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)

The biology of the normal colonic mucosa suggests that colon cancer originates from normal colon stem cells. CD44 cancer stem cells have been identified in breast and prostate cancer, and we therefore examined whether CD44 similarly identified colon cancer stem cells. Initial assays found CD44(hi) colon tumor cells to have enhanced soft agar colony-forming ability. Subsequently, CD44(hi) cells isolated from 4 primary colon adenocarcinoma xenografts were found to be highly tumorigenic in immune deficient mice. CD44(hi) cells consistently formed tumors with 1,000 cells, and in multiple experiments, as few as 10 and 100 CD44(hi) cells formed tumors in 7/10 and 21/28 mice, respectively. In contrast, CD44(-) colon tumor cells were either nontumorigenic or 10-50-fold less tumorigenic. CD44(hi) cells could be serially passaged up to 4 times in vivo, suggesting self-renewal capacity, and formed tumors that recapitulated the heterogeneity of the original patient tumor. CD44(hi) cells were significantly enriched for nuclear activated beta-catenin, a key element in normal stem/progenitor cells and in early colon tumor progression. Bromodeoxyuridine (BrdU) labeling studies indicated that CD44(hi) cells divide slowly relative to the CD44(-) cells, suggesting their tumorigenicity is not simply due to faster proliferation. Aldehyde dehydrogenase (ALDH) sort further increased the tumorigenicity of CD44(hi) cells from 2/2 patient tumors, but CD133 tumor cells in our hands did not have increased tumorigenicity. Our observations indicate that CD44 is a marker of stem-like cells in colon cancer, and support the use of additional markers to further purify colon cancer stem cells.
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PMID:Characterization of a subpopulation of colon cancer cells with stem cell-like properties. 1907 81

Prominin 1/CD133 is a marker of transplantable cancer stem cells. We have generated anti-peptide antibodies against a N-terminal epitope of CD133 belonging to a ganglioside-binding domain. The labelling of colon cancer cells with these antibodies was inhibited by various gangliosides including GM1 and GD3, but not GT1b. CD133 immunolabelling progressively decreased to undetectable levels in post-confluent cultures, possibly through ganglioside-mediated epitope masking since the staining was partially recovered after chemical disruption of lipid rafts. We suggest that selected gangliosides could modulate the accessibility of CD133 and regulate cell-cell contacts involving CD133(+) stem cells at the earliest steps of tumour development.
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PMID:The first extracellular domain of the tumour stem cell marker CD133 contains an antigenic ganglioside-binding motif. 1921 24

Nuclear beta-catenin and CD133 are linked with two hallmarks of colon cancer, wingless-type mouse mammary tumour virus integration site (WNT)-pathway dysregulation and colon cancer stem cells (Co-CSCs), respectively. Both molecules may be related, as Co-CSCs were proposed to require activated WNT-signalling and as CD133 was postulated as a WNT/beta-catenin target gene. Herein, we investigated the expression of these markers on serial sections of 162 stage IIA colonic adenocarcinomas. We found that the expression of these molecules is statistically independent and that they mark distinct but overlapping subpopulations of the tumour cells. Moreover, we show that their combined evaluation can identify colon cancer cases with vastly reduced survival (hazard ratio (HR) 13.4, 95% confidence interval (CI): 4.7-38.2) and a high risk of tumour progression (HR 6.8, 95%CI: 3.1-15.0). In conclusion, the independence of these markers may on the one hand have implications for their presumed value to identify Co-CSCs; on the other hand it allows their combined analysis to become a powerful tool to identify high risk cases of stage IIA colon cancer.
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PMID:CD133 and nuclear beta-catenin: the marker combination to detect high risk cases of low stage colorectal cancer. 1940

In colon cancer, CD133 has recently been used to enrich for a subset of tumour cells with tumour-initiating capabilities and was therefore suggested to mark colon cancer stem cells. However, this molecule has surprisingly been shown to lack functional importance for tumour initiation itself. Herein, we investigated whether CD133 may be relevant for colon cancer metastasis in patients, and as metastasis requires several additional biological characteristics besides tumour initiation, we examined the effects of knocking down CD133 expression in colon cancer cell lines on proliferation, migration, invasion, and colony formation. We demonstrate that high CD133 expression correlates strongly with synchronous liver metastasis in a matched case-control collection, while siRNA-mediated knock down of this factor has no significant effect on the mentioned biological characteristics. Thus, we conclude that CD133 expression is a marker with high prognostic impact for colon cancer, while it seems to have no obvious functional role as a driving force of this malignancy.
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PMID:The cancer stem cell marker CD133 has high prognostic impact but unknown functional relevance for the metastasis of human colon cancer. 1962 38

