Development Of Colorectal Adenocarcinoma Research Articles

MUC15 Inhibits Dimerization of EGFR and PI3K–AKT Signaling and Is Associated With Aggressive Hepatocellular Carcinomas in Patients

Aberrant expression of MUC15 correlates with development of colorectal adenocarcinoma, and MUC15 has been reported to prevent trophoblast invasion of human placenta. However, little is known about the role of MUC15 in pathogenesis of hepatocellular carcinoma (HCC). We analyzed HCC samples and matched nontumor liver tissues (controls) collected from 313 patients who underwent hepatectomy in Shanghai, China, from January 2006 through September 2009. Levels of messenger RNAs and proteins were determined by immunohistochemical, quantitative reverse transcription polymerase chain reaction, and immunoblot analyses. Statistical analyses were used to associate levels of MUC15 with tumor features and patient outcomes. Levels of MUC15 messenger RNA and protein were reduced in a greater percentage of HCC samples than control tissues. Tumors with reduced levels of MUC15 were more likely to have aggressive characteristics (eg, high levels of α-fetoprotein, vascular invasion, lack of encapsulation, and poor differentiation) than those with low levels. Patients whose tumors had reduced levels of MUC15 had shorter overall survival times (24 months vs 46 months for patients with tumors with high levels of MUC15) and time to disease recurrence. Stable expression of MUC15 in HCC cell lines (SMMC-7721 and HCC-LM3) reduced their proliferation and invasive features in vitro, and ability to form metastatic tumors in mice. MUC15 reduced transcription of the matrix metalloproteinases 2 and 7 increased expression of tissue inhibitor of metalloproteinase-2, which required phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling. Physical interaction between MUC15 and epidermal growth factor receptor led to its relocation and degradation within early endosomes and was required for inactivation of phosphoinositide 3-kinase-v-akt murine thymoma viral oncogene homolog signaling. Reduced levels of MUC15 in HCCs are associated with shorter survival times of patients and reduced time to disease recurrence. Expression of MUC15 in HCC cells reduces their aggressive behavior in vitro and in mice by inducing dimerization of epidermal growth factor receptor and decreasing phosphoinositide 3-kinase signaling via v-akt murine thymoma viral oncogene homolog.

Expression of Wnt5a, APC, β-catenin and their clinical significance in human colorectal adenocarcinoma

To study the expression of Wnt5a gene mRNA and Wnt5a, APC, β-catenin proteins in human colorectal adenocarcinoma (CRC) and explore its clinical significance. Wnt5a mRNA level was measured in 30 patients with CRC and paired non-tumor tissues by real-time PCR. Immunohistochemical staining of Wnt5a, APC, β-catenin was performed in samples of 62 patients with CRC using SP system. The relative expression level of Wnt5a mRNA in fresh CRC is 0.1232 ± 0.0140, which is significantly higher than that in adjacent colorectal mucosa (0.0497 ± 0.0074, P = 0.02). A low expression of Wnt5a protein was observed in 38 of 62 CRC. Wnt5a protein expression was closely correlated with the tumor types and the degree of tumor differentiation (P < 0.05). There was no apparent relationship with lymph node metastasis, depth of myometrial invasion and TNM stages (P > 0.05). APC protein was decreased in 38 of 62 CRC. The expression of APC was closely correlated with the tumor types (P < 0.05). There was no apparent relationship with the degree of tumor differentiation, lymph node metastasis, depth of myometrial invasion and TNM stages (P > 0.05). The expression of β-catenin was observed in cytoplasm and/or cell nuclei in 50 of 62 CRC. The positive rate of β-catenin expression was closely correlated with the degree of tumor differentiation, lymph node metastasis, depth of myometrial invasion and TNM stages (P < 0.05). There was no apparent relationship with the tumor types (P > 0.05). The expressions of Wnt5a (r = 0.271, P = 0.027) and APC (r = 0.343, P = 0.004) were correlated with that of β-catenin in CRC, respectively, but there was no correlation between the expressions of Wnt5a and APC protein (r = 0.218, P = 0.078) in the tumors. Wnt5a, APC and β-catenin genes might be involved in the carcinogenesis and development of CRC. It is hypothesized that down-regulation of APC and Wnt5a proteins may be one of causes of ectopic expression of β-catenin in CRC.

