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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Constitutive activation of the Wnt signaling pathway is a root cause of many colon cancers. Activation of this pathway is caused by genetic mutations that stabilize the beta-catenin protein, allowing it to accumulate in the nucleus and form complexes with any member of the lymphoid enhancer factor (LEF1) and T-cell factor (TCF1, TCF3, TCF4) family of transcription factors (referred to collectively as LEF/TCFs) to activate transcription of target genes. Target genes such as MYC, CCND1, MMP7 and TCF7 (refs. 5-9) are normally expressed in colon tissue, so it has been proposed that abnormal expression levels or patterns imposed by beta-catenin/TCF complexes have a role in tumor progression. We report here that LEF1 is a new type of target gene ectopically activated in colon cancer. The pattern of this ectopic expression is unusual because it derives from selective activation of a promoter for a full-length LEF1 isoform that binds beta-catenin, but not a second, intronic promoter that drives expression of a dominant-negative isoform. beta-catenin/TCF complexes can activate the promoter for full-length LEF1, indicating that in cancer high levels of these complexes misregulate transcription to favor a positive feedback loop for Wnt signaling by inducing selective expression of full-length, beta-catenin-sensitive forms of LEF/TCFs.
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PMID:Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer. 1132 60

T-cell prolymphocytic leukemia (T-PLL) is a rare malignant proliferation of lymphoid cells with a postthymic phenotype. Previous cytogenetic and molecular studies reported complex karyotypes with recurrent chromosomal abnormalities, including translocations involving either TCL1 at 14q32.1 or MTCP1 at Xq28, inactivation of the ATM gene by deletion and/or mutation, and isochromosomes 8. For extensive study of chromosomal imbalances in T-PLL, we analyzed 22 tumoral DNAs using comparative genomic hybridization (CGH). Abnormal CGH profiles were detected in all cases, demonstrating highly recurrent gains and losses and largely extending the abnormalities previously established. Only a few nonrecurrent abnormalities were observed, in contrast to the genetic instability anticipated from ATM inactivation. Nine recurrent regions of loss were identified at 8p (frequency 86%), 11q (68%), 22q11 (45%), 13q (41%), 6q (36%), 9p (27%), 12p (23%), 11p11-p14 (23%), and 17p (23%), as well as four regions of gain at 8q (82%), 14q32 (50%), 22q21-qter (41%), and 6p (23%). Several recurrent chromosomal abnormalities were simultaneously present in each case (mean, 5.7; up to 10), none being mutually exclusive of another. Fluorescence in situ hybridization analysis confirmed and extended 22q11 and 13q losses, giving final frequencies of 55% and 45%, respectively. Analysis of one case over a 7-year period confirmed the overall genetic stability of T-PLL and showed that tumor progression was associated with the onset of a few chromosomal abnormalities. This study establishes a complex pattern of highly recurrent chromosomal abnormalities in T-PLL, including some, such as chromosome 13 deletion, commonly found in other lymphoid malignancies.
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PMID:A complex pattern of recurrent chromosomal losses and gains in T-cell prolymphocytic leukemia. 1139 95

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

B-cell malignancies account for the majority of lymphoid tissue neoplasia. Similar to normal B cells, malignant B cells in most Hodgkin's and non-Hodgkin's types of lymphomas express B-cell receptor (BCR) on their membrane. Since neoplastic B cells retain the capacity to respond to microenvironmental signals, and in many respects still behave as normal B cells, it does not seem bizarre that the BCR, which dominates the biology of normal B cells, can remain equally important for some malignant B cells. Indirect evidence suggests that retained BCR expression, and in certain cases coupled with stimulation by antigen (Ag), may be necessary for the viability of some B-cell tumors. The aim of this review is to consider the evidence regarding the role of the BCR in tumorigenesis of B-cell lymphomas, and discuss different approaches used in evaluating this role in the persistence and progression of these malignancies. The diversity in B-cell lymphomas prevents easy classification of these cancers based on their dependence on BCR expression. It seems likely that some malignant B cells need BCR expression, or additionally, stimulation by Ag in order to survive. However, through accumulation of additional genetic changes, the original tumor can give rise to a clone that no longer requires signals from the BCR to survive. Thus, most B-cell lymphomas may initially retain dependence on BCR expression that governs normal B-cell physiology and may lose it only at later stages of tumor progression, through the accumulation of additional transforming events.
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PMID:Malignant B cells and antigenic receptor: necessity or habit? 1238 17

