Colon cancer is traditionally regarded as the most commonly diagnosed gastrointestinal malignant disease. Nevertheless, despite advances in diagnosis and novel therapeutic options, the clinical ...outcomes of patients are still not satisfactory.
To investigate the prognostic role of Notch3, an immunohistochemical study was performed on samples of colon adenocarcinoma tissues and adjacent non-pathological mucosa in Caucasian patients.
Paraffin-embedded colon adenocarcinoma samples were assessed immunohistochemically for Notch3 protein. Connections between Notch3 immunoexpression and clinicopathological factors including the 5-year overall survival (OS) were evaluated.
The level of the Notch3 immunohistochemical reactivity was correlated with the grade of the histological differentiation (
< 0.001). A strong expression of Notch3 protein was detected more frequently in patients with G3 tumours than in patients with G1 tumours. Moreover, the significant difference was also detected between the patients with G1 tumour and those with G2. In the G2 patients a strong reactivity was described more frequently. The Kaplan-Meier survival analysis showed that the overall survival rate in the group of patients with a low expression level of Notch3 was significantly greater than that for patients with a moderate or strong level of Notch3 immunoreactivity (
< 0.001). A multivariate analysis demonstrated that the grade of tumour differentiation (
= 0.001) and Notch3 expression (
< 0.001) were independent risk factors for worse survival.
The high level of Notch3 immunoexpression was demonstrated to be associated with malignancy-related clinicopathological factors and 5-year overall survival of patients.
The current study investigated the expression of Snail1 protein in colon adenocarcinoma samples to assess its prognostic significance by correlating its expression with the clinicopathological ...variables and survival of Caucasian patients.
To investigate the clinicopathological and prognostic roles of Snail1 expression, the immunohistochemical analysis was performed in colon tumour tissues and adjacent non- pathological mucosa.
It should be noted that only trace expression of this protein was revealed in adjacent non-tumour colorectal mucosa, whereas the high expression was demonstrated in well differentiated, moderately differentiated, and poorly differentiated tumours.
The Kaplan-Meier survival analysis showed that the overall survival rate in the group of patients with a low expression level of Snail1 was significantly longer than that for patients with a moderate or strong level of Snail1 immunoreactivity (
< 0.001). The 5-year overall survival for patients with a low, moderate, or strong level of Snail1 immunoexpression was 100%, 25.7%, and 2%, respectively. The Snail1-moderate patients had an average survival time of 44.886 months (95% CI: 40.855-48.916), whereas the Snail1-strong expression groups had an average survival time of 21.706 (95% CI: 17.863-25.549). The statistical analysis revealed that the level of the Snail1 immunohistochemical reactivity was correlated with the grade of the histological differentiation. A multivariate analysis demonstrated that the grade of tumour differentiation (HR = 2.150; 95% CI: 1.380-3.349,
= 0.001) and Snail1 expression (HR = 3.901; 95% CI: 2.436-6.247,
< 0.001) were the independent risk factors for worse survival.
In colon adenocarcinoma patients, the expression of Snail1 may act as the independent risk factors for worse survival.
Glutathione peroxidase 2 (Gpx-2) is a selenoenzyme with antioxidant capabilities that may play a role in cancer development. Hence, we investigated the immunohistochemical expression of Gpx-2 protein ...in colon adenocarcinoma samples derived from patients with colon adenocarcinoma who did not receive any form of treatment prior to the surgical procedure. The associations between the immunohistochemical expression of Gpx-2 and clinical parameters were analysed using the Chi2 test and Fisher’s exact test. A Kaplan–Meier analysis and the log-rank test were used to verify the relationship between the intensity of Gpx-2 expression and the 5-year survival rate of patients. In total, 101 (80.80%) samples had strong Gpx-2 protein expression and 24 (19.20%) samples were characterized with low expression. The high expression of Gpx-2 was correlated with the histological grade of the tumour (p < 0.001), PCNA immunohistochemical expression (p < 0.001), depth of invasion (p = 0.001) and angioinvasion (p < 0.001). We can conclude that high expression of Gpx-2 is correlated with reduced survival of colon adenocarcinoma patients (log-rank, p < 0.001).
