Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The attachment of microtubule plus ends to kinetochores and to the cell cortex is essential for the fidelity of chromosome segregation. Here, we characterize the causes underlying the high rates of chromosome instability (CIN+) observed in colorectal tumor cells. We show that CIN+ tumor cells exhibit inefficient microtubule plus-end attachments during mitosis, accompanied by impairment of chromosome alignment in metaphase. The mitotic abnormalities associated with CIN+ tumor cells correlated with status of adenomatous polyposis coli (APC). Importantly, we have shown that a single truncating mutation in APC, similar to mutations found in tumor cells, acts dominantly to interfere with microtubule plus-end attachments and to cause a dramatic increase in mitotic abnormalities. We propose that APC functions to modulate microtubule plus-end attachments during mitosis, and that a single mutant APC allele predisposes cells to increased mitotic abnormalities, which may contribute to tumor progression.
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PMID:Chromosome instability in colorectal tumor cells is associated with defects in microtubule plus-end attachments caused by a dominant mutation in APC. 1466 41

The MUC1 tumor antigen is overexpressed on most breast tumors and metastases. It interacts with signaling proteins such as the ErbB kinases and beta-catenin, and is involved in mammary gland oncogenesis and tumor progression. Herein, we report a novel interaction between MUC1 and adenomatous polyposis coli (APC), a tumor suppressor involved in downregulating beta-catenin signaling. Initially identified in colorectal cancer, APC is also downregulated in breast tumors and presumably involved in mammary carcinogenesis. MUC1 and APC co-immunoprecipitate from the ZR-75-1 human breast carcinoma cell line and co-localize in mouse mammary glands and tumors. These studies also indicate that the association of MUC1 and APC may be increased by epidermal growth factor stimulation. Intriguingly, the co-immunoprecipitation of MUC1 and APC increases in human breast tumors and metastases as compared to adjacent normal tissues, indicating that this association may play a role in the formation and progression of breast tumors.
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PMID:MUC1 can interact with adenomatous polyposis coli in breast cancer. 1502 Feb 26

Individuals with heterozygous germline adenomatous polyposis coli (APC) mutations or familial adenomatous polyposis (FAP) are born with normal appearing colons but later develop hundreds to thousands of polyps. Tumor progression apparently starts after somatic loss of the normal APC allele, but germline APC mutations may potentially alter niche stem cell survival through dominant-negative interactions or haploinsufficiency. Although morphologically occult, altered stem cell turnover or clonal evolution rates may be detected by measuring the diversity of crypt sequences, with greater diversity expected with longer lived stem cell lineages. Methylation pattern diversity (numbers of unique patterns per crypt) was higher in normal appearing crypts from four of five FAP colons compared to six non-FAP colons and one attenuated FAP colon. Simulations indicate higher FAP crypt diversity is consistent with slower clonal evolution from enhanced stem cell survival, either through increased stem cell numbers or decreased stem cell lineage extinction, which is predicted to increase progression rates to cancer. Enhanced stem cell survival was associated with APC mutations that remove some but not all catenin-binding repeats. Therefore, some APC mutations may be common in colorectal cancers because they confer occult pretumor "caretaker" and "gatekeeper" defects. FAP crypts accumulate more alterations from slower stem cell clonal evolution rather than increased error rates. In non-FAP crypts, enhanced stem cell survival conferred by somatic heterozygous APC mutations would favor fixation through occult clonal niche expansions. Heterozygous APC mutations may change stem cell survival during colorectal pretumor progression.
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PMID:Enhanced stem cell survival in familial adenomatous polyposis. 1503 24

The adenomatous polyposis coli (APC) tumor suppressor is a major regulator of the Wnt signaling pathway in normal intestinal epithelium. APC, in conjunction with AXIN and GSK-3beta, forms a complex necessary for the degradation of beta-catenin, thereby preventing beta-catenin/T-cell factor interaction and alteration of growth-controlling genes such as c-MYC and cyclin D1. Inappropriate activation of the Wnt pathway, via Apc/APC mutation, leads to gastrointestinal tumor formation in both the mouse and human. In order to discover novel genes that may contribute to tumor progression in the gastrointestinal tract, we used cDNA microarrays to identify 114 genes with altered levels of expression in Apc(Min) mouse adenomas from the duodenum, jejunum, and colon. Changes in the expression of 24 of these 114 genes were not observed during mouse development at embryonic day 16.5, postnatal day 1, or postnatal day 14 (relative to normal adult intestine). These 24 genes are not previously known Wnt targets. Seven genes were validated by real-time reverse transcription-PCR analysis, whereas four genes were validated by in situ hybridization to mouse adenomas. Real-time reverse transcription-PCR analysis of human colorectal cancer cell lines and adenocarcinomas revealed that altered expression levels were also observed for six of the genes Igfbp5, Lcn2, Ly6d, N4wbp4 (PMEPA1), S100c, and Sox4.
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PMID:Transcriptional profiles of intestinal tumors in Apc(Min) mice are unique from those of embryonic intestine and identify novel gene targets dysregulated in human colorectal tumors. 1566 92