The Prevalence of Colorectal Adenoma in Solid Organ Transplant Recipients: A Case Control Study

Purpose: It is not conclusively clear whether immunosuppression in solid organ recipients confers increased risk to the development of colorectal adenocarcinoma, which in most cases arise from colorectal adenomas. The aim of this study is to determine whether there is an increased prevalence of colorectal adenomas in solid organ transplant recipients compared to immunocompetent subjects. Methods: We conducted a retrospective study at a single inner city tertiary care center. Charts of 1092 patients who had undergone heart, liver and kidney transplants between 1995 and 2010 were reviewed. All individuals who had at least one completed colonoscopy following the transplant were included. We excluded those with history of colon cancer prior to the transplant, history of inflammatory bowel disease, history of HIV and incomplete records. One hundred and eighty two patients who met the criteria were enrolled. Demographic data, comorbidities and polyp description when present were collected. Similar information was collected on a control group of 71 individuals with no prior transplants. Results: A total of 182 transplant recipients underwent colonoscopy after their transplant (64% male, 64% black, Mean age 57±12, 74% were over 50 years of age). The adenoma detection rate in the transplant recipients was 21.4% compared to 25.4% in the control group (p=0.50). The adenoma detection rate among transplant recipients aged over 50 was 24.6%. Advanced adenomas were seen in 7.7% of study population compared to 7.0% in the control population. We found 4 (2.2%)carcinoma cases in the transplant group, there were no carcinomas found in the control group. The quality of bowel preparation was rated as good in 57% of the transplant population and 47% in the control group. Conclusion: We did not find any significant statistical difference in the detection rate of adenomas between solid organ transplant recipients and our control population. Our study was limited by a small number of controls as well as the retrospective nature of the study.

Vitamin D receptor expression is associated with colon cancer in ulcerative colitis

Since the 1970s, it has been well known that long-standing ulcerative colitis (UC) disposes to the development of colorectal adenocarcinoma (CRC). To date, CRC associated with UC is thought to arise along a pathway of dysplasia, however, primary factors for developing of UC-related dysplasia and cancer are unclear. Vitamin D, which works through binding the vitamin D receptor (VDR) has an important role in cancer progression and immune response. In this study, we investigated the impact of VDR expression on UC as well as colon cancer. We examined retrospectively the expression of VDR in extraction specimens of UC (n=124) patients by immunohistochemistry. We counted VDR positive cells in at least 10 fields in each case to evaluate the frequency of VDR positive cells in ductal epithelium. In addition, effect of VDR expression on inflammation was analyzed. On a normal mucosa, the expression of VDR was recognized in 58.8% of ductal cells. In UC patient, the expression of VDR was considerably decreased compared to normal mucosa, VDR positive rate was only 3.4+/-9.0%. Importantly, dysplasia and UC-CRC patients showed lower rate of VDR expression compared to non-colon cancer patients, whose expression rates were 0.6+/-1.3% and 3.8+/-10%, respectively. Moreover, long-term UC patients (more than ten years) who were at high-risk of developing CRC showed significantly lower VDR expression than short-term patients. We did not detect direct association of VDR expression with inflammation and clinical stage of UC. These findings suggested that correlation seems to exist between the level of VDR expression and carcinogenesis in UC. VDR could be a possible marker to detect dysplasia and cancer in ulcerative colitis.

Association of upregulated GATA-4 transcription factor colorectal adenocarcinoma with metastatic and primary tumors