Using an ICR mouse model bearing a syngeneic Ehrlich ascitis carcinoma, the present study was undertaken to examine the effects of crude, water-soluble propolis (CWSP) on tumor progression, chemotherapeutic efficacy, and hematopoiesis in the peripheral blood. It was demonstrated that CWSP, administered subcutaneously, resulted in marked regression of tumor growth in mice, at the early phase after tumor inoculation (CWSP, p < 0.05 vs. saline control). Molecular analysis indicated that the CWSP is composed of 8.4% protein, 4.2% quercetin plus a variety of saccharides with a molecular weight of 29 kDa. Orally administered CWSP did not produce any regression for the observation period (oral CWSP, p > 0.05 vs. saline control). Peritoneal injection of CWSP into neonatal mice resulted in an increased lymphocyte/polymorphonuclear leukocyte ratio activity, indicating the potential activation of lymphoid cell lineages. These observations suggest that subcutaneously injected CWSP could regulate the development of tumors by possibly stimulating multicellular immunity. In addition, oral administration of CWSP concurrently with 5-fluorouracil (5-FU) or mitomycin C (MMC), significantly increased tumor regression as compared with the respective chemotherapy alone, illustrating the adjuvant effect of orally administered CWSP for tumor regression when combined with chemotherapeutic agents. To examine further the potential usefulness of CWSP for chemotherapeutic regimens, which induce profound multilineage hematopoietic suppression, mice that received CWSP orally in addition to a 5-FU or MMC were followed for absolute numbers of platelets and white and red blood cells. The oral administration of CWSP significantly ameliorated the cytopenia induced by 5-FU, resulting in recovery of white as well as red blood cell counts (5-FU plus CWSP, p < 0.05 vs. 5-FU alone or water control; white blood cells on day 15, red blood cells on day 25), but no marked effects on platelet counts was observed (5-FU plus CWSP, p > 0.05 vs. 5-FU alone or water control). On the other hand, CWSP significantly reduced all three MMC-induced cytopenias, especially at the later stage of the chemotherapeutic course (after day 30), suggesting repetitive requirements of oral administration of CWSP. In summary, subcutaneous administration of an aqueous CWSP resulted in marked regression of transplanted tumors. Orally administered CWSP combined with chemotherapeutic agents significantly increased tumor regression and ameliorated the cytopenia induced by the chemotherapeutic agents alone. These results suggest the benefits of potential clinical trials using CWSP combined with chemotherapeutic agents in order to maximize enhanced immunity while potentially minimizing postchemotherapeutic deteriorated reactions.
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PMID:Antitumor and anticytopenic effects of aqueous extracts of propolis in combination with chemotherapeutic agents. 1247 Apr 25

Matrix metalloproteinase 7 (MMP-7) may play a key role in the progression of various human malignant tumors. Nuclear beta-catenin enhances the activating expression of MMP-7 genes by binding with the T-cell factor/lymphoid enhancer factor family of transcription factors. We immunohistochemically examined the expression of MMP-7 and beta-catenin to better understand the significance of these factors in the progression of esophageal squamous cell carcinoma. The entire coding region of beta-catenin exon 3 was also analyzed by direct sequencing in all cases. We found that MMP-7 was expressed in 7 (20.6%) of 34 esophageal squamous cell carcinomas. There was a significant relationship between MMP-7 expression and tumor invasion into adjacent structures (P < 0.05). Aberrant nuclear expression of beta-catenin was found in 12 of 34 (35.3%) esophageal cancers and correlated with MMP-7 expression, the statistical difference being (P < 0.05). None of the 34 esophageal cancers examined carried mutations in beta-catenin exon 3. MMP-7 expression correlates with penetrating tumor progression in esophageal cancer. Nuclear translocation of beta-catenin, without mutations in beta-catenin exon 3, is associated with MMP-7 expression.
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PMID:Interrelation between expression of matrix metalloproteinase 7 and beta-catenin in esophageal cancer. 1249 94

