Development Of Colonic Adenocarcinoma Research Articles

The expression and role of Galectin-1 in colon adenocarcinoma

Objective To observe the expression and clinical significance of Galectin-1 in human colon adenocarcinoma. Methods Expression of Galectin-1 mRNA and protein was detected by in situ hybrid method and immunohistochemistry method in 75 cases of colon adenocarcinoma tissues, 43 cases of mucosa adjacent to cancer, and 75 cases of normal colon mucosa, and correlations between expression of Galectin-1 and clinicopathological features was analyzed. Results The results of in situ hybrid revealed that the expression of Galectin-1 mRNA in colon adenocarcinoma tissues (84.00%) was significantly higher than those of mucosa adjacent to cancer (34.88%) and normal esophageal mucosa epithelial tissue (22.67%), there were significant differences in Galectin-1 mRNA expression among three groups (P 0.05), but closely related to TNM staging and lymph node metastasis (P<0.05). The results of correlation analysis of Galectin-1 mRNA and protein expressions demonstrated that the expression of Galectin-1 mRNA and protein in colon adenocarcinoma tissues displayed positive correlation (r=0.600, P<0.01). Conclusion Expressions of Galectin-1 mRNA and protein in colon adenocarcinoma tissues are significantly higher than those in mucosa adjacent to cancer and normal coion epithelium tissues, and Galectin-1 at high level plays an important role in occurrence and development of colon adenocarcinoma. Expressions of Galectin-1 mRNA and protein are both associated with TNM staging and lymph node metastasis, but not related to histologic grade and invasion depth, suggesting Galectin-1 may be an important molecular marker for diagnosis of malignant degree of colon adenocarcinoma. Galectin-1 mRNA and protein expression displays positive correlation. Key words: Colon adenocarcinoma; Galectin-1; In situ hybridization; Immunohistochemistry

Endoplasmic reticulum stress, unfolded protein response and development of colon adenocarcinoma.

When misfolded proteins accumulate in the endoplasmic reticulum (ER), the cell is said to experience ER stress. This triggers an unfolded protein response (UPR) to restore the balance between misfolded proteins and ER chaperones such as BiP. UPR signalling is required for the growth of many solid cancers. In chronic ER stress, factors including CHOP have been shown to mediate cell death. Colorectal adenocarcinoma arises due to progressive changes within pre-malignant lesions. Our aim was to test the hypothesis that the expression of BiP and CHOP correlates with the progression of those pre-malignant lesions.Eighty-one patients with colon neoplasms treated at Rouen University Hospital between January 1, 2003 and January 1, 2013 were randomly selected. The expression of BiP and CHOP was estimated by immunohistochemical staining of a tissue microarray generated from colon cores: normal tissue, low-grade and high-grade adenoma, invasive colon adenocarcinoma and lymph node metastasis of colon adenocarcinoma. In parallel, nine cases comprising areas from normal epithelium to dyplasia to invasive carcinoma and included in the TMA were analysed on whole sections.As colon epithelium shows increasing evidence of pre-malignant and then malignant changes, BiP expression significantly increases (p for trend < 0.001), whereas CHOP expression is attenuated (p for trend < 0.001).We identified a positive relationship between BiP expression and colon carcinogenesis, and a negative correlation for CHOP expression. These findings are consistent with a model in which ER stress accompanies oncogenesis and in which loss of proteins that mediate the toxicity of ER stress, such as CHOP, may facilitate tumorigenesis. This raises the exciting possibility that restoration of the negative feedback loop of UPR, if achievable, might antagonise the malignant process.

