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Colon Cancers (colon + cancers)

Distribution by Scientific Domains

Medical Sciences	94%
Life Sciences	5%

Distribution within Medical Sciences

Oncology & Radiotherapy	75%
Immunology	5%
6 Other Subdomains	20%

Selected Abstracts

Model-based prediction of defective DNA mismatch repair using clinicopathological variables in sporadic colon cancer patients

CANCER, Issue 7 2010
Frank Sinicrope MD
Abstract BACKGROUND: Colon cancers with defective DNA mismatch repair (MMR) have a favorable prognosis and may lack benefit from 5-fluorouracil,based adjuvant chemotherapy. The authors developed models to predict MMR deficiency in sporadic colon cancer patients using routine clinical and pathological data. METHODS: TNM stage II and III colon carcinomas (n = 982) from 6 5-fluorouracil,based adjuvant therapy trials were analyzed for microsatellite instability and/or MMR protein expression. Tumor-infiltrating lymphocytes (TILs) were quantified (n = 326). Logistic regression and a recursive partitioning and amalgamation analysis were used to identify predictive factors for MMR status. RESULTS: Defective MMR was detected in 147 (15%) cancers. Tumor site and histologic grade were the most important predictors of MMR status. Distal tumors had a low likelihood of defective MMR (3%; 13 of 468); proximal tumors had a greater likelihood (26%; 130 of 506). By using tumor site, grade, and sex, the logistic regression model showed excellent discrimination (c statistic = 0.81). Proximal site, female sex, and poor differentiation showed a positive predictive value (PPV) of 51% for defective MMR. In a patient subset (n = 326), a model including proximal site, TILs (>2/high-power field), and female sex showed even better discrimination (c statistic = 0.86), with a PPV of 81%. CONCLUSIONS: Defective MMR is rare in distal, sporadic colon cancers, which should generally not undergo MMR testing. Proximal site, poor differentiation, and female sex detect 51% of tumors with defective MMR; substituting TILs for grade increases the PPV to 81%. These data can increase the efficiency of MMR testing to assist in clinical decisions. Cancer 2010. © 2010 American Cancer Society. [source]

Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion

EMBO MOLECULAR MEDICINE, Issue 6-7 2009
Frédéric Varnat
Abstract Human colon cancers often start as benign adenomas through loss of APC, leading to enhanced ,CATENIN (,CAT)/TCF function. These early lesions are efficiently managed but often progress to invasive carcinomas and incurable metastases through additional changes, the nature of which is unclear. We find that epithelial cells of human colon carcinomas (CCs) and their stem cells of all stages harbour an active HH-GLI pathway. Unexpectedly, they acquire a high HEDGEHOG-GLI (HH-GLI) signature coincident with the development of metastases. We show that the growth of CC xenografts, their recurrence and metastases require HH-GLI function, which induces a robust epithelial-to-mesenchymal transition (EMT). Moreover, using a novel tumour cell competition assay we show that the self-renewal of CC stem cells in vivo relies on HH-GLI activity. Our results indicate a key and essential role of the HH-GLI1 pathway in promoting CC growth, stem cell self-renewal and metastatic behavior in advanced cancers. Targeting HH-GLI1, directly or indirectly, is thus predicted to decrease tumour bulk and eradicate CC stem cells and metastases. [source]

Multiple primary cancer: an increasing health problem.

EUROPEAN JOURNAL OF CANCER CARE, Issue 6 2009
Strategies for prevention in cancer survivors
LÓPEZ M.L., LANA A., DÍAZ S., FOLGUERAS M.V., SANCHEZ L., COMENDADOR M.A., BELYAKOVA E., RODRÍGUEZ J.M. & CUETO A. (2009) European Journal of Cancer Care Multiple primary cancer: an increasing health problem. Strategies for prevention in cancer survivors This study was set to look for associations between the sites of the first and subsequent tumours in patients with multiple primary cancer (MPC) diagnosed from 1975 to 2002 in the reference hospital of a Spanish northern region, and propose prevention strategies. Patient and tumour variables were measured. Crude and standardized incidence rates per 100 000 inhabitants were obtained, and the association between MPC incidence and time was analysed by means of lineal regression. Relative risks were calculated to analyse associations between tumour sites. A total of 2737 MPC cases were registered (male/female ratio = 2). The percentage of MPC with respect to the total cancer increased from 1.78% in the 1975,1979 period to 7.08% in the 2000,2002 period (R2 = 0.92; P = 0.003). Great increase of incidence by time was found (R2 = 0.90; P = 0.004). Breast, prostate and bladder cancers increase risk of second tumour in female genital organs [RR 4.78 (3.84,5.93)], urinary system [RR 3.69 (2.89,4.69)] and male genital organs [RR 3.76 (2.84,4.69)] respectively. The MPC incidence is increasing. Interventions for MPC prevention, according to the European Code against Cancer, should be implemented early after the first cancer principally if patients suffer breast, bladder, prostate, larynx and colon cancers. [source]

Interleukin-4 downregulates CD127 expression and activity on human thymocytes and mature CD8+ T cells

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 5 2010
Angela M. Crawley
Abstract Signaling via the IL-7 receptor complex (IL-7R,/CD127 and IL-2R,/CD132) is required for T-cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL-2R,-sharing (,C) cytokines decrease CD127 expression on CD4+ and CD8+ T cells in mice (IL-2, IL-4, IL-7, IL-15) and in humans (IL-2, IL-7), suggesting a common function. IL-4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL-4 in regulating CD127 expression and IL-7 activity in human thymocytes and mature CD8+ T cells is unknown and was therefore investigated. IL-4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA+) CD8+ T cells, without altering membrane-bound CD127 mRNA expression. Pre-treatment of thymocytes or CD8+ T cells with IL-4 inhibited IL-7-mediated phosphorylation of STAT5 and decreased proliferation of CD8+ T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8+ T cells, IL-4 is a potential contributor to impaired CD8+ T-cell function in some anti-viral and anti-tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL-7 activity is impaired and IL-4 concentrations are elevated. [source]

