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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Colon carcinoma is the second most common cause of death from cancer. The isolation and characterization of tumorigenic colon cancer cells may help to devise novel diagnostic and therapeutic procedures. Although there is increasing evidence that a rare population of undifferentiated cells is responsible for tumour formation and maintenance, this has not been explored for colorectal cancer. Here, we show that tumorigenic cells in colon cancer are included in the high-density CD133+ population, which accounts for about 2.5% of the tumour cells. Subcutaneous injection of colon cancer CD133+ cells readily reproduced the original tumour in immunodeficient mice, whereas CD133- cells did not form tumours. Such tumours were serially transplanted for several generations, in each of which we observed progressively faster tumour growth without significant phenotypic alterations. Unlike CD133- cells, CD133+ colon cancer cells grew exponentially for more than one year in vitro as undifferentiated tumour spheres in serum-free medium, maintaining the ability to engraft and reproduce the same morphological and antigenic pattern of the original tumour. We conclude that colorectal cancer is created and propagated by a small number of undifferentiated tumorigenic CD133+ cells, which should therefore be the target of future therapies.
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PMID:Identification and expansion of human colon-cancer-initiating cells. 1712 71

Stem cells are characterized by self-renewal and multipotency to produce multiple lineages of progenitor and differentiated cells. PROM1 gene encodes CD133 protein, which is a cell surface marker of hematopoietic stem cells, prostatic epithelial stem cells, pancreatic stem cells, leukemic stem cells, liver cancer stem cells, and colorectal cancer stem cells. Here, comparative integromics analyses on PROM1 orthologs were performed. Human PROM1 RefSeq NM_006017.1 was a truncated transcript, while AK027422.1 was the representative human PROM1 cDNA. Chimpanzee PROM1 gene, consisting of 27 exons, was identified within NW_001234057.1 genome sequence. Chimpanzee 5-transmembrane protein CD133 showed 99.2% and 60.9% total-amino-acid identity with human and mouse CD133 orthologs, respectively. Only 2 of 8 Asn-linked glycosylation sites in primate CD133 orthologs were conserved in rodent CD133 orthologs. Comparative proteomics revealed that CD133 orthologs were relatively divergent between primates and rodents. PROM1 mRNA was expressed in human embryonic stem (ES) cells, trachea, small intestine, NT2 cells, diffuse-type gastric cancer, and colorectal cancer. Human PROM1 mRNA transcribed from exon 1A was the major transcript. Comparative genomics revealed that the region around exon 1A corresponding to 5'-UTR of human PROM1 mRNA was not conserved in mouse and rat. Intron 2 of PROM1 orthologs was relatively well conserved among mammals. Tandem TCF/LEF-binding sites with 7-bp spacing within intron 2 were conserved among human, chimpanzee, mouse, and rat PROM1 orthologs. Together these facts indicate that canonical WNT signaling activation is implicated in CD133 expression in ES cells, adult stem cells, and cancer stem cells.
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PMID:Comparative genomics on PROM1 gene encoding stem cell marker CD133. 1748 31

Human colorectal cancer is one of the best, if not the best, understood tumour diseases. These tumours develop stepwise via an adenoma-carcinoma sequence. The steps in this process can easily be discriminated with light microscopy. The breakthrough in understanding carcinogenesis was the finding that mutations in tumour suppressor genes and oncogenes accumulate in parallel with these steps. This accumulation is the cause for the malignant progression of colorectal cancers, leading to highly invasive and migrating tumour cells. This concept is known as the multistep carcinogenesis model and has become the paradigm of tumour progression in general. But this model does not explain the complex, heterogeneous histology of colorectal tumours or the good differentiation of metastases, which are expected to have lost their differentiation because of the accumulation of mutations. Here, we present the model of migrating tumour stem cells, which explains these contradictions in the context of the histology of colorectal tumours. Thus colorectal tumours consist of tumour stem cells, which have recently been defined as a small CD133-positive population of tumour cells. These cells trans-differentiate into epithelial cells, which represent the main mass of the colorectal tumours. Moreover, the tumour stem cells are the active component of migration and invasion, thus conferring the malignant phenotype. Taken together, mutations confer to the tumour cells the capability to live outside of their stem cell niche and intestinal compartment. In addition, the trans-differentiation potential of the tumour cell confers plasticity to the tumour and thus contributes to the heterogeneity of colorectal cancers.
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PMID:The migrating cancer stem cells model--a conceptual explanation of malignant tumour progression. 1793 98