e15093 Background: GATA-4 zinc finger transcription factor is involved in regulation of cellular development, proliferation, and differentiation and is important in embryonic development of gastrointestinal tract. However, GATA-4 is not expressed in normal adult colonic mucosa. Its protein expression in colonic adenocarcinoma has not been systematically evaluated and small number of samples was previously reported as negative. Nuclear factor-B (NF-B) activation was shown to promote the growth of the colon tumors in experimental models and was correlated with tumor angiogenesis and progression in human colorectal cancer. Methods: Forty cases of colorectal adenocarcinoma were evaluated. The benign colonic mucosa and the matching metastatic tumors of the same patients were also included in the study. TMAs which included 139 samples were evaluated by immunohistochemistry and nuclear and cytoplasmic GATA-4 expression was scored (0–3+). NF-B activation was detected as nuclear reactivity for p65. Results: GATA-4 was expressed in 32% of colorectal adenocarcinoma, but not in benign colonic mucosa (p=0.0001, Chi-Square). GATA-4 was also significantly more expressed in metastatic (41%) than in primary (21%) colorectal adenocarcinoma (p&lt;0.0001, Chi-Square). NF-B activation was not present in any of the samples of benign colonic mucosa, but it was detected in 64% adenocarcinomas (p&lt;0.0001, Chi-Square). While there was no difference in NF-B activation between primary vs. metastatic adenocarcinoma, a strong positive association between GATA-4 expression and NF-B activation (p&lt;0.0001, Linear-by- Linear) was found. Conclusions: GATA-4, a developmental transcription factor is not expressed by normal colonic mucosa, but is present in 1/5 of primary tumors that gave rise to distant metastases and in almost 1/2 of their respective metastases. GATA- 4 is also strongly positively associated with NF-B activation previously described to have a role in human cancer progression. GATA-4 may have a role in colorectal adenocarcinoma development and progression and it should be further evaluated in prospective studies as a putative adverse prognostic factor in colorectal adenocarcinoma. No significant financial relationships to disclose.

Intestinal Low-grade Tubuloglandular Adenocarcinoma in Inflammatory Bowel Disease

Chronic idiopathic inflammatory bowel disease (IBD) with extensive colonic involvement predisposes to the development of colorectal adenocarcinoma. Among the types of cancer occurring in this setting is an unusually well-differentiated low-grade tubuloglandular adenocarcinoma (LGTGA) that has not been studied systematically thus far. A review of 149 IBD-associated cancer resections performed at our institution yielded 17 patients (11%) with 21 tumors classified as LGTGA based on the following histologic characteristics: very well-differentiated small to medium diameter glands with round or tubular profiles, low-grade cytologic characteristics and absence or paucity of desmoplastic reaction. Twelve patients had ulcerative colitis, 4 Crohn disease, and 1 indeterminate colitis. Their median age was 41.5 years (range, 28 to 58 y). Five patients had separate synchronous cancers of conventional types. LGTGAs ranged from 0.4 to 10 cm in size and varied in gross appearance. They included 5 flat lesions that were not identified visually but were detected either by palpation of the unfixed surgical specimen (1 case) or histologically in random sections (4 cases). The invasive glands usually bore a close histologic resemblance to overlying low-grade or indefinite dysplastic crypts. Twelve carcinomas (57%) with well-defined superficial regions of LGTGA progressed histologically to conventional adenocarcinoma in deeper regions. These tumors were significantly more advanced than 9 carcinomas that maintained low-grade histology throughout. Follow-up of 13 patients (76%) for a mean 4.0 years (range, 0.75 to 9.0 y) disclosed 10 (77%) with favorable outcomes and 3 (23%) with adverse outcomes. Two adverse outcomes were attributable to synchronous advanced-stage conventional cancers and the third to progression from LGTGA to poorly differentiated adenocarcinoma. The mucosa overlying and surrounding LGTGA showed low-grade dysplasia (LGD) in 18 cases (86%), indefinite dysplasia with focal LGD in 1 case (5%), and LGD with focal high-grade dysplasia (HGD) in 2 cases (10%). Immunohistochemical studies disclosed expression of MUC2 in 72%, MUC6 in 0%, CK7 in 69%, and CK20 in 100%. Coexpression of CK7 and CK20 was conserved in regions of conventional adenocarcinoma derived from LGTGA. Silencing of immunohistochemical expression of hMLH1 occurred in 6 of 11 tumors tested (55%), implicating defective DNA replication error repair in their pathogenesis. We conclude that LGTGA is a distinct clinicopathologic entity characterized by direct derivation from LGD mucosa of IBD, very well-differentiated morphology, frequent coexpression of CK7 and CK20, and frequent silencing of hMLH1. Histologic progression from LGTGA to conventional types of adenocarcinoma parallels clinical progression to more aggressive neoplasia. The potential of LGD to give rise directly to LGTGA, and by way of LGTGA to more aggressive cancers, reinforces recommendations in favor of aggressive management of IBD patients diagnosed with LGD.