CD133 has been postulated to be a colon cancer stem cell (CSCs) marker. Recent investigations suggest that CSCs might contribute to cancer recurrence and resistance to conventional therapies. This study aimed to evaluate the role of CD133 in residual cancer cells after chemoradiotherapy (CRT) for rectal cancer. Forty patients with rectal cancer underwent CRT followed by surgery. Total RNAs of rectal cancer cells before (n=30) and after (n=40) CRT were isolated. Intratumoral CD133, vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR) levels were measured using real-time reverse transcription polymerase chain reaction. Immunohistochemical staining of CD133 after CRT was also investigated. CD133 in residual cancer cells was higher than in stromal cells in post-CRT specimens (p<0.0001). The levels of CD133 were found to have increased in post-CRT specimens (p=0.0184), while VEGF and EGFR levels decreased during CRT (p<0.0001 and p=0.0002, respectively). Patients who developed distant recurrence had a higher post-CRT CD133 compared with those patients without recurrence (p=0.0136). Elevated post-CRT CD133 was associated with poor disease-free survival (p=0.0168). Immunohistochemical staining of the cytoplasmic and apical/endoluminal membranous CD133 was observed in residual cancer cells after CRT. CD133 expression in residual cancer cells after CRT may indicate a treatment resistant phenotype in putative CSCs. Elevated CD133, but not VEGF or EGFR, on FFPE specimens may be a predictive marker of distant recurrence and poor survival after preoperative CRT in rectal cancer.
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PMID:Elevated CD133, but not VEGF or EGFR, as a predictive marker of distant recurrence after preoperative chemoradiotherapy in rectal cancer. 1972 47

In this study, high-throughput microRNA (miRNA) expression analysis revealed that the expression of miR-140 was associated with chemosensitivity in osteosarcoma tumor xenografts. Tumor cells ectopically transfected with miR-140 were more resistant to methotrexate and 5-fluorouracil (5-FU). Overexpression of miR-140 inhibited cell proliferation in both osteosarcoma U-2 OS (wt-p53) and colon cancer HCT 116 (wt-p53) cell lines, but less so in osteosarcoma MG63 (mut-p53) and colon cancer HCT 116 (null-p53) cell lines. miR-140 induced p53 and p21 expression accompanied with G(1) and G(2) phase arrest only in cell lines containing wild type of p53. Histone deacetylase 4 (HDAC4) was confirmed to be one of the important targets of miR-140. The expression of endogenous miR-140 was significantly elevated in CD133(+hi)CD44(+hi) colon cancer stem-like cells that exhibit slow proliferating rate and chemoresistance. Blocking endogenous miR-140 by locked nucleic acid-modified anti-miR partially sensitized resistant colon cancer stem-like cells to 5-FU treatment. Taken together, our findings indicate that miR-140 is involved in the chemoresistance by reduced cell proliferation through G(1) and G(2) phase arrest mediated in part through the suppression of HDAC4. miR-140 may be a candidate target to develop novel therapeutic strategy to overcome drug resistance.
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PMID:Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells. 1973 43

The cancer stem cell (CSC) model, in which a small population of cells within a tumor possesses the ability to self-renew and reconstitute the phenotype of primary tumor, has gained wide acceptance based on evidence over the past decade. It has also been reported that cancer cell lines contain a CSC subpopulation. However, phenotypic differences between CSCs and non-CSCs in cancer cell lines are not better defined than in primary tumors. Furthermore, some cell lines do not have a CSC population, revealed as a side population and expression of CD133. Thus, the identification of CSCs in cancer cell lines remains elusive. Here, we investigated the CSC hierarchy within HCT116 colon cancer cells, which do not have a CD133-positive subpopulation. We examined the expression of alternative CSC markers epithelial specific antigen (ESA) and CD44 in floating-sphere-derived cells, which are known to be the cells of enriching CSCs. Sphere-derived HCT116 cells exhibited heterogeneous expression of ESA and CD44. The two major subpopulations of HCT116 sphere cells (ESA(low)CD44(-/low) and ESA(high)CD44(high)) exhibited a biological/proliferative hierarchy of sphere-forming and soft agar colony-forming activity. However, there was no difference between the two subpopulations in the incidence of xenograft tumors. When ESA(low)CD44(-/low) cells were allowed to aggregate and re-form floating-spheres, the biological/proliferative hierarchy of parental HCT116 spheres was reconstituted, in terms of ESA and CD44 expression. Thus, HCT116 cells have plasticity when they are set in floating-spheres, suggesting that maintenance of the HCT116 cell line conforms to a stochastic model, not a CSC model.
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PMID:Maintenance of HCT116 colon cancer cell line conforms to a stochastic model but not a cancer stem cell model. 1973 48

