective antitumor immunity. 1726 27

Molecular links between apoptosis, tumorigenesis and drug resistance provide starting points for new therapeutic approaches and for a targeted cancer therapy. The discovery of the p53-related genes p63 and p73 raised the possibility that they may be cancer-associated genes and as a consequence that p53 is not the only component in predicting prognosis and response to chemotherapy, but instead the status of a network that contains p53, p73 and p63. This review focuses on the status and interrelationship of the p53 family members in human cancer as critical elements for tumor progression and response to therapy. Literature up to December 2006 is reviewed. p63 and p73--as well as p53--each use multiple promoters and alternative splicing to generate an array of isoforms, including full-length isoforms with a transactivation (TA-) domain homologous to that of full-length p53, and amino-terminally truncated (DeltaN-) isoforms. Whereas the full-length TA isoforms of p63 and p73 can activate downstream target genes and induce apoptosis, the DeltaN isoforms which lack the transactivation domain can act as dominant inhibitors of the full-length forms of p53, p63 and p73, inhibiting transactivation of target genes and induction of apoptosis. Deregulated dominant negative p63 and p73 isoforms play an oncogenic role in human cancer and contribute to chemoresistance. Thus, therapeutic modulation of TAp63/DeltaNp63, TAp73/DeltaNp73 and mutant p53 levels might be used to target the large percentage of human tumors that harbor p53 mutations and/or overexpress DeltaNp63 or DeltaNp73. Interfering with the expression or function of DeltaNp63 and/or DeltaNp73 and/or mutant p53 in tumor cells may render such tumors more responsive to therapy and reduce their aggressiveness and metastatic capacity.
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PMID:One, two, three--p53, p63, p73 and chemosensitivity. 1728 42


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