The main focus of the Symposium was the fact that cell types of the innate and adaptive immune systems can have tumor-favoring as well as tumor antagonistic effects, both in a preventive and therapeutic mode. It was shown that macrophages (Mphi) and dendritic cells within a tumor exert tumor-favoring effects through the action of certain cytokines. Inflammatory reactions could favor the onset and growth of tumors. Dual immune functions were shown with CD4+ T cells and certain matrix metalloproteinase (MMP) activities favoring tumor progression and CD8+ T cells and certain heat shock proteins having antitumor action. Lack of antitumor action despite positive immune stimulation was also shown to depend on the existence of barriers to tumor infiltration by lymphocytes; remodeling of vasculature, e.g., by IFNgamma-induced cytokines like MIG and IPIO, reversed this type of impediment. Certain CXC cytokines increased tumor progression, whereas others, particularly those induced by IFNgamma, had the opposite effect; stromal-derived factor-1 and its receptor CXCR4 affected tumor propensity to metastasize in certain organs. Stromal-derived factor-1 induced MMP9, which in turn regulated the bioavailability of vascular endothelial growth factor and the cascade of its tumor-favoring effects, whereas granulocyte colony-stimulating factor decreased MMP9 and the consequences of its action. The effects of certain proinflammatory cytokines and vascular endothelial growth factor functions in angiogenesis and lymphoangiogenesis were also discussed. The favoring effects of fever-like thermal stress on the function of molecules instrumental in lymphoid cell adhesion to vessels and infiltration into sites of immune actions were described. The mechanisms involved in the development of immune memory and those conditioning Type I and CTL responses were also discussed. A number of presentations were concerned with laboratory studies aimed at developing clinical regimens with potential activity in the prevention or treatment of cancer. Prevention of Her2/neu breast cancer in transgenic mice was achieved by suitable regimens with IL12 combined with vaccines, including DNA-based vaccines administered in conjunction with electroporation. Vaccination with shared tumor antigen MUCI or cyclin B was discussed, and its clinical translation was described. The prevention of TRAMP prostate tumor in transgenic mice by anti-CTLA4 antibody plus vaccine was described, as was the translation of these regimens to the clinics. Clinical successes in melanoma patients using antimelanoma antigen antibodies in a therapeutic mode and precautions to be exerted in evaluating in vivo immune responses based on in vitro assays were emphasized. The symposium was concluded with an overall discussion focused on basic questions related to the capability of immunity to exert tumor-favoring or antitumor effects depending on conditions determined by both tumor and host functions.
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PMID:Fourteenth Annual Pezcoller Symposium: the novel dichotomy of immune interactions with tumors. 1278 11

Deletions in the long arm of chromosome 6 (6q) are among the most frequent chromosome aberrations in lymphoid neoplasms. Recently, the region of minimal deletion (RMD1) in 6q27 was narrowed down to 5-9 Mb. In the present study, we aimed to define the distal border of the commonly lost region in 6q27 more precisely and to identify and investigate tumor-suppressor genes (TSGs) from this region. Twenty-nine cases, in which our previous fluorescence in situ hybridization (FISH) screening that used a set of 36 YAC probes revealed loss in 6q25-27, were further investigated by means of FISH. In all cases, deletions of 6q27 extended from yeast artificial chromosome (YAC) 977e10 spanning the proximal border of RMD1 to the most telomeric YAC 933f7 within the recently established YAC-contig of this region. An interstitial homozygous deletion, flanked by the telomeric probe TelVysion6q and YAC 971g12, was detected, which substantially narrows down the RMD1. To identify candidate TSGs down-regulated in malignant lymphomas from this region of homozygous loss, we performed electronic profiling of expressed sequences mapped to this region. This analysis suggested the gene PDCD2 originally thought to be involved in programmed cell death to be probably down-regulated in malignant B-cell lymphomas compared to normal B lymphocytes. Nevertheless, mutation analyses failed to identify mutations in the coding region of PDCD2 in nine lymphomas with FISH-proved 6q27 deletions. Furthermore, epigenetic studies in these nine and an additional 48 lymphomas did not show altered methylation of the PDCD2 locus in these tumors. Possibly haploinsufficiency is effectual in accelerating tumor progression.
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PMID:Identification of candidate tumor-suppressor genes in 6q27 by combined deletion mapping and electronic expression profiling in lymphoid neoplasms. 1280 Jan 55

