Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mutations in the human adenomatous polyposis (APC) gene are causative for familial adenomatous polyposis (FAP), a rare condition in which numerous colonic polyps arise during puberty and, if left untreated, lead to colon cancer. The APC gene is a tumor suppressor that has been termed the "gatekeeper gene" for colon cancer. In addition to the 100% mutation rate in FAP patients, the APC gene is mutated in >80% of sporadic colon and intestinal cancers. The Apc gene in mice has been mutated either by chemical carcinogenesis, resulting in the Min mouse Apcdelta850, or by heterologous recombination, resulting in the Apcdelta716 or Apedelta1368 mice (M. Oshima et al., Proc. Natl. Acad. Sci. USA, 92: 4482-4486, 1995). Although homozygote Apc-/- mice are embryonically lethal, the heterozygotes are viable but develop numerous intestinal polyps with loss of Apc heterozygosity within the polyps (M. Oshima et al., Proc. Natl. Acad. Sci. USA, 92: 4482-4486, 1995). The proinflammatory, prooncogenic protein cyclooxygenase (COX)-2 has been shown to be markedly induced in the Apcdelta716 polyps at an early stage of polyp development (M. Oshima et al., Cell, 87: 803-809, 1996). We demonstrate here that treatment with the specific COX-2 inhibitor rofecoxib results in a dose-dependent reduction in the number and size of intestinal and colonic polyps in the Apcdelta716 mouse. The plasma concentration of rofecoxib that resulted in a 55% inhibition of polyp number and an 80% inhibition of polyps > 1 mm in size is comparable with the human clinical steady-state concentration of 25 mg rofecoxib (Vioxx) taken once daily (A. Porras et al., Clin. Pharm. Ther., 67: 137, 2000). Polyps from both untreated and rofecoxib- or sulindac-treated Apcdelta716 mice expressed COX-1 and -2, whereas normal epithelium from all mice expressed COX-1 but minimal amounts of COX-2. Polyps from either rofecoxib- or sulindac-treated mice had lower rates of DNA replication, expressed less proangiogenic vascular endothelial-derived growth factor and more membrane-bound beta-catenin, but showed unchanged nuclear localization of this transcription factor. This study showing the inhibition of polyposis in the Apcdelta716 mouse suggests that the specific COX-2 inhibitor rofecoxib (Vioxx) has potential as a chemopreventive agent in human intestinal and colon cancer.
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PMID:Chemoprevention of intestinal polyposis in the Apcdelta716 mouse by rofecoxib, a specific cyclooxygenase-2 inhibitor. 1124 90

A hallmark of transforming growth factorbeta (TGFbeta) action is the induction of the synthesis and secretion of extracellular-matrix adhesion molecules and induction of the cell-surface expression of integrin receptors for these molecules (termed extracellular-matrix remodeling). The signal pathways leading to extracellular-matrix remodeling and the significance of extracellular-matrix remodeling in TGFbeta function is not well-understood. In the epithelium-derived human colon cancer cell line Moser, TGFbeta induces extracellular-matrix remodeling in a protein kinase Calpha-dependent manner. In this study we showed that TGFbeta was a potent inducer of the homotypic cell-cell adhesion molecule E-cadherin and its undercoat-associated proteins, the catenins and dramatically increased the amount of E-cadherin/gamma-catenin complex formation. We found that the induction of E-cadherin and alpha- and beta-catenin by TGFbeta was also dependent on protein kinase Calpha, whereas the induction of gamma-catenin was independent of protein kinase Calpha but dependent on other protein kinase C isoforms. We also found that protein kinase Calpha-dependent induction of extracellular-matrix remodeling and subsequent cell-matrix interaction requiring both fibronectin and laminin were a prerequisite for the induction of E-cadherin (and alpha- and beta-catenin but not gamma-catenin) by TGFbeta. We therefore concluded that two signal pathways exist in TGFbeta-regulated expression of E-cadherin and the catenins. We also concluded that a functional significance of TGFbeta-induced extracellular matrix remodeling is the activation of signal transduction mechanisms through increased interaction between extracellular matrix fibronectin and laminin and their cell-surface integrin receptors, which lead to the induction of E-cadherin (and alpha- and beta-catenin).
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PMID:Requirement of protein kinase Calpha, extracellular matrix remodeling, and cell-matrix interaction for transforming growth factorbeta-regulated expression of E-cadherin and catenins. 1126 98