Expression of TRPV5 and TRPV6 in development of colonic adenocarcinoma

Expression of TRPV5 and TRPV6 in development of colonic adenocarcinoma

HYPOXIC INFLAMMATION, A DEADLY BRIDGE TO MALIGNANT TRANSFORMATION AND A FERTILE SOIL FOR CANCER PREVENTION

The interplay of the inflammatory microenvironment with its hypoxic niche and the potential mechanism by which they lead to malignant transformation has long been the subject of great controversy and continues to be an area of great in terest today. In our previous studies we have examined this subject by using Gia2 knock out mice as the focus of our research. These mice are well known for their tendency to develop chronic inflammation in the sub mucosa of their gut, with gradual worsening and development of colon adenocarcinoma in most as they age. It has also attracted our attention that they develop a significant increase in the number of hypoxic niches in their sub mucosa , proven by EF5 staining.In contradistinction to MSI- high colon adenocarcinomas, we have also shown that histone deacetylation rather than MLH1 promote r methylation is the main mechanism of MLH1 and MSH2 deactivation in these mice. Here we show that hypoxic niches evolve under massive selective pressure of the inflammatory microenviron ment as a protective shield offering survival advantage by the up regulation of NFKb and its downstream pathways, which indeed independent of true hypoxia leads to stabilization of HIF as well, securing a dual mechanism for perpetuation and expansion of hypoxic niches. We incorporated wester n blot and Luciferase assay of cells exposed to hypoxia+/-inflammatory cytokines to acquire data.

Abstract 1841: Dietary morin suppresses colitis-associated colorectal carcinogenesis in rats

Abstract A flavonol, morin, found in almonds, mill, fig and other moraceae which are used as dietary agents and also as herbal medicine. Morin acts as a potent antioxidant, xanthine oxidase inhibitor, PKC inhibitor, cell proliferation inhibitor, apoptosis inducer, modulator of LOX and COX activities. Based on our previous studies on chemopreventive ability of morin in tongue and colon carcinogenesis (Carcinogenesis 20: 1477-84, 1999; Int J Cancer 83: 381-6, 1999; Oncol Rep 6:1333-40, 1999), we aimed to determine possible inhibitory potential of this compound in colitis-associated colon carcinogenesis in rats initiated with AOM and promoted by DSS. Male F344 rats initiated with a single s.c. injection of AOM (20 mg/kg bw) were promoted by 1.5% DSS in their drinking water for 7 days. They were then given a basal diet containing 50, 250 and 1000 ppm of morin for 17 weeks. At wk 20, the development of colonic adenocarcinoma was significantly inhibited by feeding with morin at a dose level of 1000 ppm (45% incidence, p=0.0141; and 0.73 +/- 1.01 multiplicity, p&amp;lt;0.05), when compared to the AOM/DSS group (93% incidence and 2.36 +/- 1.95 multiplicity). The incidence and multiplicity of adenocarcinomas in the rats received 50 ppm (60% incidence and 1.20 +/- 1.23 multiplicity) and 250 ppm (64% incidence and 1.09 +/- 1.04 multiplicity) of morin in diet were also smaller than that of the AOM and DSS group, but the differences were insignificant. The treatments inhibited colonic inflammation, and also modulated proliferation, apoptosis, and expression of several pro-inflammatory cytokines, such as NF-kappaB, Stat3, TNF-alpha and IL-1beta in the adenocarcinomas. Feeding with morin lowered tissue polyamine levels of colonic mucosa. Our findings indicate that dietary morin is able to inhibit colitis-related colon carcinogenesis in rats. Also, our model provides knowledge applicable to prevent inflammation-associated colon cancer in humans. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1841. doi:10.1158/1538-7445.AM2011-1841

Up-regulated expression of Notch1 and Jagged1 in human colon adenocarcinoma

Deregulated expression of Notch molecules is observed in many malignant tumors, however, the expression of Notch1 and Jagged1 in colon adenocarcinoma is still unknown. This study is to investigate the expression of Notch1 and Jagged1 in human colon adenocarcinoma. Sixty-five human colon adenocarcinoma and 60 adjacent nontumor colon tissue sections were detected by immunohistochemistry. Ten paired fresh surgical human colon adenocarcinoma and adjacent nontumor colon samples were analyzed by Western blot and RT-PCR. Both Notch1 and Jagged1 were expressed in the cytoplasm of neoplastic cells of colon adenocarcinoma tissue. The protein and mRNA levels of both molecules were higher in colon adenocarcinoma than in adjacent nontumor tissue. Moreover, Notch1 was positively correlated with tumor stage. This investigation demonstrates that Notch1 and Jagged1 are up-regulated in human colon adenocarcinoma and suggests that Notch1/Jagged1 signaling might play a role in the development of colon adenocarcinoma.