Integrative approach for prioritizing cancer genes in sporadic colon cancer,

GENES, CHROMOSOMES AND CANCER, Issue 11 2009
James F. Reid
The current multistep carcinogenesis models of colon cancer do not fully capture the genetic heterogeneity of the disease, which is additionally complicated by the presence of passenger and driver genetic alterations. The aim of this study was to select in the context of this significant heterogeneity additional genes functionally related to colon cancer development. High-throughput copy number and gene expression data of 36 microsatellite stable sporadic colon cancers resected from patients of a single institution characterized for mutations in APC, KRAS, TP53 and loss of 18q were analyzed. Genes whose expression correlated with the underlying copy number pattern were selected, and their association with the above listed mutations and overall survival was evaluated. Gain of 20q was strongly associated with TP53 mutation, and overall survival with alterations on 7p, 8p, 13q, 18q, and 20q. An association with 18q loss and gain of 8q24 was also observed. New candidate genes with a potential role in colon cancer are PLCG1 on 20q, DBC1 on 8q21, and NDGR1 on 8p24. In addition, an unexpected pattern of loss and mutability was found in the region upstream of the KRAS gene. By integrating copy number alterations with gene expression and mutations in colon cancer associated genes, we have developed a strategy that identifies previously known molecular features and additional players in the molecular landscape of colon cancer. © 2009 Wiley-Liss, Inc. [source]

The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers

GENES, CHROMOSOMES AND CANCER, Issue 11 2008
Chunguang Guo
MicroRNAs (miRNA/miR) are a class of small noncoding RNAs implicated in the pathogenesis of various malignancies. In the current study, using micro(RNA) arrays, we found a ubiquitous loss of miR-126 expression in colon cancer lines when compared to normal human colon epithelia. Reconstitution of miR-126 in colon cancer cells resulted in a significant growth reduction as evidenced in clonogenic assays. A search for miR-126 gene targets revealed p85,, a regulatory subunit involved in stabilizing and propagating the phosphatidylinositol 3-kinase (PI3K) signal, as one of the potential substrates. Restoration of miR-126 in cancer cells induced a ,3-fold reduction in p85, protein levels, with no concomitant change in p85,, a gene that is functionally related to p85, but not a supposed target of miR-126. Additionally, using reporter constructs, we show that the p85,-3, untranslated region is directly targeted by miR-126. Furthermore, this miR-126 mediated reduction of p85, was accompanied by a substantial reduction in phosphorylated AKT levels in the cancer cells, suggesting an impairment in PI3K signaling. Finally, in a panel of matched normal colon and primary colon tumors, each of the tumors demonstrated miR-126 down-regulation together with an increase in the p85, protein level. Taken together, we propose that miR-126 regulates PI3K signaling partly by targeting p85,, and that the loss of miR-126 may provide a selective growth advantage during colon carcinogenesis. © 2008 Wiley-Liss, Inc. [source]

Mutational inactivation of TGFBR2 in microsatellite unstable colon cancer arises from the cooperation of genomic instability and the clonal outgrowth of transforming growth factor , resistant cells

GENES, CHROMOSOMES AND CANCER, Issue 2 2008
Swati Biswas
The mutational inactivation of transforming growth factor , receptor type II (TGFBR2) occurs in ,30% of colon cancers and promotes the formation of colon cancer by inhibiting the tumor suppressor activity of the TGFB signaling pathway. TGFBR2 mutations occur in >90% of microsatellite unstable (MSI) colon cancers and affect a polyadenine tract in exon 3 of TGFBR2, called BAT-RII, which is vulnerable to mutation in the setting of DNA mismatch repair (MMR) system deficiency. In light of the vulnerable nature of the BAT-RII tract in the setting of MMR inactivation and the favorable effects of TGFBR2 inactivation in colon cancer, analysis of TGFBR2 inactivation provides an opportunity to assess the roles of genomic instability vs. clonal selection in cells acquiring TGFBR2 BAT-RII tract mutations in MSI colon cancer formation. The contribution of genomic instability and/or clonal evolution to the mutational inactivation of TGBFR2 in MSI colon cancers has not been studied in a systematic way that would allow a determination of the relative contribution of these two mechanisms in the formation of MSI colon cancer. It has not been demonstrated whether the BAT-RII tract mutations are strictly a consequence of the BAT-RII region being hypermutable in the setting of MMR deficiency or if the mutations are rather a consequence of clonal selection pressure against the TGFB receptor. Through the use of defined cell line systems, we show that both genomic instability and clonal selection of TGFB resistant cells contribute to the high frequency of TGFBR2 mutations in MSI colon cancer. © 2007 Wiley-Liss, Inc. [source]

Mutations in the ataxia telangiectasia and rad3-related,checkpoint kinase 1 DNA damage response axis in colon cancers

