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

The gastrointestinal epithelium is known to undergo constant and rapid renewal resulting in millions of cells being shed into the fecal stream every day. The conventional wisdom was that these cells disintegrate upon exfoliation and will not survive the transit through the intestinal tract. In 1990, we (P.N.) made the discovery that a significant number of these cells remain intact and viable and that they can be isolated. The implications of this important discovery became apparent when we demonstrated that these cells are exclusively of colonic origin, are anatomically representative of the entire colon, and can be used for clinical investigations of disease processes. The term coprocytobiology (CCB) was coined to encompass the broad range of applications of this new technology. The somatic cell sampling and recovery (SCSR) process involves the isolation of exfoliated colonocytes from a small sample of stool ( approximately 1 g) collected and transported in a unique medium at ambient temperature, providing cells for the detection of a number of biomarkers of disease propensity. These exfoliated colonocytes express cytokeratins indicating epithelial lineage as well as colon-specific antigen. Over the years, the study of exfoliated colonocytes has provided striking new insights into the biology of colon cancer and inflammatory bowel disease, including detection of p53 gene mutations, reverse transcriptase polymerase chain reaction amplification, and identification of CD44 splice variants, neoplasia-associated specific binding of plant lectins, and expression of COX-2, the inducible form of cyclooxygenase. The functional diversity of cells isolated by SCSR is revealed by the demonstration of cell surface markers such as secretory component, IgA, and IgG on the one hand and the amplification and cloning of the human insulin receptor and the expression of the multidrug resistance gene mdr-1 on the other hand. This review portrays the immense potential of CCB as a powerful tool for investigating the pathophysiology of disease, identifying genetic variants in pharmacogenetics, assessment of mucosal immunity, and several other applications that use somatic cells.
 ...
PMID:Coprocytobiology: on the nature of cellular elements from stools in the pathophysiology of colonic disease. 1270 72

The invasion of cancer cells at primary tumor sites and their migration during metastatic spread require the expression of cell adhesion and motility proteins. Whether accelerated cell motility is necessary in these two processes is not universally accepted. In this study we took advantage that CD44, a cell adhesion protein, has different metastatic potentials depending on its splicing isoforms to examine how they affect cell motility. We established stable transfectants of standard and variant isoforms of CD44 in SW620 cells, a human colon carcinoma cell line that does not express CD44. The morphology of the cells varied according to the CD44 isoform expressed, but actin filament distribution remained unchanged. Using the wound assay in a two-dimensional in vitro cell motility system, we found that the expression of standard CD44 increases cell motility, whereas CD44 isoforms containing an exon sequence associated with metastatic dissemination has a slowing effect. Cell proliferation was also decreased by the expression of variant CD44 isoforms. Overall, colon cancer cells expressing variant CD44 isoforms had slower cell motility, possibly due to alterations in their cell adhesion properties. In conclusion, this study suggests that, contrary to common models, the metastatic phenotype is associated with a slow rate of cell migration when tested in vitro.
 ...
PMID:Motility of colon cancer cells: modulation by CD44 isoform expression. 1451 73

CD44 is a family of transmembrane glycoproteins that serve as a major receptor for hyaluronate and the splice variants play a very important role in tumor progression and metastasis. We examined the relationship between cancer progression and mRNA levels of CD44 variant exon 6 (CD44v6) in specimens of colon cancer at different diagnostic stages from 31 patients using real time RT-PCR analysis. Increased mRNA levels of CD44v6 were observed in 82% of the specimens in comparison with those in the corresponding non-cancerous tissue specimens. A statistically significant correlation between the CD44v6 expression and the cancerous state was found in most specimens at all Dukes stages. None of the other parameters were related to the expression in the cancerous specimens. Quantitative real time RT-PCR analysis showed that there was no correlation of CD44v6 expression with tumor progression, although CD44v6 is upregulated in transformation. Thus, CD44v6 expression may be a clinically useful indicator of colon cancer.
 ...
PMID:CD44 variant exon 6 expressions in colon cancer assessed by quantitative analysis using real time reverse transcriptase-polymerase chain reaction. 1453 19

Identifying molecular markers for colon cancer is a top priority. Using a pooled sample approach with Affymetrix GeneChip technology, we assayed colon cancers derived from a series of clinical stages to identify molecular markers of potential prognostic value. Of 12000 genes assessed, osteopontin emerged as the leading candidate tumor progression marker. Osteopontin is a secreted glycoprotein known to bind integrins and CD44. Its actual molecular function remains elusive but its increased expression correlates strongly with tumor progression.
 ...
PMID:Osteopontin identified as colon cancer tumor progression marker. 1474 11