Prominin 1 (PROM1, CD133) is a unique transmembrane glycoprotein encoded by the PROM1 gene. It is a cell surface marker of various stem cells including hematopoietic, prostatic epithelial, pancreatic, leukemic, liver cancer, and colorectal cancer stem cells. Here, we studied tissue specificity of PROM1 transcription isoforms and the methylation level of its two main promoters (P1 and P2) in different human cell lines. Only transcripts lacking the 4th exon (the CD133.s1 form) were expressed in cell lines studied. Moreover, these transcripts, if sufficiently abundant, were initiated simultaneously and independently from both promoters P1 and P2. In cell lines with low levels of the total PROM1 transcript, the transcription was likely initiated from other promoters. Promoter P1 was hypermethylated in all cell lines under study, and therefore, methylation can hardly play an important role in its regulation. In contrast, the methylation of promoter P2 was tissue specific, and hypomethylation of this promoter is probably necessary but not sufficient for efficient transcription of the PROM1 gene. Therefore, we report an unusual instance of different mechanisms of transcription activity regulation for two closely located promoters of the same gene.
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PMID:Methylation of the prominin 1 TATA-less main promoters and tissue specificity of their transcript content. 1860 31

CD133 has been reported to be a cancer-initiating cell marker in colorectal carcinoma. The objective of this study was to evaluate the frequency of CD133 expression in colorectal cancer, the distribution of CD133-positive cancer cells, and their relationship to clinicopathological features, including survival. An immunohistochemical examination of CD133 expression and a clinicopathological analysis were performed in the 189 consecutive colorectal cancer patients. CD133 expression was seen at the luminal surface of cancer glands mainly with cribriform features. Expression was detected in only 29 of the 189 tumors (15.3%). Of these, 21 tumors (11.1%) showed CD133 overexpression. All 21 tumors with CD133 overexpression were diagnosed as well- or moderately-differentiated adenocarcinoma. There was no difference in the distribution of CD133 expressing cells between the invasive area and surface area. Although there was no difference in recurrence-free survival between patients with CD133 overexpression and without, the patients with CD133 overexpression had significantly poorer overall survival (P = 0.03). CD133 overexpression is a risk factor for poorer overall survival in patients with well- and moderately-differentiated adenocarcinoma. Expression of this cancer-initiating cell marker may vary with the histological type of the cancer, and further investigation of the relationship between its expression and clinicopathological features may be necessary.
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PMID:Immunohistochemical detection of CD133 expression in colorectal cancer: a clinicopathological study. 1875 69

Colon cancer cells have previously been demonstrated to contain a subpopulation of CD133+ tumour cells that have the ability to initiate tumour growth and are thus referred to as colon cancer-initiating cells or colon cancer stem cells (CSCs). As CD133 is currently one of the best markers to characterise colon CSCs, we analysed CD133+ tumour cells in colorectal cancer specimens using immunohistochemistry. We show that CD133 detection is specific and that the CD133 antigen is localised on the glandular-luminal surface of colon cancer cells, whereas undifferentiated tumour cells at the front of invasion are CD133-. In addition, CD133+ cells are characterised in situ by lack of CK20 expression, whereas they are positive for EpCAM. Moreover, we show that CD133 expression in colorectal cancer is an independent prognostic marker that correlates with low survival in a stratified patient collective. Our results indicate that in colorectal cancer, the CD133+ tumour cells can be detected by immunohistochemistry, which facilitates their further characterisation in situ.
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PMID:CD133 expression is an independent prognostic marker for low survival in colorectal cancer. 1878 Nov 71

5-Fluorouracil (5FU) and oxaliplatin are standard therapy for metastatic colorectal cancer (CRC), but the development of chemoresistance is inevitable. Because cancer stem cells (CSC) are hypothesized to be chemoresistant, we investigated CSC properties in newly developed chemoresistant CRC cell lines and sought to identify targets for therapy. The human CRC cell line HT29 was exposed to increasing doses of 5FU (HT29/5FU-R) or oxaliplatin (HT29/OxR) to achieve resistance at clinically relevant doses. Western blotting and flow cytometry were done to determine molecular alterations. The insulin-like growth factor-I receptor (IGF-IR) monoclonal antibody (mAb) AVE-1642 was used to inhibit signaling in vitro and in vivo using murine xenograft models. HT29/5FU-R and HT29/OxR showed 16- to 30-fold enrichment of CD133(+) cells and 2-fold enrichment of CD44(+) cells (putative CRC CSC markers). Resistant cells were enriched 5- to 22-fold for double-positive (CD133(+)/CD44(+)) cells. Consistent with the CSC phenotype, resistant cells exhibited a decrease in cellular proliferation in vitro (47-59%; P < 0.05). Phosphorylated and total IGF-IR levels were increased in resistant cell lines. HT29/5FU-R and HT29/OxR cells were approximately 5-fold more responsive to IGF-IR inhibition relative to parental cells (P < 0.01) in vitro. Tumors derived from HT29/OxR cells showed significantly greater growth inhibition in response to an IGF-IR mAb than did parental cells (P < 0.05). Chemoresistant CRC cells are enriched for CSC markers and the CSC phenotype. Chemotherapy-induced IGF-IR activation provided for enhanced sensitivity to IGF-IR-targeted therapy. Identification of CSC targets presents a novel therapeutic approach in this disease.
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PMID:Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. 1924 28