GENES, CHROMOSOMES AND CANCER, Issue 12 2007
Kriste A. Lewis
In response to certain types of DNA damage, ataxia telangiectasia and rad3-related (ATR) phosphorylates checkpoint kinase 1 (CHEK1) resulting in cell cycle arrest and subsequent DNA repair. ATR and CHEK1 contain mononucleotide microsatellite repeat regions, which are mutational targets in tumors with defective mismatch repair (MMR). This study examined the frequency of such mutations in colon cancers and their impact on biologic behavior. Screening for ATR mutations in 48 tumors was performed using denaturing high-performance liquid chromatography (DHPLC) and confirmed with sequencing analysis. The CHEK1 exon 7 A(9) region was sequenced in 20 of the 27 (74%) tumors with high frequency of microsatellite instability (MSI-H). Univariate and multivariate analyses were used to examine associations with clinical outcomes. Frequent mutations in MSI-H colon cancers were identified within the ATR (37%)/CHEK1(5%) damage response pathway. Stage and MSI status both independently predicted overall survival (OS) and disease-free survival (DFS). ATR status was not associated with stage, but was associated with a trend toward improved DFS: 0/9 cancers recurred in MSI-H cases harboring ATR mutations vs. 4/18 recurrences in MSI-H cases without ATR mutations. This suggests that ATR mutations may affect clinical behavior and response to therapy in MSI-H colon cancers. © 2007 Wiley-Liss, Inc. [source]

Dietary patterns and risk of cancer: A factor analysis in Uruguay

INTERNATIONAL JOURNAL OF CANCER, Issue 6 2009
Eduardo De Stefani
Abstract A multisite case,control study on factor analysis and several cancer sites (mouth and pharynx, esophagus, stomach, colon, rectum, larynx, lung, breast, prostate, bladder, kidney) was conducted in Uruguay. The study included 3,528 cases and 2,532 controls. Factor analysis (principal components) was modeled among controls. This patterning method retained 4 factors per sex, labeled as prudent, drinker, traditional and Western. Odds ratios for these cancer sites, stratified by sex, were estimated using polytomous regression. Whereas the prudent pattern was mainly negatively associated with cancers of the upper aerodigestive tract, the Western pattern showed a strong increase in breast, lung and colon cancers. The study allowed for the reproducibility of the prudent, drinker and Western patterns, whereas the traditional pattern appears to be country specific. © 2008 Wiley-Liss, Inc. [source]

Nox1 is over-expressed in human colon cancers and correlates with activating mutations in K-Ras

INTERNATIONAL JOURNAL OF CANCER, Issue 1 2008
Eunice Laurent
Abstract The NADPH-oxidase 1 (Nox1) is a homolog of gp91phox, the catalytic subunit of the phagocyte superoxide-generating NADPH-oxidase. Nox1 is expressed in normal colon epithelial cells and in colon tumor cell lines, and overexpression in model cells has been implicated in stimulation of mitogenesis and angiogenesis and inhibition of apoptosis. This suggests that aberrant expression of Nox1 could contribute to the development of colorectal cancer. Herein, we examine the expression of Nox1 mRNA in 24 colon tumors of various stages compared with paired adjacent normal tissue from the same patient, and correlate expression with some common mutations associated with colon cancer. Nox1 was overexpressed compared with paired normal tissue in 57% of tumors as early as the adenoma stage, with no correlation of expression level with tumor stage. Overexpression of Nox1 mRNA correlated with Nox1 protein levels assessed by immunofluorescence and immunohistochemistry with an antibody specific for Nox1. There was a strong correlation between Nox1 mRNA level and activating mutations in codons 12 and 13 of K-Ras. Eighty percent (8/10) of tumors with codons 12 and 13 mutations had a 2-fold or more increase in Nox1 mRNA, and 70% (7/10) had a 5-fold or greater increase. Transgenic mice expressing K-RasG12V in the intestinal epithelium also expressed markedly elevated Nox1 in both small and large intestine. There was no correlation between inactivating mutations in the tumor suppressor p53 and Nox1 expression. We conclude that Nox1 mRNA and protein are overexpressed in colon cancer and are strongly correlated with activating mutations in K-Ras. © 2008 Wiley-Liss, Inc. [source]

Adenovirus-mediated small hairpin RNA targeting Bcl-XL as therapy for colon cancer

INTERNATIONAL JOURNAL OF CANCER, Issue 6 2007
Hongbo Zhu
Abstract Bcl-XL, an anti-apoptotic protein of Bcl-2 family, is overexpressed in colon cancers. To determine Bcl-XL's potential feasibility as a therapeutic target, we constructed a recombinant adenovirus that expressed a U6 promoter-driven small hairpin RNA (shRNA) targeting Bcl-XL (Ad/Bcl-XL shRNA) and evaluated the vector's ability to induce RNA interference in vivo and alter apoptosis induction in colon cancer cells and tumours. Ad/Bcl-XL shRNA effectively knocked down Bcl-XL expression in colon cancer cells and decreased their viability. Treatment with Ad/Bcl-XL shRNA but not control vectors led to dramatically increased cleavage of cellular apoptosis-related enzymes caspase-9, caspase-3 and poly(ADP-ribose) polymerase. Ad/Bcl-XL shRNA also significantly suppressed the growth of subcutaneous tumours derived from DLD1 cells in a nude mouse model and did so without causing any obvious damage to normal tissues or normal human fibroblasts. Together, our results support the feasibility of using adenovirus-mediated RNA interference therapy targeting Bcl-XL against colon cancers and warrant further studies of its safety and efficacy. © 2007 Wiley-Liss, Inc. [source]

