Browsing by Subject "Colorectal carcinoma"
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- PublicationOpen Accessa1-acid glycoprotein (AGP): a possible carrier of sialyl lewis X (slewis X) antigen in colorectal carcinoma(Murcia : F. Hernández, 2005) Croce, M.V.; Sálice, V.C.; Lacunza, E.; Segal-Eiras, A.Objectives: 1- to detect a1-acid glycoprotein (AGP) and sialyl Lewis x (sLex) in colorectal malignant, benign and normal samples; 2- to isolate AGP from colorectal cancer and 3- to study its immunoreactivity with an anti-sLex monoclonal antibody (MAb). Materials and methods: tissue and serum samples from 88 patients with colorectal cancer, 22 adenomas and 23 normal were included. Expression of AGP and sLex was studied by immunohistochemistry (IHC); isolation approach: AGP was precipitated with ammonium sulphate and immunoprecipitated with anti-AGP MAb. The immune complex formed was isolated by protein ASepharose CL-4B affinity chromatography and further eluted; fractions were analysed by SDS-PAGE and Western-blot. Statistical analysis was performed by means of Principal Component Analysis. Results: by Western blot employing anti-AGP MAb and sLex MAbs, isolated fractions from malignant samples showed a band at about 45kD. IHC revealed that AGP was expressed in 70% of colorectal carcinoma samples, 50% of benign and 35% of normals. SLex was detected in 31% of malignant samples, 41% of benign and in one normal sample. In malignant samples, AGP reaction comprised the whole specimen with a strong and homogeneous staining while normal and benign samples showed a restricted reaction. In cancer, sLex expression consisted in an intense reactivity in membrane, cellular debris and some cytoplasmic foci while normal and benign samples were occasionally stained. A statistically significant positive correlation was found between AGP and sLex expression. Serum AGP levels were measured by radial immunodiffusion and statistical comparative analysis with tissue expression did not show a correlation between both parameters. Conclusion: AGP may constitute a carrier of sLex in colorectal cancer.
- PublicationOpen AccessBag-3 expression is involved in pathogenesis and progression of colorectal carcinomas(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2013) Yang, Xue; Tian, Zhong; Gou, Wen-feng; Takahashi, Hiroyuki; Xing, Ya-nan; Takano, Yasuo; Zheng, Hua-ChuanBcl-2-associated athanogene 3 (Bag-3) belongs to a member of the Hsc70 binding co-chaperone Bag-family proteins and has critical roles in protein homeostasis, cell survival, actin organization, cell adhesion, cell motility and tumor metastasis. To clarify the role of Bag-3 in colorectal carcinogenesis and subsequent development, its expression was examined by immunohistochemistry (IHC) and in situ hybridization (ISH) on tissue microarrays containing colorectal carcinomas, adenomas, non-neoplastic mucosa (NNM) and metastatic carcinomas in lymph node and liver. Colorectal carcinoma tissue and cell lines were studied for Bag-3 expression by RT-PCR, Western blot and immunofluorescence. The results demonstrated that Bag3 was distinctly expressed in Colo201, Colo205, DLD-1, HCT-15, HCT-116, HT-29, KM-12, SW480, SW620, and WiDr at both mRNA and protein levels. Carcinoma showed stronger Bag-3 expression than adjacent NNM by IHC and Western blot (P<0.05), while its mRNA had the opposite by real-time PCR and ISH (P<0.05). Metastatic carcinoma more frequently expressed Bag-3 mRNA in lymph node and liver than in primary carcinoma (P<0.05). Immunohistochemically, Bag-3 expression was seen to gradually decrease from carcinoma, adenoma to NNM (P<0.05). There was a positive correlation between Bag-3 expression and TNM staging and GRP94 expression (P<0.05), but no relationship to patient age or sex, tumor size, depth of invasion, lymphatic or venous invasion, lymph node metastasis, differentiation or prognosis of colorectal carcinomas (P>0.05). Our study indicated that aberrant Bag-3 expression might be involved in colorectal adenoma-adenocarcinoma sequence and subsequent progression.