5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics but with limited success. This could partly be due to the enrichment of cancer stem cells (CSCs) that are resistant to conventional chemotherapy. Therefore, validation of a nontoxic agent that can either cause reversal of chemoresistance or promote the killing of CSCs would be highly desirable. The current study examines whether curcumin, the major active ingredient of turmeric, either alone or together with FOLFOX, would be an effective strategy to eliminate colon CSCs. Exposure of colon cancer HCT-116 or HT-29 cells to FOLFOX that inhibited their growth led to the enrichment of CSC phenotype as evidenced by increased proportion of CD133-, CD44-, and/or CD166-positive cells and epidermal growth factor receptor (EGFR) levels. Treatment of FOLFOX-surviving colon cancer cells with either curcumin alone or together with FOLFOX resulted in a marked reduction in CSCs, as evidenced by the decreased expression of CD44 and CD166 as well as EGFR and by their ability to form anchorage-dependent colonies. They also caused disintegration of colonospheres. Increased expression of EGFR in FOLFOX-surviving cells could be attributed to hypomethylation of the EGFR promoter, whereas an opposite phenomenon was observed when the FOLFOX-surviving cells were treated with curcumin and/or FOLFOX. These changes were accompanied by parallel alterations in the levels of DNA methyltransferase 1. In conclusion, our data suggest that curcumin by itself or together with the conventional chemotherapeutic could be an effective treatment strategy for preventing the emergence of chemoresistant colon cancer cells by reducing/eliminating CSCs.
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PMID:Elimination of Colon Cancer Stem-Like Cells by the Combination of Curcumin and FOLFOX. 1995 94

CD133 has been identified as a cancer stem cell marker in colon and several other cancers, but its function is still unknown. We examined the CD133 expression in 44 human cancer cell lines, and found five of the 8 positive lines were from colon cancer. The CD133 positive subpopulation of colon cancer cells showed more vigorous growth and lower differentiation. Induction of differentiation reduced the CD133-positive population. Knockdown of CD133 expression in colon cancer cells could not induce cellular differentiation. Care must be taken if CD133 is used as the only marker of cancer stem cells in colon cancer, especially in established cell lines. CD133 negatively correlates with cell differentiation, but it is not a regulator of differentiation.
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PMID:Expression of CD133 correlates with differentiation of human colon cancer cells. 2002 82

Colon cancer stem cells (CSC) can be identified with AC133, an antibody that detects an epitope on CD133. However, recent evidence suggests that expression of CD133 is not restricted to CSCs, but is also expressed on differentiated tumor cells. Intriguingly, we observed that detection of the AC133 epitope on the cell surface decreased upon differentiation of CSC in a manner that correlated with loss of clonogenicity. However, this event did not coincide with a change in CD133 promoter activity, mRNA, splice variant, protein expression, or even cell surface expression of CD133. In contrast, we noted that with CSC differentiation, a change occured in CD133 glycosylation. Thus, AC133 may detect a glycosylated epitope, or differential glycosylation may cause CD133 to be retained inside the cell. We found that AC133 could effectively detect CD133 glycosylation mutants or bacterially expressed unglycosylated CD133. Moreover, cell surface biotinylation experiments revealed that differentially glycosylated CD133 could be detected on the membrane of differentiated tumor cells. Taken together, our results argue that CD133 is a cell surface molecule that is expressed on both CSC and differentiated tumor cells, but is probably differentially folded as a result of differential glycosylation to mask specific epitopes. In summary, we conclude that AC133 can be used to detect cancer stem cells, but that results from the use of this antibody should be interpreted with caution.
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PMID:The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation. 2006 53


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