Frequent inactivation of SPARC by promoter hypermethylation in colon cancers

INTERNATIONAL JOURNAL OF CANCER, Issue 3 2007
Eungi Yang
Abstract Epigenetic modification of gene expression plays an important role in the development of human cancers. The inactivation of SPARC through CpG island methylation was studied in colon cancers using oligonucleotide microarray analysis and methylation specific PCR (MSP). Gene expression of 7 colon cancer cell lines was evaluated before and after treatment with the demethylating agent 5-aza-2,-deoxycytidine (5Aza-dC) by oligonucleotide microarray analysis. Expression of SPARC was further examined in colon cancer cell lines and primary colorectal cancers, and the methylation status of the SPARC promoter was determined by MSP. SPARC expression was undetectable in 5 of 7 (71%) colorectal cancer cell lines. Induction of SPARC was demonstrated after treatment with the demethylating agent 5Aza-dC in 5 of the 7 cell lines. We examined the methylation status of the CpG island of SPARC in 7 colon cancer cell lines and in 20 test set of colon cancer tissues. MSP demonstrated hypermethylation of the CpG island of SPARC in 6 of 7 cell lines and in all 20 primary colon cancers, when compared with only 3 of 20 normal colon mucosa. Immunohistochemical analysis showed that SPARC expression was downregulated or absent in 17 of 20 colon cancers. A survival analysis of 292 validation set of colorectal carcinoma patients revealed a poorer prognosis for patients lacking SPARC expression than for patients with normal SPARC expression (56.79% vs. 75.83% 5-year survival rate, p = 0.0014). The results indicate that epigenetic gene silencing of SPARC is frequent in colon cancers, and that inactivation of SPARC is related to rapid progression of colon cancers. © 2007 Wiley-Liss, Inc. [source]

Predominant T helper type 2-inflammatory responses promote murine colon cancers

INTERNATIONAL JOURNAL OF CANCER, Issue 9 2006
Emi Osawa
Abstract Colon cancer is one of the most serious complications of inflammatory bowel diseases, especially ulcerative colitis (UC). Previous studies have shown that characteristic immunological event during inflammation in UC is the expression of T helper-type 2 (Th2) cell-derived cytokines. In this study, we investigated the influence of a predominant Th2-type cytokine response in colitis on carcinogen-induced colon tumors. Wild type (WT), interferon gamma (IFN-,) gene deficient (,/,) [Th2 dominant] or interleukin (IL)-4,/, [Th1-dominant] mice of BALB/c background were used in this study. To compare tumor formation, mice were given the carcinogen azoxymethane (AOM) and intrarectal administration of trinitrobenzene sulfonic acid (TNBS), to induce colitis. Thirty-three weeks after initial treatment, the total colon was examined. When IFN-,,/, mice were treated with AOM and TNBS, significantly higher number of tumors were seen (8.4 ± 1.7) than in WT (3.3 ± 2.9) or IL-4,/, (3.1 ± 3.4) mice, which received identical treatments. A separate set of experiment, using less doses of AOM and TNBS also showed the higher frequency of tumor formation in IFN-,,/, mice than in IL-4,/, mice. Histologically, the tumors were well- or moderately-differentiated adenocarcinomas. No invasion into the submucosal or serosal layers of the intestine was seen. In immunohistological staining, some tumors in IFN-,,/, mice showed distinct nuclear expression of ,-catenin, in contrast to the strong membrane staining seen in tumors of IL-4,/, mice. In conclusion, colonic inflammation associated with Th2-donimant cytokine responses enhanced the formation of malignant neoplasms. © 2005 Wiley-Liss, Inc. [source]

Body size and composition and colon cancer risk in women

INTERNATIONAL JOURNAL OF CANCER, Issue 6 2006
Robert J. MacInnis
Abstract Studies of colon cancer risk in males have reported strong positive associations with obesity, particularly with central adiposity. The association has been weaker and less consistent for women. In a prospective cohort study of women, body measurements were taken directly; fat mass and fat-free mass being estimated by bioelectrical impedance analysis and central adiposity by waist circumference and waist-to-hip ratio (WHR). Among 24,072 women followed on average for 10.4 years, 212 colon cancers were ascertained via the population cancer registry. We reviewed medical records of all cases and classified them according to anatomic site and stage. The central adiposity measures of WHR (hazard ratio per 0.1 unit increase = 1.31, 95% confidence interval (CI) 1.08,1.58) and waist circumference (hazard ratio per 10 cm increase = 1.14, 95% CI 1.02,1.28) were positively associated with colon cancer risk. There was little or no association between other anthropometric measures and risk of colon cancer. There was some evidence that the associations were stronger for proximal tumors, but no evidence that risk differed by stage for any of the anthropometric measures. Central adiposity appears to be associated with colon cancer risk in women. © 2005 Wiley-Liss, Inc. [source]

Fas ligand expressed in colon cancer is not associated with increased apoptosis of tumor cells in vivo

INTERNATIONAL JOURNAL OF CANCER, Issue 2 2003
Aileen Houston
Abstract Expression of Fas ligand (FasL/CD95L) may help to maintain colon cancers in a state of immune privilege by inducing apoptosis of antitumor immune effector cells. Colon tumor-derived cell lines appear to be relatively insensitive to apoptosis mediated by their own or exogenous FasL in vitro, despite expression of cell surface Fas. In our present study, we sought to investigate if FasL upregulated in human colon cancers leads to any increase in apoptosis of the tumor cells in vivo. FasL and Fas receptor (APO-1/CD95) expression by tumor cells were detected immunohistochemically. Apoptotic tumor cell death was detected by immunohistochemistry for caspase-cleaved cytokeratin-18. FasL expression did not correlate with the extent of apoptosis of tumor cells. There was no significant local difference in the frequency of apoptosis of tumor cells between tumor nests that expressed FasL (mean = 2.4%) relative to those that did not (mean = 2.6%) (p = 0.625, n = 10; Wilcoxon signed rank). FasL expressed by the tumor cells appeared to be functional, since FasL expression in tumor nests correlated with diminished infiltration of tumor-infiltrating lymphocytes (TILs). TILs were detected using immunohistochemistry for CD45. Expression of FasL by tumor nests was associated with a mean 4-fold fewer TILs relative to FasL-negative nests (range 2.4,33-fold, n = 10, p < 0.003). Together, our results indicate that colon tumors are insensitive to FasL-mediated apoptosis in vivo. © 2003 Wiley-Liss, Inc. [source]