- PublicationOpen AccessBRAF mutation: Current and future clinical pathological applications in colorectal carcinoma(Universidad de Murcia. Departamento de Biología Celular e Histología, 2019) Yan Seen Ng, Jessica; Tai Lu, Cu; King yin Lam, AlfredThe aims are to review the relevance of the BRAF mutations in the clinical settings of colorectal carcinoma. All the literature concerning BRAF mutations and colorectal carcinoma published in PubMed from 2010 to 2018 was reviewed. Multiple variants of BRAF mutations exist in colorectal cancer, the most common type being V600E. The mutation is found in 5 to 15% of colorectal carcinomas and is less common in Asian populations. BRAF mutations are linked with older age, female gender, cigarette smoking and are more common in the right (proximal) portion of the large intestine. BRAF mutations are associated with carcinomas of high histological grade and advanced cancer stages. Often BRAF mutated carcinomas demonstrate adverse histological features such as lymphovascular invasion, perineural invasion, tumour budding and lymph node metastases. BRAF mutations are found in serrated polyposis syndrome and have a negative correlation with hereditary nonpolyposis colorectal cancer (HNPCC). An array of methods of detection of BRAF mutation in colorectal carcinoma are available, such as immunohistochemistry and next generation sequencing, etc. Combinatorial approaches involving anti-BRAF therapies targeting both MAPK signalling as well as the PI3K/mTOR pathway could be a new approach for treatment of metastatic colorectal carcinoma. To conclude, BRAF mutation is important in the pathogenesis of colorectal cancer. Further research on the detection method as well as its role in target therapy will help to improve the management of patients with colorectal cancer
- PublicationOpen AccessDifferential expression of p53 family proteins in colorectal adenomas and carcinomas: Prognostic and predictive values(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Bahnassy, Abeer A.; Zekri, Abdel-Rahman N.; Salem, Salem E.; Abou-Bakr, Amany A.; Sakr, Mona A.; Abdel-Samiaa, Ayman G.; Al-Bradei, ManalWe studied the contribution of p53 family proteins and their isoforms to the development and progression of colorectal carcinoma in relation to VEGF. Methods: p53, p63, p73 and VEGF proteins were assessed in 45 colorectal adenomas (CRAs), 80 carcinomas (CRCs) and 36 normal colonic tissue samples (NCT) by immunohistochemistry. Different p63 and p73 isoforms were assessed by RT-PCR. Aberrant protein and RNA expressions were correlated to patients' characteristics, disease free and overall survival (DFS& OS). Results: p53, p63, p73 and VEGF proteins were detected in 22.2%, 73.3%, 33.3%, 46.7% CRAs; in 68.8%, 38.8%, 62.5%, 62.5% CRCs and 16.7%, 83.3%; 13.9%, 27.8% NCT (p<0.05 except for VEGF). Commonest isoforms were TAp63a, DNp63, TAp73a in CRA and DNp63, TAp63a, DNp73, TAp73ß in CRC. Significant correlations were found between aggressive tumor phenotypes and aberrations in p73, p53, p63, VEGF. DFS correlated with advanced stage, p73 and VEGF aberrations. While advanced stage, positive lymph nodes, p73 and p53 correlated with OS. Prognosis was worse in patients with aberrant p63& p73 than in those with normal p63& p73 expression regardless of p53 gene status (p<0.05). Conclusions: p53 family proteins and VEGF play a pivotal role in colorectal carcinogenesis. p53 prognostic potential is augmented by p73 and p63 aberrations indicating a synergistic effect between the three family members. Nodal status, stage, p73, VEGF and p53 could be used as predictors of DFS and OS.
- PublicationOpen AccessExpression of differentiation-related genes in colorectal cancer, possible implications for prognosis(Murcia : F. Hernández, 1998) van Belzen, N.; Dinjens, W.N.M.; Eussen, B.H.J.Although differentiation grade is an important prognostic factor for colorectal tumors, its usefulness is limited since its predictive value for tumor behavior is not very significant. This might be related to the subjective nature of histological assessment of differentiation grade, which allows the distinction of only three grades, and with limited reproducibility. Characterization of the differentiation process at the biochemical level may improve our understanding of normal and malignant differentiation, and is expected to provide molecular markers with higher discriminative potential than histomorphology. Several studies have compared gene expression in undifferentiated and differentiated colon carcinoma c e l l s , and many differentially expressed genes have been identified. Some of these, including HLA class I, nucleophosmin, adenylosuccinate lyase, a-tubulin, and a novel gene designated Drgl, were found to be expressed at different levels in neoplastic as compared to normal tissue. In this review the rationale, implementation, and results of this approach are discussed, as well as the characteristics of two novel differentially expressed genes, ICTl (previously named DS-1) and Drgl .