Melatonin suppresses AOM/DSS-induced large bowel oncogenesis in rats

The inhibitory effects of exogenous melatonin (MEL) on colon oncogenesis were investigated using an azoxymethane (AOM)/dextran sodium sulfate (DSS) rat model. Male F344 rats initiated with a single intraperitoneal injection of AOM (20 mg/kg bw) were promoted by 1% (w/v) DSS in drinking water for 7 days. They were then given 0.4, 2 or 10 ppm MEL in drinking water for 17 weeks. At week 20, the development of colonic adenocarcinoma was significantly inhibited by the administration with MEL dose-dependently. MEL exposure modulated the mitotic and apoptotic indices in the colonic adenocarcinomas that developed and lowered the immunohistochemical expression of nuclear factor kappa B, tumor necrosis factor α, interleukin-1β and STAT3 in the epithelial malignancies. These results may indicate the beneficial effects of MEL on colitis-related colon carcinogenesis and a potential application for inhibiting colorectal cancer development in the inflamed colon.

Abstract PR-13: Inhibition of chronic colitis-induced carcinogenesis in IL-10 knockout mice by dietary supplementation of black raspberries

Abstract PR-13 Epidemiological and experimental studies indicate that inflammation is associated with the development of colon cancer. For example, it is known that patients with ulcerative colitis have an increased incidence of colon cancer, and anti-inflammatory drugs and bioactive food components that suppress colonic inflammation reduce the risk of colon cancer. IL-10 is an important regulatory anti-inflammatory cytokine associated with the development of colonic colitis. 100% of IL-10 knockout (KO) mice develop colitis after 3 months of age; histopathology reveals transmural inflammation, predominantly in the cecum. We have shown that the administration of a diet containing twice the recommended amount of iron leads to the development of colonic adenocarcinoma in more than 80% of IL-10 KO mice within 5 months. In the present study, we evaluated the effects of a dietary supplementation of black raspberries on spontaneous colitis-induced carcinogenesis in IL-10 KO mice. Beginning at 4 weeks of age, mice were administered black raspberry powder in AIN-93G diet at concentrations of 5% and 10% until termination of the experiment at 23 weeks. The colorectal tumor incidence in IL-10 KO mice fed control AIN-93G diet was 71.4% (10/14 mice with tumors). Significant reductions in colonic tumor incidence [38% (5/13 mice) and 30.8% (4/13 mice)] were observed in mice receiving 5% and 10% black raspberry diets, respectively. Histopathologic analysis of chronic inflammatory activity in the colon showed that the berries significantly inhibited the overall inflammatory index, including the extent of inflammation, ulcer formation and epithelial hyperplasia. Mechanistic studies suggest that inhibition of colitis-associated carcinogenesis by dietary berries might relate to their effects on modulation of myeloperoxidase-labeled inflammatory cells, nitro-oxidative stress, and cell proliferation. We conclude that black raspberries, as a food-based prevention agent, have potential for the prevention of inflammation-related carcinogenesis in the colon. (Supported by NIH grants R01-CA104741 and -CA103180). Citation Information: Cancer Prev Res 2008;1(7 Suppl):PR-13.

A Novel Prodrug of 4′-Geranyloxy-Ferulic Acid Suppresses Colitis-Related Colon Carcinogenesis in Mice

The inhibitory effects of a novel prodrug, 3-(4′-geranyloxy-3′-methoxyphenyl)-2-trans-propenoyl-L-alanyl-L-proline (GAP), of the secondary metabolite 4′-geranyloxy-3′-methoxyphenyl)-2-trans-propenoic acid (4′-geranyloxy-ferulic acid), on colon carcinogenesis was investigated using an azoxymetahen (AOM)/dextran sodium sulfate (DSS) model. GAP was synthetically derived from ferulic acid. Male CD-1 (ICR) mice initiated with a single intraperitoneal injection of azoxymethane (10 mg/kg body weight) were promoted by 1% (wt/vol) DSS in drinking water for 7 days. They were then given modified AIN-76A diet containing 0.01% or 0.05% GAP for 17 wk. At Week 20, the development of colonic adenocarcinoma was significantly inhibited by GAP feeding at dose levels of 0.01% [60% incidence (P = 0.0158) with a multiplicity of and 1.13 ± 1.13 (P < 0.05)] and 0.05% [53% incidence (P = 0.0057) with a multiplicity of 0.08 ± 1.08 (P < 0.01)], when compared to the AOM/DSS group (95% incidence with a multiplicity of 3.10 ± 3.06). Dietary GAP modulated the mitotic and apoptotic indexes in the crypt cells and lowered 8-hydroxy-2′-deoxyguanosine (8-OHdG)-positive cells in the colonic mucosa. Urinary level of 8-OHdG was lowered by GAP feeding. Additionally, dietary GAP elevated the immunoreactivity of an inducible form of heme oxygenase 1 in the colonic mucosa. Our results indicate that GAP is able to inhibit colitis-related colon carcinogenesis by modulating proliferation and oxidative stress in mice.