Evaluation of p53 codon 72 polymorphism in adenocarcinomas of the colon and rectum in La Plata, Argentina

To evaluate the potential association between p53 codon 72 polymorphism and sporadic colorectal adenocarcinoma development,and human papillomavirus (HPV) infection. One-hundred and nine controls and 53 patients with colon cancer from the city of La Plata, Argentina were analyzed. p53 codon 72 genotypes and HPV infection were identified using allele-specific polymerase chain reaction and nested polymerase chain reaction, respectively. The differences in the distribution of p53 codon 72 polymorphism between the cases and controls were statistically significant. The arginine allele had a prevalence of 0.65 in controls and 0.77 in cases. The corresponding odds ratio for the homozygous arginine genotype was 2.08 (95% CI, 1.06-4.05; P<0.05). Lack of association was found between p53 polymorphism and HPV infection in the set of adenocarcinomas. The findings of the present study indicate that p53 codon 72 arginine homozygous genotype may represent a genetic predisposing factor for colon cancer development. However,further studies are needed in order to elucidate the role of p53 codon 72 polymorphism in colorectal cancer.

Inhibition of chronic ulcerative colitis-associated colorectal adenocarcinoma development in a murine model by N-acetylcysteine.

Long-term ulcerative colitis (UC) patients are at increased risk for developing colorectal cancer. In order to develop strategies for preventing UC-associated carcinogenesis, we studied the effect of the antioxidant N-acetylcysteine (NAC) on UC-associated cancer development in a mouse model. Female C57BL/6J mice were subjected to long-term administration of dextran sulfate sodium (DSS) in the drinking fluid and 2-fold iron-enriched AIN76A diet, with or without NAC. In the DSS-plus-2-fold iron positive control group, gross tumor incidence was 88.5% (23/26 mice) after 12 DSS cycles (1 DSS cycle = 7 day DSS treatment period followed by 10 day recovery period). The tumor multiplicity was 2.1 +/- 0.2 tumors/tumor-bearing mouse, and the tumor volume was 0.054 +/- 0.019 cm3. With 0.2% NAC administration, tumor incidence was significantly reduced (68%, 17/25 mice; P < 0.05), as was the tumor multiplicity (1.5 +/- 0.1 tumors/tumor-bearing mouse; P < 0.05). The tumor volume was lower (0.014 +/- 0.004 cm3), but not significantly decreased. The proliferation index was significantly decreased in non-cancerous epithelia (48.5 +/- 6.0% vs 32.0 +/- 3.7%; P < 0.05), but not in tumor cells. NAC significantly induced apoptosis in both non-cancerous epithelia and colorectal adenocarcinoma. The number of cells immunostained-positive for nitrotyrosine was markedly decreased in the non-cancerous mucosa of NAC-treated mice (102.4 +/-16.6 positive cells/mm2 mucosa vs 53.6 +/- 14.9 cells/mm2; P < 0.05). In addition, the number of inducible nitric oxide synthase (iNOS)-positive inflammatory cells in the non-cancerous mucosa of the distal colon was markedly decreased by NAC. This study indicates that the antioxidant NAC has the potential to serve as a preventive agent for UC-associated colorectal cancer, possibly via inhibition of cellular proliferation and nitrosative stress-caused cellular damage.

Colorectal neoplasia in ulcerative colitis-recent advances.

It is recognized that ulcerative colitis (UC) predisposes to the development of colorectal adenocarcinoma (CRC), and the molecular pathway for this process differs from that for sporadic CRCs. However, several important details regarding the risk factors for and the molecular changes underlying UC-related colorectal carcinogenesis have only come to light lately. First, recent data suggest environmental factors related to long-standing inflammation contribute more to this increased cancer risk than an inherited susceptibility. Second, molecular changes that may represent the first steps in the development of neoplasia are being increasingly identified in non-dysplastic, colitic mucosa. Third, there is now good evidence suggesting that UC-related CRC may develop along more than one molecular pathway. These emerging data will hopefully contribute to attempts to prevent the development of UC-related CRC, e.g. through refining surveillance programmes. Details of the molecular heterogeneity of UC-related dysplasia and CRC may also help develop reliable tools for diagnosing the former and for predicting the behaviour of the latter. Finally, there is increasing awareness of non-epithelial colorectal malignancies which are associated with UC and may potentially increase in incidence with changes in the medical management of this inflammatory disease.

Molecular characterization of colorectal neoplasia in translational research.