- PublicationOpen AccessImmunohistochemical and Western blot analysis of two protein tyrosine phosphatase receptors, R and Z1, in colorectal carcinoma, colon adenoma and normal colon tissues(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2014) Woźniak, Marta; Gamian, Elżbieta; Łaczmańska, Izabela; Sąsiadek, Maria M.; Duś-Szachniewicz, Kamila; Ziółkowski, PiotrTwo classes of proteins, namely tyrosine kinases (PTK) and phosphatases (PTP), play an important role in cell proliferation and differentiation, thus leading to an acceleration or inhibition of tumour growth. The role of the above proteins in colorectal carcinoma (CRC) growth is a well-known event. In this study we carried out immunohistochemical and Western blot analysis of colorectal carcinoma, adenoma and normal colon tissue in relation to two protein tyrosine phosphatase receptors, R and Z1. Twenty-five cases of CRC were analyzed and the results were compared with similar data obtained in non-malignant tissues. High expression of both PTP receptors was observed in all examined cases of CRC, adenoma and normal colon tissue in this study. These results are not in line with recently published data, showing that genetic coding for PTPRR and PTPRZ1 were hypermethylated in CRC’s. We presume that the protein tyrosine phosphatase overexpression in colorectal carcinoma is not enough to protect from the progression of disease.
- PublicationOpen AccessInterpretation of P16 expression as a marker of HPV in colorectal cancer(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2022) Hafez, Fatma Samy; Meckawy, Ghada Refaat; Alorabi, Mohamed; Shakweer, Marwa MosaadBackground. Colorectal cancer is one of the most prevalent types of tumors worldwide. P16INK4a is a widely used immunohistochemical marker for high-risk HPV infection. The purpose of this study is to explore the relationship between P16 expression as an indicator of HPV infection and colorectal cancer in Egyptian patients, as well as its association with histopathological characteristics. Material and methods. The study was performed on 59 cases of colorectal carcinoma cases and 30 specimens of normal colonic mucosa. Results. p16 protein was detected in 22% (13 of 59) of patients with colorectal carcinoma. No evidence of P16 expression in all 30 cases of non-neoplastic colonic mucosa was found. More frequent expression of P16 was seen in distal carcinomas. Conclusion. our study demonstrated that P16 protein is expressed in a reasonable percent of colorectal carcinoma cases, suggesting a role of HPV in colorectal carcinogenesis. The present study highlights the role of p16 protein expression which is important in the pathogenesis in colorectal carcinoma, especially regarding distal tumors
- PublicationOpen AccessKeratin 20 - A diagnostic and prognostic marker in colorectal cancer?(F. Hernandez y JuanF. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología., 2012) Harbaum, Lars; Pollheimer, Marion J.; Kornprat, Peter; Lindtner, Richard A.; Schlemmer, Andrea; Rehak, Peter; Langner, CordColorectal cancer cells characteristically show strong expression of keratin 20 (K20) and lack expression of keratin 7 (K7). The biological significance of reduced K20 expression, however, is unclear. 381 colorectal cancers with 148 corresponding metastases were evaluated for K20 and K7 expression by immunohistochemistry using a tissue microarray technique. K20 immunoreactivity was assessed semiquantitatively as either negative, low (<50% of cancer cells) or high (≥50% of cancer cells). Progression-free and cancer-specific survivals were determined using the Kaplan-Meier method. Expression of K20 was observed in 348 out of 372 (94%) evaluable primary tumors, with 135 (36%) cases showing low K20 and 213 (57%) cases high K20 expression, while 24 (6%) tumors completely lacked K20 immunoreactivity. Reduced K20 expression (lack of staining or low expression) was significantly associated with poor differentiation, large tumor size and mismatch repair deficiency, but did not significantly affect patients’ outcome. Immunoreactivity of K20 and K7 in metastatic tissues matched well with that of corresponding primary tumors, with high concordance for lymph node (p<0.001) and distant metastases (p<0.001), respectively. In conclusion, our data illustrate the value of keratin subtyping in carcinoma of unknown primary (CUP) syndrome: K20 expression is common in colorectal cancer and the K20 high / K7 negative immunoprofile represents the predominant phenotype. Reduced K20 expression may, however, lead to false-negative assessment of metastatic deposits if only small amounts of tissue are obtained (e.g. in needle biopsies), particularly in poorly differentiated cancers. Reduced expression of K20 may be used to select tumors for microsatellite instability testing.