Cancer incidence patterns among Vietnamese in the United States and Ha Noi, Vietnam,

INTERNATIONAL JOURNAL OF CANCER, Issue 4 2002
Gem M. Le
Abstract Nearly 600,000 persons have immigrated to the United States from Vietnam since the end of the Vietnam War. Despite the rapid growth of the U.S. Vietnamese population, little is known about cancer incidence in this migrant group. Using population-based data from the Surveillance, Epidemiology and End Results program, California Cancer Registry and International Agency for Research on Cancer, we compared cancer incidence rates for Vietnamese in the United States (1988,1992) to rates for residents of Ha Noi, Vietnam (1991,1993); non-Hispanic whites were included to serve as the U.S. reference rates. Lung and breast cancers were the most common among Vietnamese males and females, respectively, regardless of geographic region. Rates of cancers more common to U.S. whites, such as breast, prostate and colon cancers, were elevated for U.S. Vietnamese compared to residents in Ha Noi but still lower than rates for U.S. whites. Rates of cancers more common to Asian countries, such as stomach, liver, lung and cervical cancers, were likewise elevated for U.S. Vietnamese compared to residents of Ha Noi and exceeded corresponding rates for whites. Incidence patterns for stomach, liver, lung and cervical cancers may reflect increased risk of exposures in this migrant population and should be further explored to uncover the relative contributions of environmental and genetic factors to cancer etiology. © 2002 Wiley-Liss, Inc. [source]

Accelerated growth of intestinal tumours after radiation exposure in Mlh1-knockout mice: evaluation of the late effect of radiation on a mouse model of HNPCC

INTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 2 2006
Yutaka Tokairin
Summary Mlh1 -knockout mice have been developed as a useful model of hereditary non-polyposis colorectal cancer (HNPCC). In this study, we analyzed the pathology of gastrointestinal tumours (GIT) in these mice in detail and examined the possible effects of ionizing radiation on the induction of intestinal tumours to evaluate the late response to radiotherapy in HNPCC. Mlh1,/, mice spontaneously developed GIT and thymic lymphomas by 48 weeks. GIT included not only well differentiated adenocarcinomas but also poorly differentiated and mucinous adenocarcinomas, suggesting that this mouse is a good model for HNPCC. In contrast to colon cancers from HNPCC patients, however, carcinomas of Mlh1,/, mice expressed p53 and showed a lack of transforming growth factor (TGF) -,RII mutation, which resulted in the expression of TGF-,RII protein. Irradiation of 10-week-old Mlh1,/, mice accelerated GIT development but had little effect at 2 weeks. Mlh1+/, and Mlh1+/+ mice were not susceptible to spontaneous or radiation-induced thymic lymphomas and GIT until 72 weeks after birth. The development and pathology of GIT in Mlh1,/, mice suggest that this mouse is a good model for HNPCC, although tumour-related responsible genes might be different from HNPCC. As X-ray exposure promoted carcinogenesis of GIT in adult Mlh1,/, mice, an increased risk of secondary cancers after radiotherapy for HNPCC patients should be taken into consideration. [source]

Breast lymphoma in Sjögren's syndrome complicated by acute monocular blindness

INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 2 2010
Helmar F. SOLDEVILLA
Abstract A 69-year-old hypertensive woman presented with eye and mouth dryness, bilateral parotid gland enlargement, associated with anasarca and proteinuria. Family history was notable for malignancies including breast, nasopharyngeal and colon cancers. Physical exam disclosed hypertension, bilaterally enlarged, firm, non-tender parotid glands, fine bibasilar crackles and bipedal edema. Anti Ro/Sjögren's syndrome antigen A antibody was positive, with negative tests for anti La/Sjögren's syndrome antigen B and anti-nuclear antibody (ANA). Chest radiographs showed basal infiltrates. Sjögren's syndrome associated with glomerulonephritis and interstitial lung disease was diagnosed, and she received pulse methylprednisololone followed by oral prednisone with dramatic improvement. Two months later, while on prednisone 5 mg/day, she returned to the clinic with an enlarging fixed non-tender right breast mass. She underwent modified radical mastectomy of the right breast, and pathologic report revealed diffuse, small cell, non-Hodgkin's lymphoma of the breast; axillary lymph nodes were negative for tumor. She opted for alternative therapy and did not return to the clinic until 7 months later when she developed sudden monocular blindness in the right eye with no other systemic manifestations. Magnetic resonance imaging (MRI) revealed swelling and enhancement of intracanalicular and pre-chiasmatic segments of the right optic nerve and right side of the optic chiasm. Considerations were Devic's disease versus metastases. She received pulse methylprednisolone therapy (1 g/day for 3 days) with partial recovery of vision. She is scheduled for lymphoma chemotherapy to include rituximab. [source]

Colon cancer cell adhesion in response to Src kinase activation and actin-cytoskeleton by non-laminar shear stress,