Colon carcinoma arising in inflammatory bowel disease often exhibits aggressive behavior compared to sporadic carcinomas. The rationale for the different biological behaviors of these two groups of tumors is not fully understood. In this study, we have examined carcinomas arising in inflammatory bowel disease (IBD) and sporadic carcinomas (SCA) for molecular differences that may provide clues for the behavioral disparity of these tumors. Thirty-eight colon carcinomas (12 from ulcerative colitis, 5 from Crohn's disease, and 21 SCA) were analyzed by immunohistochemistry for cell adhesion molecules (E-cadherin, beta-catenin, CD44), cell cycle regulatory proteins (cyclin D1, p27, p21), mismatch repair proteins (hMLH1, hMSH2), cyclooxygenase-2 and DPC4. Carcinomas arising in IBD showed significant decrease in expression of cell adhesion molecules, the cell cycle inhibitor protein, p21, and increased expression of cyclooxygenase-2 compared to sporadic carcinomas. No differences were observed in the expression of cell cycle regulatory proteins p27, cyclin D1, DPC4 and mismatch repair proteins between these two groups of tumors. Decreased expression of p21 as well as adhesion molecules may provide increased impetus for the aggressive behavior of tumors arising in inflammatory bowel disease.
 ...
PMID:Comparative analysis of cell adhesion molecules, cell cycle regulatory proteins, mismatch repair genes, cyclooxygenase-2, and DPC4 in carcinomas arising in inflammatory bowel disease and sporadic colon cancer. 1506 31

Regulation of epithelial cell proliferation and apoptosis are important determinants of colonic crypt homeostasis, and their dysregulations are key features of colon cancer. In this study, we investigated whether CD44, an adhesion protein overexpressed in colon cancer, plays a role in colonocyte proliferation and apoptosis, and the molecular mechanisms involved in these processes. Using a CD44 knockout mouse model devoid of a gross phenotype, we found that CD44 null colonocytes have alterations at the ultrastructural and molecular levels. Mitochondria in CD44 null colonocytes at the top of the crypt have disrupted cristae. The ratio of anti-apoptotic Bcl-xl to pro-apoptotic Bak was shifted toward apoptosis in CD44 null colon due to decreased Bcl-xl expression. Caspase 9 was upregulated and active in CD44 null colon. Its expression shifted from a location restricted to the top of the control crypts to the whole crypt axis in CD44 null colon. Caspase 3 was also activated in CD44 null colon suggesting that CD44 null colonocytes are apoptotic via the intrinsic pathway. Cell cycle regulators, cyclin A, p21, and pRb protein were abrogated in CD44 null mice. Overall, CD44 negatively regulates apoptosis via the mitochondrial pathway in the colonic epithelium through the regulators/effectors of cell cycle and apoptosis.
 ...
PMID:CD44 negatively regulates apoptosis in murine colonic epithelium via the mitochondrial pathway. 1512 1

Overexpression of CD44, especially its variant isoforms, occurs consistently in colon cancer, as compared to autologous normal colon, and this change occurs also in most other types of cancer. One of the basic features of malignant transformation is the acquisition of resistance to apoptosis. In this study, we asked whether the expression of CD44 and some of its variant isoforms commonly found in colon cancer participate in resistance to apoptosis and what are the mechanisms involved. A human colon cancer cell line, SW620, which does not express CD44 was stably transfected with standard, v3-10, and v8-10 containing isoforms of CD44. Mock-transfected and CD44-transfected cells were exposed to etoposide to induce apoptosis. Apoptotic and concomitant changes relevant to the mechanisms of apoptosis were monitored by flow cytometry, DNA fragmentation, and immunoblot analyses. It was observed that resistance to apoptosis induced by etoposide is promoted by CD44 expression in SW620, and this resistance is better sustained by the full variant isoform, v3-10. Concomitant alterations in caspase 9, caspase 3, Bcl-xl, and Bak indicated that the resistance to apoptosis in this model involved the mitochondrial pathway. The differential response of CD44 transfectants was associated with a downregulation of pRb and phosphorylated AKT. The results of this study are consistent with the conclusion that expression of variant CD44 isoforms which is characteristic of colon cancer, and most other types of cancer, confers a selective advantage to resist apoptosis, thereby promoting cell transformation into a malignant phenotype, in conjunction with other anti-apoptotic factors.
 ...
PMID:CD44 promotes resistance to apoptosis in human colon cancer cells. 1521 46