- PublicationOpen AccessLoss of MUC2 expression correlates with progression along the adenoma-carcinoma sequence pathway as well as de novo carcinogenesis in the colon(Murcia : F. Hernández, 2007) Mizoshita, T.; Tsukamoto, T.; Inada, K.I.; Hirano, N.; Tajika, M.; Nakamura, T.; Ban, H.; Tatematsu, M.Aims: We have previously demonstrated links between clinicopathological findings and phenotypes using several gastric and intestinal phenotypic markers in stomach and pancreatic cancers. However, the clinicopathological significance of the phenotype and Cdx2 expression has hitherto remained unclear in colorectal carcinogenesis. Methods and results: We examined the correlation between gastric and intestinal phenotypic expression in 91 primary early carcinomas of the colon. MUC2 expression demonstrated a significant decrease from tubular/ tubulovillous adenomas with moderate atypia, through intramucosal carcinomas, to cancers with submucosal invasion (P<0.0001). Intramucosal de novo carcinomas (flat type carcinomas without adenomatous components) exhibited a greater decrease of MUC2 than intramucosal lesions with adenomatous components. Expression of MUC5AC also decreased significantly with progression according to the tubular/tubulovillous adenomacarcinoma sequence, carcinomas with villous adenomatous components having a higher level compared with their tubular adenomatous counterparts, suggesting differences in the pathway of malignant transformation. Cdx2 nuclear expression was maintained in all of the adenomas and early carcinomas examined. Conclusions: Our data suggest that the reduction of MUC2 expression may be associated with the occurrence and progression of colorectal carcinomas in both adenoma-carcinoma sequence pathway and de novo carcinogenesis. Tumor-suppressive effects of Cdx2 may be preserved during early stages of colorectal carcinogenesis.
- PublicationOpen AccessOverexpression of GRP78 and GRP94 is involved in colorectal carcinogenesis(Editores F. Hernandez y Juan F. Madrid. Murcia, Universidad de Murcia, Departamento de Biologia Celular e Histologia, 2011) Takahashi, Hiroyuki; Wang, Jian-ping; Zheng, Hua-Chuan; Masuda, Shinji; Takano, YasuoGlucose-related proteins (GRPs) are ubiquitously expressed in the endoplasmic reticulum and assist in protein folding and assembly, consequently considered to be molecular chaperones. GRP78 and GRP94 expression was induced by glucose starvation and up-regulated in samples taken from several different malignant tissues. To clarify the roles of both molecules in tumorigenesis and progression of colorectal carcinomas, immunohistochemistry (IHC) was performed on tissue microarrays containing colorectal carcinomas, adenomas and the non-neoplastic mucosa (NNM) using antibodies against GRP78 and GRP94. Their expression was correlated with the clinicopathological parameters of carcinomas. Both proteins were also studied in colorectal carcinoma cell lines (DLD-1, HCT-15, SW480 and WiDr) by IHC and Western blot. There was a gradually increased GRP78 expression from colorectal NNMs, carcinomas, to low-grade and high-grade adenomas (P<0.05), while up-regulated GRP94 expression from NNM, low-grade adenoma, high-grade adenoma, to carcinoma (P<0.05). The expression was similar in all the carcinoma cell lines. GRP78 expression was negatively correlated with lymphatic invasion or low GRP94 expression of the carcinomas (P<0.05), while there was no correlation of GRP94 expression with other parameters of carcinomas (P>0.05). Multivariate analysis showed that venous invasion, lymph node metastasis and UICC staging (P<0.05), but not age, sex, tumor size, differentiation, depth of invasion, lymphatic invasion, GRP78 and GRP94 expression (P>0.05), were independent prognostic factors for carcinomas. It is suggested that up-regulated expression of GRP78 and GRP94 could possibly be involved in the pathogenesis of colorectal carcinomas.