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2004
Vijayalakshmi Thamilselvan
Abstract Malignant cells shed from tumors during surgical resection or spontaneous metastasis experience physical forces such as shear stress and turbulence within the peritoneal cavity during irrigation, laparoscopic air insufflation, or surgical manipulation, and within the venous or lymphatic system. Since physical forces can activate intracellular signals that modulate the biology of various cell types in vitro, we hypothesized that shear stress and turbulence might increase colon cancer cell adhesion to extracellular matrix, potentiating metastatic implantation. Primary human malignant colon cancer cells isolated from resected tumors and SW620 were subjected to shear stress and turbulence by stirring cells in suspension at 600 rpm for 10 min. Shear stress for 10 min increased subsequent SW620 colon cancer cell adhesion by 40.0,±,3.0% (n,=,3; P,<,0.001) and primary cancer cells by 41.0,±,3.0% to collagen I when compared to control cells. In vitro kinase assay (1.5,±,0.13 fold) and Western analysis (1.34,±,0.04 fold) demonstrated a significant increase in Src kinase activity in cells exposed shear stress. Src kinase inhibitors PP1 (0.1 µM), PP2 (20 µM), and actin-cytoskeleton stabilizer phalloidin (10 µM) prevented the shear stress stimulated cell adhesion to collagen I. Furthermore, PP2 inhibited basal (50.0,±,2.8%) and prevented shear stress induced src activation but phalloidin pretreatment did not. These results raise the possibility that shear stress and turbulence may stimulate the adhesion of malignant cells shed from colon cancers by a mechanism that requires both actin-cytoskeletal reorganization an independent physical force activation of Src kinase. Blocking this pathway might reduce tumor metastasis during surgical resection. Published 2004 Wiley-Liss, Inc. [source]

Incidence and odds ratio of appendicitis as first manifestation of colon cancer: A retrospective analysis of 1873 patients

JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 11 2006
Hung-Wen Lai
Abstract Background and Aim:, Obstruction of the lumen of the appendix is the major cause of appendicitis. Tumors could obstruct this lumen and cause appendicitis in the elderly. The association between appendicitis and colon cancer has not been sufficiently investigated, and this study was designed to clarify this association. Methods:, This was a retrospective study. Patients diagnosed with acute appendicitis from January 1998 to December 2003 at the Taipei Veterans General Hospital were surveyed. Patients found to have colon cancers immediately or subsequently after appendectomy were included and analyzed. Results:, A total of 1873 patients were diagnosed as having appendicitis of whom 16 were found to have colon cancer. The incidence of appendicitis associated with colon cancer was 0.85%. The time from appendectomy to the recognition of colonic cancer was at a median delay of 5.8 months. From the Taiwan Cancer Research Annual Report, the incidence of colon cancer was 31.91/100 000 in the year 2000. The odds ratio of colon cancer incidence had a 38.5-fold increase among patients older than 40 with acute appendicitis. Conclusions:, In patients over 40 years who present with symptoms of acute appendicitis the possibility of a coexistent colonic neoplasm should always be kept in mind. These patients should undergo colonoscopy 6 weeks after surgery to exclude the possibility of a coexistent colorectal cancer. [source]

Organ-specific endoglin (CD105) expression in the angiogenesis of human cancers

PATHOLOGY INTERNATIONAL, Issue 12 2006
Rahmawati Minhajat
Some markers of angiogenic endothelial cells are emerging as targets for cancer therapy. The present study compared the expression of CD105 with that of other endothelial markers in cancers from various organs. Surgically resected cancer tissues from 188 patients comprising brain (n = 17), lung (n = 38), breast (n = 30), stomach (n = 30), colon (n = 31), liver (n = 32), and kidney (n = 10) cancers were immunohistochemically analyzed on tissue microarrays using a panel of eight endothelial markers. CD31 was expressed in vascular endothelial cells in cancer lesions as well as in non-cancerous areas (30,100%) in all core tissue samples. CD105 expression was intense and restricted to capillary endothelial cells in cancer lesions (>73%). In contrast, positive expression of CD105 was seen in <20% of non-cancerous areas in the same organs. However, no significant difference in CD105 expression in vascular endothelial cells between cancer lesions and non-cancerous areas from liver and renal cancer samples was found. Vascular endothelial growth factor (VEGF), Flt1, and Flk1 were also expressed, but only sporadically and in few samples (<30%), and transforming growth factor (TGF)-,1 and TGF-,RII were negative in vascular endothelial cells but generally positive in cancer cells. CD44 was strongly expressed in sinusoidal endothelial cells of the liver (90,100%). These results show that CD105 is expressed specifically in the tumor angiogenesis of brain, lung, breast, stomach, and colon cancers. [source]

Mutational analysis of hypoxia-related genes HIF1, and CUL2 in common human cancers

APMIS, Issue 12 2009
SANG WOOK PARK
Hypoxia is a general feature of solid cancer tissues. Hypoxia upregulates hypoxia-inducible factor 1, (HIF1,) that transactivates downstream genes and contributes to cancer pathogenesis. HIF1, is upregulated not only by hypoxia but also by genetic alterations in HIF1,-related genes, including VHL. Cullin 2 (CUL2) interacts with the trimeric VHL-elongin B-elongin C complex and plays an essential role in the ubiquitinated degradation of HIF1,. The aim of this study was to explore whether HIF1, and CUL2 genes are somatically mutated, and contribute to HIF1, activation in common human cancers. For this, we have analyzed the coding region of oxygen-dependent degradation domain of HIF1, in 47 colon, 47 gastric, 47 breast, 47 lung, and 47 hepatocellular carcinomas, and 47 acute leukemias by a single-strand conformation polymorphism assay. In addition, we analyzed mononucleotide repeat sequences (A8) in CUL2 in 55 colorectal and 45 gastric carcinomas with microsatellite instability (MSI). We found one HIF1, mutation (p.Ala593Pro) in the hepatocellular carcinomas (1/47; 2.1%), but none in other cancers. We found two CUL2 frameshift mutations in colon cancers (p.Asn292MetfsX20), which were exclusively detected in high MSI cancers (4.9%; 2/41). Our data indicate that somatic mutation of HIF1, is rare in common cancers, and somatic mutation of CUL2 occurs in a fraction of colorectal cancers (colorectal cancers with high MSI). The data suggest that neither HIF1, nor CUL2 mutation may play a central role in HIF1, activation in gastric, colorectal, breast, lung and hepatocellular carcinomas, and acute leukemias. [source]