Over the past decade, the advances in our understanding of stem cell biology and the role of stem cells in diseases, such as colorectal cancer, have been remarkable. In particular, discoveries related to the control of stem cell proliferation and how dysregulation of proliferation leads to oncogenesis have been foremost. For intestinal stem cells, the WNT family of growth factors, and events such as the regulation of the nuclear localization of beta-catenin, seem to be central to normal homeostasis, and mutations in the components of these pathways seem to lead to the development of colorectal cancer. A paradigm of abnormal stem cell biology is illustrated by patients with familial adenomatous polyposis, who have mutations in the adenomatous polyposis coli gene. The wild-type protein encoded by this gene is important for the prevention of mass beta-catenin accumulation in the nucleus and the subsequent overtranscription of cell cycle proteins. This review discusses the basic mechanisms behind stem cell regulation in the gut and follows their role in the natural history of tumor progression.
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PMID:Mechanisms of disease: from stem cells to colorectal cancer. 1667 6

Nuclear beta-catenin staining in soft tissue sarcomas (STSs) has been shown to correlate with tumor progression as assessed by proliferative activity or poor prognosis. Frequent activation of Wnt signaling pathway has been also shown in synovial sarcoma (SS), suggesting a specific role of this pathway in SS. We examined roles of nuclear beta-catenin staining within soft tissue sarcomas. Immunohistochemical detection of nuclear beta-catenin accumulation correlated with cyclin D1 overexpression in spindle cell and pleomorphic sarcomas (P = .037), and the expression of these proteins evenly distributed throughout each section. In some cases, strong beta-catenin nuclear staining was observed in highly pleomorphic and mitotic cells. Furthermore, tumors with nuclear beta-catenin accumulation showed statistically significant increasing cyclin D1 mRNA expression level compared with those without (P = .023). Cyclin D1 mRNA expression levels were statistically higher in tumors with cyclin D1 overexpression than in tumors without (P = .037), suggesting that cyclin D1 overexpression is due to transcriptional activation. However, these correlations could not be detected in SS. In biphasic SS, beta-catenin nuclear staining was observed in spindle cells, whereas cyclin D1 nuclear staining was seen in glandular areas where beta-catenin kept membranous expression. Mutations in exon 3 of the beta-catenin gene and in the mutation cluster region of adenomatous polyposis coli gene were absent in this series of cases. Thus, cyclin D1 could be considered as one of the targets of the nuclear beta-catenin in spindle cell and pleomorphic sarcomas. A possible association between beta-catenin accumulation and spindle cell morphogenesis may exist in SS.
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PMID:Nuclear beta-catenin correlates with cyclin D1 expression in spindle and pleomorphic sarcomas but not in synovial sarcoma. 1673 9

The etiology and significance of genomic instability (GIN), a hallmark of human cancers, remains controversial. The paradigm that inactivation of tumor suppressors [e.g. p53 or adenomatous polyposis coli (APC) genes] leads to GIN is largely based on experiments in vitro and in animal models. It remains unclear whether GIN is a cause or a result of cancer, particularly in patients. Precancerous Barrett's esophagus (BE) provides a clinical model to investigate GIN in cancer progression. We analyzed specimens from endoscopic biopsies or esophagectomies in patients with BE (ten cases, including five cases with multilayered epithelium (ME)), BE-associated esophageal adenocarcinoma (ten cases), or with normal gastro-esophageal junction (five cases). Chromosomal enumeration probe Cep 7, 11, 12, 17 and 18 were detected by fluorescence in situ hybridization (FISH). Expression of p53 and APC were determined by immunohistochemistry. Increased p53 expression, a measurement of p53 mutations, was observed in BE with high grade dysplasia (HGD) and in BE-associated esophageal cancer (EC). The expression of wild type APC was decreased in BE with HGD and in advanced EC. Chromosomal abnormalities were found in all EC samples. Numeric changes of chromosome 7, 11 and 12 were observed in BE in 14%, 64% and 43% of cases, respectively. Aneusomy of chromosome 11 and 12 were found in ME and in BE without dysplasia, in the presence of normal expression pattern of p53 and APC. Our results suggest that GIN is an early event that occurs at precancerous stages prior to changes in tumor suppressor genes (p53 and APC) in BE-associated tumorigenesis in patients, suggesting that GIN may serve as a causative link between chronic inflammation and cancer.
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PMID:Genomic instability in precancerous lesions before inactivation of tumor suppressors p53 and APC in patients. 1685 98