- PublicationOpen AccessReduced expression of EphA5 is associated with lymph node metastasis, advanced TNM stage, and poor prognosis in colorectal carcinoma(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Gu, Shudong; Feng, Jia; Jin, Qin; Wang, Wei; Zhang, ShuColorectal carcinoma (CRC) is the third most common cancer and a major cause of morbidity and mortality throughout the world. The prognosis of patients has improved markedly over the last 15 years because of the introduction of new therapy including molecular target drugs. To comprehensively understand the molecular process of carcinogenesis of colorectal carcinoma is essential for the diagnosis, prognosis and treatment. EphA5 is a member of the Eph family and plays a critical role in carcinogenesis of lung cancer, prostate cancer, and breast cancer. The expression profile and the role of EphA5 in colorectal carcinoma have not been well investigated till now. In this study, a set of colorectal carcinoma specimens was subjected to immunohistochemical assay using an EphA5 specific antibody. The relationship between the expression of EphA5 and clinicopathological parameters was statistically analyzed. EphA5 was positively expressed in all tested normal mucosa specimens (120/120, 100%) and partly in colorectal carcinoma specimens (70/120, 58.3%). The loss of EphA5 protein was associated with depth of wall invasion (P=0.002), poor tumor differentiation (P<0.001), lymph node metastasis (P<0.001), and advanced TNM stage (P<0.001). The survival analysis showed that patients with reduced expression of EphA5 had a poor overall survival (P=0.017). Our data indicate that EphA5 receptor may be a tumor suppressor in colorectal carcinoma and it may be a new therapeutic target for colorectal carcinoma.
- PublicationOpen AccessREG IV overexpression in an early stage of colorectal carcinogenesis, An immunohistochemical study(Murcia : F. Hernández, 2010) Li, Xiao-Han; Zheng, Yang; Zheng, Hua-Chuan; Takahashi, Hiroyuki; Yang, Xiang-Hong; Masuda, Shinji; Takano, YasuoTo clarify the role of REG IV, a new member of the regenerating gene (REG) family, in tumorigenesis and progression of colorectal carcinoma (CRC), 320 CRC specimens, 123 corresponding adjacent noncancerous mucosa (ANCMs), 46 corresponding nonadjacent non-cancerous mucosa (NANCMs) and 86 adenomas were investigated immunohistochemically to compare REG IV expression with clinicopathological features. In addition, double immunofluorescence labeling was performed to analyze the localization of REG IV and the intestinal mucin, MUC2. The expression of REG IV in CRCs was significantly lower than in NANCMs, ANCMs or adenomas, and inversely correlated with poor differentiation and venous invasion. In cases of ANCM, REG IV expression was positively correlated with the depth of invasion, lymph node metastasis and Duke’s staging of corresponding cases. The expression of REG IV in CRC was significantly linked to that of MUC2 and the EGFR phosphorylated on Tyr1068, but not to that of MUC5AC, EGFR, Akt, or Akt phosphorylated on Ser473 or Thr308. The double immunofluorescence revealed coexpression, but independent localization, of REG IV and MUC2 in NANCMs, ANCMs, adenomas and CRCs, except for mucinous carcinomas. Univariate analysis using the Kaplan-Meier method indicated no correlation between REG IV expression and the cumulative survival rate of CRC patients. In conclusion, REG IV expression was upregulated in ANCMs and adenomas, then decreased in CRCs. This indicated that REG IV overexpression may be an early event in CRC carcinogenesis. Its expression in CRCs was positively linked to MUC2 and phosphorylation of the EGFR on Tyr1068, suggesting that REG IV may be a useful marker for intestinal type mucinous carcinoma and a good candidate as a molecular therapeutic target for CRCs.