Model-based prediction of defective DNA mismatch repair using clinicopathological variables in sporadic colon cancer patients

The intratumoral distribution of nuclear ,-catenin is a prognostic marker in colon cancer

CANCER, Issue 10 2009
David Horst MD
Abstract BACKGROUND: Most colon cancers harbor mutations of APC or ,-catenin, both of which may lead to nuclear ,-catenin accumulation in the tumor cells and constitutively activated expression of its target genes. In many colon cancers, however, nuclear ,-catenin accumulation is heterogeneous throughout the tumor and often confined to the tumor margin. Herein, the authors investigated whether the intratumoral distribution of nuclear ,-catenin can serve as a prognostic marker for survival and tumor progression of stage IIA colon cancer patients. METHODS: In total, 142 patients with primarily resected, moderately differentiated stage IIA colon cancer were included in this study. The patterning of nuclear ,-catenin expression was evaluated on immunohistochemically stained whole tissue sections of the tumors and was correlated with cancer-specific survival and disease-free survival using univariate and multivariate statistical analyses. RESULTS: Four distinct patterns of nuclear ,-catenin expression were identified, and 2 main categories comprising tumors with or without intratumoral regulation of nuclear ,-catenin were distinguished. Moreover, the results demonstrated that the patterning, and especially the regulation or absence of regulation of nuclear ,-catenin expression, was a strong predictive marker of patient survival and tumor progression. CONCLUSIONS: The current results indicated that the distribution of nuclear ,-catenin expression can be used as a good prognostic marker in patients with stage IIA colon cancer. Thus, the evaluation of nuclear ,-catenin may help to identify patients who will have a shorter than average survival and patients with a greater risk of disease progression who may be considered for adjuvant therapeutic modalities and intensified clinical aftercare in the future. Cancer 2009. © 2009 American Cancer Society. [source]

Hypermethylation of the somatostatin promoter is a common, early event in human esophageal carcinogenesis

CANCER, Issue 1 2008
Zhe Jin MD
Abstract BACKGROUND. The promoter of somatostatin (SST), a primary inhibitor of gastrin-stimulated gastric acid secretion, is hypermethylated in 80% of human colon cancers. The aim of the current study was to investigate whether and at what stage promoter hypermethylation of SST is involved in human esophageal carcinogenesis. METHODS. SST promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction (PCR) (MSP) in 260 human esophageal tissue specimens. Real-time reverse-transcriptase PCR and MSP were also performed on esophageal cancer cell lines before and after treatment with 5-aza-2,-deoxycytidine (5-Aza-dC). RESULTS. SST hypermethylation showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinomas (ESCC) and esophageal adenocarcinomas (EAC) from normal esophagus (NE) (P < .01). Both SST methylation frequency and normalized methylation value (NMV) were significantly higher in Barrett metaplasia without dysplasia or EAC (BE), low-grade and high-grade (HGD) dysplasia occurring in BE, EAC, and ESCC than in NE (P < .01). SST hypermethylation frequency was significantly lower in NE (9%) than in BE (70%), HGD (71.4%), or EAC (71.6%), whereas 14 (53.8%) of 26 ESCCs exhibited SST hypermethylation. There was a significant relation between SST hypermethylation and BE segment length, a known clinical risk factor for neoplastic progression. Demethylation of KYSE220 ESCC and OE33 EAC cells with 5-Aza-dC reduced SST methylation and increased SST mRNA expression. SST mRNA levels in native unmethylated EACs were significantly higher than in native methylated EACs (P < .05). CONCLUSIONS. SST promoter hypermethylation is a common event in human esophageal carcinomas and is related to early neoplastic progression in Barrett esophagus. Cancer 2008. © 2007 American Cancer Society. [source]

A prospective study of reproductive and menstrual factors and colon cancer risk in Japanese women: Findings from the JACC study

CANCER SCIENCE, Issue 7 2004
Koji Tamakoshi
The effects of reproductive factors on the etiology of colon cancer in Asian populations remain unexplored. So we examined 38,420 Japanese women aged 40-79 years who responded to a questionnaire on reproductive and other lifestyle factors from 1988 to 1990 in the Japan Collaborative Cohort Study for Evaluation of Cancer Risk. During an average 7.6 years of follow-up, we documented 207 incident colon cancers. Multivariate analysis indicated that colon cancer risk was likely to be lower among pa-rous women than among nulliparous. Women who had two abortions or more had a 72% higher risk of developing colon cancer [relative risk (RR) 1.72; 95% confidence interval (CI) 1.16-2.55; trend P<0.01] compared with women who never had an abortion. The RR of colon cancer among postmenopausal women significantly decreased with increasing age at menarche (trend P=0.01). No apparent association between colon cancer and gravida, age at first birth, age at menopause, or duration of menstruation was seen. These prospective data support the hypothesis that female reproductive events modify colon cancer risk, and suggest that reproductive factors, particularly age at menarche and having an abortion, may be of importance in the etiology of colon cancer among Japanese women. [source]