Development of colonic adenocarcinomas in a mouse model of ulcerative colitis

Development of colonic adenocarcinomas in a mouse model of ulcerative colitis

Synchronous colorectal adenocarcinoma and gastrointestinal stromal tumor (GIST)

Little is known about the synchronous occurrence of gastrointestinal stromal tumors (GISTs) and other gastrointestinal tumors. We present two cases of an invasive colon cancer with a synchronous small-bowel GIST; immunohistochemistry studies were performed to evaluate possible genetic similarities. This paper reports two cases of synchronous GISTs and colorectal cancer (CRC) with immunohistochemistry analysis of c-Kit expression. This paper is also a review of the existing literature on the association of GISTs and CRC and the role of c-Kit in CRC. In the last 2 years, we observed two patients with synchronous CRCs and GISTs of the small bowel. The GISTs were incidentally discovered during the work-up for CRCs and excised at the time of the colon resection. Immunohistochemistry study did not reveal an expression of c-Kit in CRCs. Clinical implications of the association between these two neoplasms are described in this paper. Synchronous CRC and GIST has been more frequently reported. Because of the limited number of cases, we cannot exclude an incidental relationship. The genetic pathways of tumorigenesis appear different for the two neoplasms. Further studies are needed to clarify a possible role of c-Kit in the development of colonic adenocarcinomas.

Impaired TGF-β Responses in Peripheral T Cells of Gαi2−/− Mice

Null mutation of heterotrimeric G protein alpha2 inhibitory subunit (Galphai2) induces Th1-skewed hyperimmune responses in the colon, leading to chronic colitis and the development of colonic adenocarcinoma. However, the underlying molecular mechanisms and cellular basis, in particular, for the role of Galphai2 in regulating immune responses, are poorly understood. We show here that peripheral T cells from Galphai2-deficient mice do not respond normally to the inhibitory effects of TGF-beta on proliferation and cytokine production, revealing a previously unappreciated cross-talk between these two signaling pathways. Lack of Galphai2 resulted in decreased phosphorylation of Smad2 and Smad3 in T cells at the basal levels as well as at the late but not early phase of TGF-beta stimulation, which appears to be ascribed to differential expression of neither cell surface TGF-beta receptors nor Smad7. The altered phosphorylation of Smad proteins involves phospholipase C-mediated signaling, a downstream signaling molecule of Galphai2, because phospholipase C inhibitors could restore Smad2 and Smad3 phosphorylation in Galphai2(-/-) T cells at levels comparable to that in wild-type T cells. Moreover, adoptive transfer of Galphai2-deficient T cells into immunocompromised mice rendered an otherwise resistant mouse strain susceptible to trinitrobenzesulfonic acid-induced colitis, suggesting that an impaired response of Galphai2-deficient T cells to TGF-beta may be one of the primary defects accounting for the observed colonic Th1-skewed hyperimmune responses. These findings shed new lights on the molecular and cellular basis of how Galphai2 down-regulates immune responses, contributing to the maintenance of mucosal tolerance.

Does any lower gastrointestinal bleeding in patients suffering from hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu) necessitate a full colonic visualization?