The beta-catenin signaling pathway is dysregulated in most cases of colon cancer resulting in an accumulation of nuclear beta-catenin and increased transcription of genes involved in tumor progression. This study examines the effect of retinol on beta-catenin protein levels in three all-trans retinoic acid (ATRA)-resistant human colon cancer cell lines: HCT-116, WiDr, and SW620. Each cell line was treated with increasing concentrations of retinol for 24 or 48 h. Retinol reduced beta-catenin protein levels and increased ubiquitinated beta-catenin in all cell lines. Treatment with the proteasomal inhibitor MG132 blocked the retinol-induced decrease in beta-catenin indicating retinol decreases beta-catenin by increasing proteasomal degradation. Multiple pathways direct beta-catenin to the proteasome for degradation including a p53/Siah-1/adenomatous polyposis coli (APC), a Wnt/glycogen synthase kinase-3beta/APC, and a retinoid "X" receptor (RXR)-mediated pathway. Due to mutations in beta-catenin (HCT-116), APC (SW620), and p53 (WiDr), only the RXR-mediated pathway remains functional in each cell line. To determine if RXRs facilitate beta-catenin degradation, cells were treated with the RXR pan-antagonist, PA452, or transfected with RXRalpha small interfering RNA (siRNA). The RXR pan-antagonist and RXRalpha siRNA reduced the ability of retinol to decrease beta-catenin protein levels. Nuclear beta-catenin induces gene transcription via interaction with T cell factor/lymphoid enhancer factor (TCF/LEF) proteins. Retinol treatment decreased the transcription of a TOPFlash reporter construct and mRNA levels of the endogenous beta-catenin target genes, cyclin D1 and c-myc. These results indicate that retinol may reduce colon cancer cell growth by increasing the proteasomal degradation of beta-catenin via a mechanism potentially involving RXR.
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PMID:Retinol decreases beta-catenin protein levels in retinoic acid-resistant colon cancer cell lines. 1721 22

The persistent activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is oncogenic and involved in colorectal neoplasia. Mutations of both regulatory subunit and catalytic subunit of PI3K have been demonstrated in colon cancers. In the present study, we show that heterozygous disruption of the phosphatase and tensin homolog (PTEN) tumor suppressor gene promoted tumor progression in APC(min/+) mice. Number and size of intestinal tumors were significantly increased in mice bearing both adenomatous polyposis coli (APC) and PTEN mutations. While APC(min/+)PTEN(+/+) mice developed adenomas, invasive carcinomas developed in APC(min/+)PTEN(+/-) mice. Large tumors often resulted in intestinal intussusception and early death of APC(min/+)PTEN(+/-) mice. Targeted array revealed that osteopontin (OPN) was the leading gene whose expression was strongly induced by deficiency of PTEN. In colon cancer cells, gain-of-function mutation of PI3K robustly increased levels of OPN and treatment with OPN reduced growth factor deprivation-induced programmed cell death. Moreover, OPN expression was strongly increased in Ras-induced transformation of intestinal epithelial cells in a PI3K-dependent manner. Inhibition of OPN expression by specific small interfering RNA reduced uncontrolled growth and invasiveness of Ras-transformed intestinal epithelial cells. Thus, our results suggest that the PI3K pathway promotes the transformation of intestinal adenoma to adenocarcinoma. OPN, a downstream effector of PI3K, protects transformed intestinal epithelial cells from programmed cell death and stimulates their anchorage-independent growth.
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PMID:Heterozygous disruption of the PTEN promotes intestinal neoplasia in APCmin/+ mouse: roles of osteopontin. 1769 63

The ataxia telangiectasia-mutated (ATM) gene has been implicated as an early barrier to the growth and progression of incipient solid tumors. Here, we show that germ-line nullizygosity for the mouse Atm gene significantly increases the proliferative index, net growth rate and multiplicity of intestinal adenomas in two distinct models of familial colon cancer: Apc(Min/+) and Apc(1638N/+). These effects of Atm deficiency are quantitatively different from deficiency for either of the genomic stability genes Bloom's syndrome helicase or DNA ligase 4, and the effect of Atm loss on tumor multiplicity is largely independent of the effect of ionizing radiation. Furthermore, the loss of heterozygosity rates at the adenomatous polyposis coli (Apc) locus are unaffected by Atm loss. Taken together, these data implicate the Atm gene product as a barrier to dysplastic growth in the early stages of intestinal tumor progression, independent of its effects on genomic stability.
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PMID:Atm is a negative regulator of intestinal neoplasia. 1770 May 32


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