Epstein-Barr virus (EBV) is a ubiquitous viral agent, well known to be associated with lymphoid, epithelial, and smooth-muscle malignancies in immunocompromised individuals. This report describes a 10-year-old patient with an EBV-related liver tumor occurring after kidney transplantation. The neoplasm presented a phenotypic spectrum, ranging from a smooth-muscle tumor to an inflammatory pseudotumor (IPT). The neoplastic cells failed to disclose CD21, CD35, or ALK expression, the latter confirmed by reverse-transcription polymerase chain reaction. Cytogenetic analysis revealed a single clonal cell population showing 46,XY,del (2)(p23),der(3)t (2;3)(p23;q29),der(21) t(Y;21)(q12;p13) karyotype. By metaphase FISH analysis, the neoplastic cells demonstrated the presence of two molecularly different but related aberrant clones, one with the loss of one ALK allele and the second with translocation of the 3'end of ALK kinase domain on the der(3) chromosome. Using FISH with an EBV-specific and 3'end ALK DNA probes, a co-localization of the viral DNA and the ALK sequences was found on the der(3) chromosome. Metaphases with loss of rearranged ALK did not show integrated virus; instead, viral particles together with an associated 3'end ALK domain formed an ex-chromosomal, episomal-like type configuration. The interphase study, using dual-color 5'/3' end ALK FISH assay, revealed 30% of nuclei with only one fused signal, confirming the total loss of one ALK allele in the subset of tumor cells. A combined immunofluorescence and FISH study indicated this separate clonal variant to correspond to desmin-positive smooth-muscle cells. In contrast, desmin-negative myofibroblasts showed the presence of both normal and rearranged ALK alleles. Our results indicate that ALK locus may be a target of EBV integration, a hitherto unreported finding. Although the sustained clonal expansion in EBV-related smooth-muscle tumors/IPTs may depend on functions provided by the EBV oncogenic proteins, the tumor phenotype may be further modified by the secondary genomic rearrangements imposed by the virus during and/or after the integration event. In this respect, the observed phenotypic heterogeneity most likely reflects divergence during neoplastic progression, with the subsequent expansion of morphologically and molecularly distinct but cytogenetically related clones.
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PMID:Complex genomic rearrangement of ALK loci associated with integrated human Epstein-Barr virus in a post-transplant myogenic liver tumor. 1293 32

The ATM/p53-dependent DNA damage response pathway plays an important role in the progression of lymphoid tumors. Inactivation of the ATM or TP53 gene is frequent in B-cell lymphocytic leukemia (B-CLL) and leads to aggressive disease. Although the ATM and p53 pathways overlap, they are not congruent, and it is unclear how the mechanism of tumor progression differs between ATM- and p53-deficient tumors. Using microarray analysis of ATM-mutant, TP53-mutant, and ATM/TP53 wild-type B-CLLs, we show that after exposure to DNA damage transcriptional responses are entirely dependent on ATM function. The p53 proapoptotic responses comprise only a part of ATM-regulated transcription; additionally, ATM regulates prosurvival responses independently of p53. Consequently, the greater severity of the TP53-mutant B-CLLs compared with ATM-mutant B-CLLs is consistent with the additive effect of defective apoptotic and elevated survival responses after DNA damage in these tumors. We also show that transcription expression profiles of ATM-deficient, TP53-deficient, and wild-type B-CLLs are indistinguishable before irradiation. Therefore, damage-induced transcriptional fingerprinting can be used to stratify tumors according to their biologic differences and simultaneously identify potential targets for treating refractory tumors.
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PMID:Microarray analysis reveals that TP53- and ATM-mutant B-CLLs share a defect in activating proapoptotic responses after DNA damage but are distinguished by major differences in activating prosurvival responses. 1295 68


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