Hereditary hemorrhagic telangiectasia (HHT) (the Osler-Weber-Rendu syndrome) is a rare autosomal dominant disease characterized by telangiectasias and arteriovenous malformations of the upper and lower respiratory tract, gastrointestinal tract, skin and central nervous system. Several previous reports have documented the appearance of a concomitant neoplasm in patients with this syndrome. To study the occurrence and the clinical characterization of colonic neoplasm in patients with HHT. We retrospectively reviewed the computerized database of the Hadassah University Hospitals (Jerusalem, Israel) for all patients with the diagnosis of HHT between January 1st, 1980 and July 30th, 2002. Cases of neoplasm were documented by review of medical charts and pathology reports. Six of the 24 patients developed malignancy. Three of the cases had extra colonic malignancy (melanoma in two patients and adenocarcinoma of urinary bladder in one patient) and three patients had adenocarcinoma of the colon. An additional three patients developed multiple colonic polyps (one patient had melanoma and one patient had adenocarcinoma of urinary bladder). HHT may be associated with the development of colonic adenocarcinoma and polyps. Therefore, in patients with HHT who present with new-onset anemia or gastrointestinal bleeding a lower gastrointestinal tract evaluation should be performed, even if their blood loss is suspected to be a manifestation of gastrointestinal HHT.

The influence of strain specific Helicobacter pylori and serum gastrin levels on development of colon adenocarcinoma

The influence of strain specific Helicobacter pylori and serum gastrin levels on development of colon adenocarcinoma

The influence of strain specific Helicobacter pylori and serum gastrin levels on development of colon adenocarcinoma

The influence of strain specific Helicobacter pylori and serum gastrin levels on development of colon adenocarcinoma

The influence of strain-specific Helicobacter pylori and serum gastrin levels on development of colon adenocarcinoma

The influence of strain-specific Helicobacter pylori and serum gastrin levels on development of colon adenocarcinoma

Down-regulation of drs mRNA in human colon adenocarcinomas.

We have previously reported that the drs gene, whose mRNA expression is down-regulated by retroviral oncogenes such as v-src and v-K-ras, has the ability to suppress transformation by v-src and v-K-ras in the rat cell line F2408. We have also isolated a human homolog of this gene (h-drs) and shown that expression of h-drs mRNA is markedly reduced in a variety of human cancer cell lines, including those of carcinomas of the colon, bladder, and ovary, suggesting that down-regulation of drs mRNA is correlated with the development of human cancers. To clarify the correlation between down-regulation of the drs gene and malignant tumor formation in human cancer tissues, we examined expression of drs mRNA in human normal tissues, colon adenoma, and adenocarcinoma tissues by in situ hybridization. Expression of drs mRNA was detected in most normal tissues tested, including those of the colon, bladder, and ovary. However, drs mRNA was hardly expressed in any of the colon adenocarcinoma tissues examined. Northern blot analyses confirmed these results. Neither gross deletion nor re-arrangement of the drs genome was detected by Southern blot hybridization in these adenocarcinoma tissues. drs mRNA was significantly expressed in colon adenoma with mild atypia but down-regulated in adenomas with moderate atypia and focal carcinoma. Our results indicate that down-regulation of drs mRNA is closely correlated with development of colon adenocarcinoma, suggesting a tumor-suppressor function of the drs gene in human cancers.

Development of colonic adenocarcinomas in a mouse model of ulcerative colitis.

Mice deficient in both interleukin-2 and beta 2-microglobulin expression (Beta 2mullnull x IL-2null mice) develop an inflammatory disease of the colon resembling ulcerative colitis. To examine long-term complications of disease in these mice, a group of 34 Beta 2mnull x IL-2null mice was monitored for 6-12 months. Development of clinical disease was assessed by wasting, general appearance, and diarrhea. Further analysis included histologic examination of the distal colon for colitis, staining of CD4+ T cells for surface activation markers, and cytoplasmic staining of CD4+ T cells for IFN-gamma and TNF-alpha. These older Beta 2mnull x IL-2null mice had activated CD4+ T cells as assessed by surface markers on flow cytometry. Cytoplasmic staining revealed IFN-gamma production, but not TNF-alpha production by CD4+ T cells. The majority of these older Beta 2mnull x IL-2null mice continued to have colitis on histology. However, they lived much longer and had less wasting in comparison to IL-2null mice. At necropsy, 11 (32%) of 34 of the Beta 2mnull x IL-2null mice had tumors in the proximal half of the colon. Histologic examination confirmed these tumors to be adenocarcinomas. These mice may be useful as a model for studying carcinogenesis in chronic colitis.