Precursors of the hormone gastrin, progastrin and glycine-extended gastrin (G-gly), have been detected in colorectal polyps and tumours, and in the blood of patients with colorectal cancer (CRC), while their expression is lower in healthy subjects. The surface glycoproteins CD133 and CD44 have been identified as possible markers for CRC stem cells. Our aims were to investigate whether progastrin and G-gly are expressed by CD133-positive cells in human CRC tissues and in the human CRC cell line DLD-1, and to determine whether this expression is biologically relevant. The great majority of the cells expressing CD133 also expressed gastrin precursors in both DLD-1 cells, which retain a stem cell-like subpopulation, and human CRC specimens. The CD133high/CD44high/progastrinhigh cells gave rise to larger tumours in SCID mice compared to CD133low/CD44low/progastrinlow cells. The CD133high/CD44high/progastrinhigh cells displayed enhanced activation of the signalling molecules JAK2, STAT3, ERK1/2 and Akt, known to regulate the induction of proliferation and/or survival by gastrin precursors. Moreover, downregulation of the gastrin gene in DLD-1 cells reduced the expression of cancer stem cell markers and abolished tumour development in SCID mice. We conclude that gastrin precursors may provide a target for therapies directed against the cells responsible for tumour development and recurrence.
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PMID:Expression of gastrin precursors by CD133-positive colorectal cancer cells is crucial for tumour growth. 1932 Nov 26

Although the concept that cancers originate from stem cells (SC) is becoming scientifically accepted, mechanisms by which SC contribute to tumor initiation and progression are largely unknown. For colorectal cancer (CRC), investigation of this problem has been hindered by a paucity of specific markers for identification and isolation of SC from normal and malignant colon. Accordingly, aldehyde dehydrogenase 1 (ALDH1) was investigated as a possible marker for identifying colonic SC and for tracking them during cancer progression. Immunostaining showed that ALDH1(+) cells are sparse and limited to the normal crypt bottom, where SCs reside. During progression from normal epithelium to mutant (APC) epithelium to adenoma, ALDH1(+) cells increased in number and became distributed farther up the crypt. CD133(+) and CD44(+) cells, which are more numerous and broadly distributed in normal crypts, showed similar changes during tumorigenesis. Flow cytometric isolation of cancer cells based on enzymatic activity of ALDH (Aldefluor assay) and implantation of these cells in nonobese diabetic-severe combined immunodeficient mice (a) generated xenograft tumors (Aldefluor(-) cells did not), (b) generated them after implanting as few as 25 cells, and (c) generated them dose dependently. Further isolation of cancer cells using a second marker (CD44(+) or CD133(+) serially) only modestly increased enrichment based on tumor-initiating ability. Thus, ALDH1 seems to be a specific marker for identifying, isolating, and tracking human colonic SC during CRC development. These findings also support our original hypothesis, derived previously from mathematical modeling of crypt dynamics, that progressive colonic SC overpopulation occurs during colon tumorigenesis and drives CRC development.
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PMID:Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. 1933 70

CD133, CD44, and CD166 are cell surface markers that have recently been associated with colorectal cancer stem cells. As which of these markers has the greatest impact on patient prognosis is currently unknown, we compared their expression and prognostic significance in 110 colorectal adenocarcinomas. We demonstrate that expression of CD133 correlates with that of CD166, while both do not correlate with CD44. We show that CD133 is the best sole marker to predict low patient survival, while the combined analysis of all three markers may be superior in identification of low-, intermediate-, and high-risk cases of colorectal cancer.
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PMID:Prognostic significance of the cancer stem cell markers CD133, CD44, and CD166 in colorectal cancer. 1962 93


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