Our previous study (Cancer Res., 60: 3323-3327, 2000) showed that frequent beta-catenin gene mutations are present in beta-catenin-accumulated crypts, which occur early in rodent colonic carcinogenesis, with a lack of the appearance of aberrant crypt foci (ACF). To clarify the nature of such lesions, we performed a sequential analysis of the morphological and biological properties of beta-catenin-accumulated crypts. Azoxymethane was administered s.c. to male F344 rats (15 mg/kg body weight) once a week for 3 weeks, and the animals were sacrificed at 5, 10, and 20 weeks after the carcinogen treatment. Both the number of crypts/lesion and the diameter of beta-catenin-accumulated crypts were significantly increased with time courses of 5, 10, and 20 weeks from carcinogen exposure (P < 0.01). Likewise, the histological abnormality in those crypts, assessed by semiquantitative analyses, was also increased with time (P < 0.01). Conversely, ACF did not show any increase in histological abnormality during the time course and maintained a monotonous histology throughout the experiment. The histological abnormality score for beta-catenin-accumulated crypts was significantly higher than for ACF at every time point (P < 0.001). The number of AgNOR/nucleus in beta-catenin-accumulated crypts was significantly higher than in ACF (P < 0.001). Beta-catenin-accumulated crypts were accompanied frequently by Paneth cells and had decreased hexosaminidase activity. Such data, together with the results in our previous report, strongly suggest that beta-catenin-accumulated crypts, which are independent of ACF, are truly premalignant lesions for colon cancer.
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PMID:Sequential analysis of morphological and biological properties of beta-catenin-accumulated crypts, provable premalignant lesions independent of aberrant crypt foci in rat colon carcinogenesis. 1160 15

The majority of colonic neoplasias contain mutations in either the adenomatous polyposis coli or the beta-catenin (beta-cat) gene, both of which result in elevated levels of cytoplasmic beta-cat. The oncogenic activity of beta-cat has been explored in vivo and in vitro with conflicting results. We tested the hypothesis that beta-cat is capable of immortalizing and transforming cultured epithelial cells that represent the precursors to colon cancer. A truncated form of beta-cat (deltaN89) was stably expressed in murine colonic epithelial cells that were conditionally immortalized by temperature-sensitive T antigen expression and contained a mutant ApcMin allele [Immorto-Min colonic epithelium (IMCE)]. IMCE cells, grown under nonpermissive conditions, were immortalized by expression of the truncated beta-cat protein as determined by sustained growth in culture and escape from senescence as measured by endogenous beta-galactosidase activity. IMCE neo cells at nonpermissive conditions underwent extensive apoptosis, an effect that was blocked by the expression of deltaN89 beta-catenin. IMCE beta-cat cells had significantly lower p19 and p53 protein levels compared to IMCE neo cells, suggesting that alterations in these two key genes may mediate the effects of beta-cat on both cellular senescence and apoptosis. IMCE beta-cat cells were also transformed as determined by growth in the absence of serum, anchorage-independent growth, and sustained tumor growth in nude mice. Stable beta-cat-expressing populations could not be generated in conditionally immortalized colonic epithelia cells with a wild-type Apc background. These studies demonstrated the immortalizing activity of stabilized beta-cat for the first time and extend the transforming ability of mutated beta-cat to a cell line representing a precursor to colorectal cancer.
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PMID:Stabilized beta-catenin immortalizes colonic epithelial cells. 1128 Jul 72

Mutations in the Adenomatous Polyposis Coli (APC) gene are responsible for familial colon cancer and also occur in the early stages of sporadic colon cancer. APC functions in the Wnt signalling pathway to regulate the degradation of beta-catenin (reviewed in refs 1-3). APC also binds to and stabilizes microtubules in vivo and in vitro, localizes to clusters at the ends of microtubules near the plasma membrane of interphase cells, and is an important regulator of cytoskeletal function. Here we show that cells carrying a truncated APC gene (Min) are defective in chromosome segregation. Moreover, during mitosis, APC localizes to the ends of microtubules embedded in kinetochores and forms a complex with the checkpoint proteins Bub1 and Bub3. In vitro, APC is a high-affinity substrate for Bub kinases. Our data are consistent with a role for APC in kinetochore-microtubule attachment and suggest that truncations in APC that eliminate microtubule binding may contribute to chromosomal instability in cancer cells.
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PMID:A role for the Adenomatous Polyposis Coli protein in chromosome segregation. 1128 19