To present recent advances in the use of molecular markers in diagnosis, in prognosis, in early detection, in novel therapies, and in understanding the molecular pathogenesis of colorectal neoplasia. A review of studies of molecular markers in colorectal neoplasia, published in English and available on MEDLINE and BioMednet, indicates that molecular markers are being increasingly studied to predict clinical outcomes in patients with colorectal adenocarcinoma (CRC). We have used this resource, together with our published and unpublished observations at the University of Alabama at Birmingham, to provide an overview of translational research related to molecular markers in colorectal neoplasia. Currently, the prognosis of patients with CRC is predicted primarily on the basis of clinicopathologic staging; however, pathologists and oncology surgeons have recently begun to investigate the use of molecular markers to diagnose and/or understand the progression of CRC. In recent years, much has been learned about the molecular events responsible for the development of CRC. Also, several studies have reported the implication of some molecular markers in metastasis and tumor aggression and their usefulness in predicting clinical outcome. In this article, we discuss the use of specific molecular markers, including tumor-associated glycoprotein 72 (TAG-72), carcinoembryonic antigen (CEA), and oncofetal tumor antigens (Lewis X and Y) in diagnosis and as targets for novel therapies, as well as the phenotypic expression of bcl-2, mucin antigens (MUC1 and MUC2), and nuclear accumulation of p53 in predicting the clinical outcome of patients with CRC. We also review the ways in which molecular markers may aid the early detection of colorectal neoplasia and promote our understanding of the earliest changes in colorectal neoplasia.

MDM2/p53 protein expression in the development of colorectal adenocarcinoma

The murine double minutes 2 (MDM2) oncoprotein inhibits p53-mediated tumor suppression. MDM2 has been shown to be overexpressed in sarcomas and more recently was implicated in the pathogenesis of carcinomas. The purpose of this study was to determine the expression pattern of MDM2 in adenomas and colorectal adenocarcinomas and decide whether there is a correlation between MDM2 and p53 protein status. Paraffin-embedded tissues from 52 colorectal cancer (CRC) specimens and their adjacent normal tissue (N-CRC) were studied. In addition, 56 sporadic adenomas were investigated for the immunohistochemical expression of MDM2 and p53 proteins. Immunoreactivity of p53 indicating p53 gene mutation (p53+) was significantly higher in CRC (44%) compared to adenomas (23.2%) ( P <0.01). None of the N-CRC specimens expressed the immunoreactive p53 protein. MDM2 overexpression (MDM2+) was similar in adenomas (30.3%) and CRC (25%), but only 2 (3.8%) of 52 N-CRC specimens showed overexpression of MDM2. In most cases MDM2 expression was associated with negative p53 expression (wild-type p53) in both adenomas ( r = 0.59, P <0.001) and CRC ( r = 0.69, P <0.0001). No correlation was found between MDM2, p53 expression, and either the histologic grade, nodal stage or morphology of the tumors. There is greater p53 mutation in CRC compared to adenomas and N-CRC. The data indicate that MDM2 is overexpressed in CRC and is significantly associated with wild-type p53 compared to N-CRC specimens from the same patient. The MDM2 expression pattern is similar in adenomas and CRC, which may suggest that MDM2 overexpression is an early event in the progression of CRC.

Carcinoma of large intestine in patients irradiated for carcinoma of cervix and uterus.

Twenty-six patients with carcinoma of colon and rectum following radiation therapy for cancer cervix and uterus have been analyzed. Nearly two thirds of the patients were more than 60 years old. The interval between irradiation and diagnosis of the second tumor varied from 5 to 30 years. Despite lack of detailed information on radiation factors in half of the patients, circumstantial evidence from this study suggests that radiation therapy may have contributed to the development of colorectal adenocarcinoma in some of the patients. Among the findings supporting this conclusion in this series are: 1. localization of second tumor at site of radiotherapy; 2. 58% of the patients had symptomatic and clinically documented chronic radiation proctocolitis at sites of subsequent tumor; 3. 69% of the patients had post-irradiation interval of more than 10 years; 4. 58% of the patients had histologic proof of radiation-related alterations in involved bowel segment; 5. occurrence of a much higher than expected percentage (58%) of mucinous (colloid) adenocarcinoma in involved region, of which 92% had clinical and/or histologic evidence of radiation proctocolitis. The overall and determinate 5-year survival in this series was 20% and 22%, respectively. It, therefore, behooves the clinician to be vigilant in the follow-up of these patients who are long-term survivors of radiation-treated carcinoma of cervix and uterus for the late development of colorectal carcinoma.