Gene mutations and altered gene expression in azoxymethane-induced colon carcinogenesis in rodents

CANCER SCIENCE, Issue 6 2004
Mami Takahashi
Studies of colon carcinogenesis in animal models are very useful to elucidate mechanisms and provide pointers to potential prevention approaches in the human situation. In the rat colon carcinogenesis model induced by azoxymethane (AOM), we have documented frequent mutations of specific genes. K-ras mutations at codon 12 were found to be frequent in hyperplastic aberrant crypt foci (ACF) and large adenocarcinomas. In addition, mutations of the ,-catenin gene in its GSK-3, phosphorylation consensus motif could also be identified in many adenomas and adenocarcinomas, and altered cellular localization of p-catenin protein was observed in all of the dysplastic ACF, adenomas and adenocarcinomas examined, indicating that activation of Wnt signaling by accumulation of ,-catenin is a major mechanism in the AOM-induced colon carcinogenesis model. Frequent gene mutations of ,-catenin and altered cellular localization of the protein are also features of AOM-induced colon tumors in mice. Expression of enzymes associated with inflammation, such as inducible nitric oxide synthase (INOS) and the inducible type of cyclooxyge-nase (COX), COX-2, is increased in AOM-induced rat colon carcinogenesis, and overproduction of nitric oxide (NO) and prostaglandins is considered to be involved in colon tumor development. We have demonstrated that increased expression of INOS is an early and important event occurring in step with ,-catenin alteration in rat colon carcinogenesis. Activation of K-ras was also found to be involved in up-regulation of INOS in the presence of inflammatory stimuli. In addition, expression levels of prostaglandin E2 (PGE2) receptors may be altered in colon cancers. For example, the EP, and EP2 subtypes have been shown to be up-regulated and EP3 down-regulated in AOM-induced colon cancers in rats and mice. EP, and EP4 appear to be involved in ACF formation, while alteration in EP2 and EP3 is considered to contribute to later steps in colon carcinogenesis. Increased expression of some other gene products, such as the targets of Wnt/,-catenin signaling, have also been reported. The further accumulation of data with this chemically-induced animal colon carcinogenesis model should provide useful information for understanding colorectal neoplasia in man. [source]

Hexosaminidase-altered Aberrant Crypts, Carrying Decreased Hexosaminidase , and , Subunit mRNAs, in Colon of 1,2-Dimethylhydrazine-treated Rats

CANCER SCIENCE, Issue 2 2001
Tetsuya Tsukamoto
Aberrant crypt foci (ACF), consisting of morphologically irregular crypts, are thought to be precancerous lesions for colon cancers. For their molecular analysis, it is necessary to avoid contamination with adjacent normal crypts and stromal cells. Decreased hexosaminidase activity in ACF, which has been histochemically demonstrated, was used in the present study to classify isolated crypts in combination with morphological changes. The length, rim diameter, and width (average±SD, ,m) of hexosaminidase-positive (Hex+) crypts were 238.6±40.4, 89.5±22.9, and 57.6±14.0, respectively. For hexosaminidase-negative (Hex-) crypts, the values were 314.4±77.8, 140.3±45.7, and 97.3±34.7, the width being 1.69 tunes greater (P<0.0001). Crypts wider than 115 ,m (approximately 2 tunes the average size of Hex+ crypts) were all from ACF, judging from hexosaminidase staining. To analyze transcription levels of Hex , and , subunits (Hexa and Hexb, respectively), real-tune relative quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis was performed using the LightCycler system. In aberrant crypts, both Hexa and Hexb were significantly down-regulated to 0.266 (P<0.002) and 0.131 (P<0.001) units, respectively, compared with those in morphologically normal crypts, with , -actin as the internal standard. This decrease could be a molecular marker for precancerous enzyme-altered ACF. [source]

The impact of spontaneous tumour perforation on outcome following colon cancer surgery

COLORECTAL DISEASE, Issue 8 2008
A. S. Abdelrazeq
Abstract Objective, The impact of spontaneous tumour perforation on survival following surgery for colon cancer is unclear. This study compares survival outcomes for patients with perforated colonic cancer with stage-matched nonperforated cancer. Method, A prospective histological database was searched for all patients undergoing resection for adenocarcinoma of the colon between 1996 and 2002. Patients with T4 cancer were selected and classified into those with spontaneous perforation at the tumour site and those with nonperforated tumour. Patients with synchronous colonic and rectal cancers, familial polyposis, inflammatory bowel disease, iatrogenic or remote colonic perforation were excluded. Histological variables were combined with clinical data obtained by case note review. Data were analysed for differences in demographics, histological variables, operative mortality, disease-free and overall survival. Multivariate analysis of factors predictive of overall survival in both groups was performed. Results, Of 960 patients identified, 52 patients had spontaneous tumour perforation and 82 patients served as the T-stage matched control group. Overall survival at 2 years was 47% and 54% and at 5 years was 28% and 33% for perforated and nonperforated cancers respectively. Patients with perforated cancers were more likely to present with metastatic disease and undergo emergency surgery with a higher 30-day mortality. There was a trend towards reduced overall survival in the perforated group (P = 0.06), but no difference in disease-free survival (P = 0.43). On multivariate testing, ,emergency surgery' and ,age >75 years' were the only independent predictors of mortality in the perforated and nonperforated group respectively. Conclusion, Both perforated and nonperforated T4 colon cancers have a poor prognosis. Spontaneous perforation of the cancer is associated with reduced overall survival, due to higher 30-day mortality, but in itself does not appear to significantly impact on disease-free survival. Rather, it is the advanced oncological stage at which perforated cancers present that determines outcome. [source]