Beta-catenin performs critical roles in development and cellular adhesion. More recently, an oncogenic role has been described. In colon cancer, decreased E-cadherin/beta-catenin association is causally linked to increased beta-catenin-regulated gene expression and increased cellular division. Whether the same pathway is active in native epithelia remains unknown. To address this question, we used the transmissible murine colonic hyperplasia model to measure changes in beta-catenin abundance, nuclear partitioning, target gene (c-myc and cyclin D1) expression, and subcellular distribution. Colonocyte hyperproliferation was associated with a 4.3 +/- 0.56 (SD)-fold increase in total cellular beta-catenin protein content, whereas modest changes in gamma-catenin and E-cadherin expression were recorded. The beta-catenin signal increased before changes in mucosal crypt length, a gross index of cellular proliferation/apoptosis. Beta-catenin detected in Triton X-100-soluble (cytosolic) cellular fractions was enriched 4.3 +/- 0.9 (SD)-fold, whereas a modest decrease of 0.9 +/- 0.09 (SD)-fold was recorded in Triton X-100-insoluble (cytoskeletal) fractions. After these changes, nuclear beta-catenin partitioning increased 2.4 +/- 0.4 (SD)-fold, accompanied by 2.5 +/- 0.4- and 4.0 +/- 0.8-fold (SD) increases in cellular c-myc and cyclin D1 levels, respectively. Thus, increased cellular cytosolic and nuclear beta-catenin levels were associated with increased beta-catenin target protein expression. Significant alterations in beta-catenin subcellular distribution were also recorded immunohistochemically. Apical/lateral junctional labeling was observed in normal crypts with increased lateral membrane staining within the upper regions. During transmissible murine colonic hyperplasia, these gradients were dissipated, and basilar plaques were formed within a subset of basal crypt cells. These findings predict that an oncogenic signaling mechanism related to non-E-cadherin-bound beta-catenin is active in hyperproliferating native colonocytes and is similar to that recorded during the early stages of colon carcinogenesis.
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PMID:Increased beta-catenin expression and nuclear translocation accompany cellular hyperproliferation in vivo. 1130 65

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

Analysis of the glycogen synthase kinase-3beta (GSK-33) activity in several colon cancer cell lines suggested a correlation between comparatively low enzyme activity and moderate to high differentiation status. Treatment of LIM2537 cells, a poorly differentiated colon cancer cell line, with the potent differentiating agent sodium butyrate resulted in 34% reduction in GSK-3beta activity in the treated cells (P < 0.028, n = 3). Decreases in GSK-3beta activity were paralleled by stabilization of cytoplasmic beta-catenin, a hallmark of Wnt signaling. However, in contrast to Wnt signaling, expression of the beta-catenin/ TCF target genes c-myc and cyclin D1 did not appear to be increased in the sodium butyrate-treated cells. Interestingly, expression of membrane-bound beta-catenin was increased in the sodium butyrate-treated cells. This suggests that, in the context of cellular differentiation, increases in beta-catenin expression may be sequestered at the cell membrane and suggests that a possible role of sodium butyrate in promoting differentiation may be via increasing the levels of beta-catenin available for cell adhesion.
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PMID:Sodium butyrate-induced differentiation of human LIM2537 colon cancer cells decreases GSK-3beta activity and increases levels of both membrane-bound and Apc/axin/GSK-3beta complex-associated pools of beta-catenin. 1134 69

Many colon cancers suffer mutations in either the adenomatous polyposis coli or beta-catenin genes that lead to stabilization of beta-catenin and activation of downstream T-cell factor (Tcf) target genes. We have developed a novel approach targeting colon cancer cells based on their aberrant beta-catenin/Tcf signaling pathway. A recombinant adenovirus, in which an apoptosis gene fadd is under the control of the promoter containing Tcf-responsive elements, selectively and efficiently kills colon cancer cells in which the beta-catenin/Tcf pathway is hyperactivated. Our data therefore provide a conceptual proof that aberrantly activated Wnt/beta-catenin/Tcf pathways can be used to selectively target colon cancers.
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PMID:Selective targeting to the hyperactive beta-catenin/T-cell factor pathway in colon cancer cells. 1138 74

We wish to identify new candidate genes involved in the pathogenesis of human colon cancer to better understand the diversity of phenotype presentation that varies from individual to individual. Our working hypothesis is that genetic polymorphism of genes in the Wingless-type (Wnt) frizzled protein receptor pathway is associated with the susceptibility to develop colon cancer. The putative role of the Wnt pathway in sporadic human malignancy of the colon suggests involvement in inherited cancer as well. beta-catenin is the crucial messenger in frizzled receptor signaling, transmitting Wnt-ligand signals such as signals from secreted apoptosis-related proteins to the nucleus. It functions as a genome denunciator by initiating amplification of oncogenes. The net effect of beta-catenin depends on the magnitude of its accumulation in the cytoplasm and, therefore, upon expression profiles of genes in the Wnt pathway. We propose that variations in allelic frequencies of genes involved in the beta-catenin cascade may either promote or impede malignant transformation of the colon. If certain polymorphisms in Wnt signaling through beta-catenin predispose to colon cancer, this might manifest as decreased binding affinity of proteins such as axin or the adenomatous polyposis coli protein to beta-catenin. Association studies are proposed to test the hypothesis, which could serve as an initial step toward understanding the complexity of tumor biology. The clinical rationale in unraveling the genetic susceptibility to cancer lies in identification of a subgroup of individuals who may benefit from beta-catenin targeting agents, which could potentially overcome this genetic instability.
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PMID:Wingless-type frizzled protein receptor signaling and its putative role in human colon cancer. 1139 98


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