Hepatic metastasis is a primary cause for failure of locoregional therapy in colorectal cancer. Increased expression of osteopontin (OPN), a ligand for alpha(v)beta3 integrin and CD44 receptors, is associated with metastasis in several types of cancer. However, the mechanism by which OPN mediates metastasis in colorectal cancer remains unknown. We hypothesized that OPN mediates invasion of colon cancer cells through basement membrane and migration through extracellular matrix (ECM). In this study, we used CT26 murine colon adenocarcinoma cells syngeneic to BALB/c mice to generate cell lines (pS-OPN) in which OPN expression was suppressed through small interfering RNA (siRNA) plasmids. CT26 wild-type cells (WT) and CT26 cells stably expressing murine-mismatch siRNA (pS-MM) served as controls. Western blotting quantified OPN protein levels and our most downregulated clone, pS-OPN-A4, demonstrated a mean 3.0-fold decrease in OPN protein expression versus WT. In vitro cell motility and invasiveness were decreased in pS-OPN-A4 by 3.6-fold (P = 0.004 versus WT) and 4.1-fold (P = 0.01 versus WT), but proliferation was similar amongst cell lines. We demonstrated that OPN suppression significantly correlates with MMP-2 downregulation. In vivo hepatic metastasis was assessed by quantifying liver weights and surface tumor nodules in 33 BALB/c mice (11/group) subjected to intrasplenic injection of tumor cells. pS-OPN-A4 resulted in a 50.4% decrease in mean liver weight compared with WT (3.79 +/- 1.49 g versus 1.88 +/- 1.34 g, P = 0.009). Only 18% of pS-OPN-A4 livers had >20 metastatic surface nodules compared with 89% for WT and 75% for pS-MM-V6. This study demonstrates that RNA interference stably reduces CT26 tumor expression of OPN and significantly attenuates CT26 colon cancer metastasis by diminishing tumor cell motility and invasiveness.
 ...
PMID:Osteopontin silencing by small interfering RNA suppresses in vitro and in vivo CT26 murine colon adenocarcinoma metastasis. 1566 2

Osteopontin (OPN) is a secreted phosphoglycoprotein known to interact with a number of integrin receptors. While increased OPN expression has been reported in a number of human cancers, and its cognate receptors (alphav-beta3, alphav-beta5, and alphav-beta1 integrins and CD44) have been identified, its role in colon cancer development and progression has not been extensively studied. We previously identified, using a combination of gene expression and tissue microarrays, that increased OPN expression is concordant with tumor stage. The current study examined the functional role of OPN in colon cancer progression and metastatic potential. The principal findings of this study were that both endogenous OPN expression (via stable transfection) as well as exogenous OPN (added to culture medium) enhanced the motility and invasive capacity of human colon cancer cells in vitro. OPN appeared to regulate motility though interaction with CD44. OPN expression also reduced intercellular (homotypic) adhesion, an important characteristic of metastatic cancer cells. Stable transfection of four poorly tumorigenic human colon cancer cell lines with OPN also resulted in enhanced tumorigenicity in vivo with increased proliferation and increased CD31 positive microvessel counts, concordant with the degree of OPN expression. Collectively, these results suggest that OPN may affect multiple functional components contributing to human colon cancer progression and solidifies its role in this process.
 ...
PMID:Osteopontin regulates multiple functions contributing to human colon cancer development and progression. 1567 49

Some markers of angiogenic endothelial cells are emerging as targets of cancer therapy. The present study compares the expression of CD105 with that of other endothelial markers in all tissue layers during the development of colon cancer. We immunohistochemically analyzed the expression of the colon adenoma-carcinoma sequence by endothelial cells using a panel of eight endothelial markers. We examined sections from endoscopic mucosal resection and surgical resection of tubular adenoma (n=31), carcinoma in adenoma (n=11), and adenocarcinoma (n=34). Cylindrical cores were punched out from donor paraffin blocks of normal mucosa adjacent to tumors, from tumor lesions of mucosa, submucosa, muscularis propria, subserosa, and serosa, and from lymph node metastases. CD31 (PECAM-1) was universally expressed in the blood vessels of adenoma-carcinoma lesions as well as in normal mucosal vessels (80-95%), with no significant differences. In contrast, cancer-associated blood vessels (up to 80%) and cancer cells themselves expressed high levels of CD105. In normal mucosa, CD105 was weakly expressed in endothelial cells of capillaries (< or =21%), and significant differences in its expression in endothelial cells between the normal mucosa and adenoma, carcinoma in adenoma, and adenocarcinoma were found. Flt-1, Flk-1, transforming growth factor-beta1, transforming growth factor-beta receptor II, and CD44 were strongly expressed in the cancer cells but were not expressed in the blood vessels. Vascular endothelial growth factor was expressed at <30% in the blood vessels of adenoma, carcinoma in adenoma, and carcinoma. Moreover, this study provided evidence that CD105 was expressed exclusively in endothelial blood vessels by double immunostaining of CD105 and D2-40. The present study shows that de novo blood vessels of colon cancer specifically express CD105. These findings provide the basis for novel antiangiogenic cancer therapies.
 ...
PMID:Endoglin (CD105) expression in angiogenesis of colon cancer: analysis using tissue microarrays and comparison with other endothelial markers. 1617 81


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>