Glutaredoxin 2 (Grx2; Glrx2) is a glutathione-dependent oxidoreductase located in mitochondria, which is central to the regulation of glutathione homeostasis and mitochondrial redox, and plays a ...crucial role in highly metabolic tissues. In response to mitochondrial redox signals and oxidative stress, Grx2 can catalyze the oxidation and S-glutathionylation of membrane-bound thiol proteins in mitochondria. Therefore, it can have a significant impact on cancer development. To investigate this further, we performed an immunohistochemical analysis of Grx2 protein expression in colon adenocarcinoma samples collected from patients with primary colon adenocarcinoma (stage I and II) and patients with metastasis to regional lymph nodes (stage III). The results of our study revealed a significant relationship between the immunohistochemical expression of Grx2 and tumor histological grade, depth of invasion, regional lymph node involvement, angioinvasion, staging, and PCNA immunohistochemical expression. It was found that 87% of patients with stage I had high levels of Grx2 expression. In contrast, only 33% of patients with stage II and 1% of patients with stage III had high levels of Grx2 expression. Moreover, the multivariate analysis revealed that the immunohistochemical expression of Grx2 protein apart from the grade of tumor differentiation was an independent prognostic factors for the survival of patients with colon adenocarcinoma. Studies analyzing Grx2 levels in patients' blood confirmed that the highest levels of serum Grx2 protein was also found in stage I patients, which was reflected in the survival curves. A higher level of Grx2 in the serum has been associated with a more favorable outcome. These results were supported by in vitro analysis conducted on colorectal cancer cell lines that corresponded to stages I, II, and III of colorectal cancer, using qRT-PCR and Western Blot.
Maintaining a balanced redox state within cells is crucial for the sustenance of life. The process involves continuous cytosolic disulfide reduction reactions to restore oxidized proteins to their ...reduced thiol forms. There are two main cellular antioxidant pathways-the thioredoxin (Trx) and glutathione (GSH)/glutaredoxin (Grx) systems. In the GSH/Grx system, glutathione reductase (GR; GSR) catalyses the reduction of GSH disulfide (GSSG) to its sulfhydryl form (GSH), which can then further reduce oxidized Grxs. GR is an essential enzyme that helps in maintaining the supply of reduced glutathione-GSH, which is a significant reducing thiol found in most cells and known for its antioxidant properties. Therefore, it can have a significant impact on cancer development. To investigate this further, we performed an immunohistochemical analysis of GR protein expression in colon adenocarcinoma samples collected from patients with primary colon adenocarcinoma (stage I and II) and patients with metastasis to regional lymph nodes (stage III). The results of our study revealed a significant relationship between the immunohistochemical expression of GR and tumour histological grade, depth of invasion, regional lymph node involvement, staging, and PCNA immunohistochemical expression. It was found that 95% of patients with stage I had low levels of GR expression, whereas 89% of patients with stage III had high levels of immunohistochemical expression. A high level of expression was also detected in the patients with stage II of the disease, where almost 63% were characterized by a high expression of GR. The Western blot method revealed that the highest level of expression was found in the LS 174T cell line, which corresponds to stage II. The results of our study indicate that the immunohistochemical expression of GR may act as an independent prognostic factor associated with colon adenocarcinoma patients' prognosis.
The Notch signalling pathway is one of the most conserved and well-characterised pathways involved in cell fate decisions and the development of many diseases, including cancer. Among them, it is ...worth noting the Notch4 receptor and its clinical application, which may have prognostic value in patients with colon adenocarcinoma. The study was performed on 129 colon adenocarcinomas. Immunohistochemical and fluorescence expression of Notch4 was performed using the Notch4 antibody. The associations between the IHC expression of Notch4 and clinical parameters were analysed using the Chi
test or Chi
test. The Kaplan-Meier analysis and the log-rank test were used to verify the relationship between the intensity of Notch4 expression and the 5-year survival rate of patients. Intracellular localisation of Notch4 was detected by the use of the immunogold labelling method and TEM. 101 (78.29%) samples had strong Notch4 protein expression, and 28 (21.71%) samples were characterised by low expression. The high expression of Notch4 was clearly correlated with the histological grade of the tumour (
< 0.001), PCNA immunohistochemical expression (
< 0.001), depth of invasion (
< 0.001) and angioinvasion (
< 0.001). We can conclude that high expression of Notch4 is correlated with poor prognosis of colon adenocarcinoma patients (log-rank,
< 0.001).
Glutaredoxin 1 (Grx1) is an essential enzyme that regulates redox signal transduction and repairs protein oxidation by reversing S-glutathionylation, an oxidative modification of protein cysteine ...residues. Grx1 removes glutathione from proteins to restore their reduced state (protein-SH) and regulate protein-SSG levels in redox signaling networks. Thus, it can exert an influence on the development of cancer. To further investigate this problem, we performed an analysis of Grx1 expression in colon adenocarcinoma samples from the Polish population of patients with primary colon adenocarcinoma (stages I and II of colon cancer) and those with regional lymph node metastasis (stage III of colon cancer). Our study revealed a significant correlation between the expression of Grx1 protein through immunohistochemical analysis and various clinical characteristics of patients, such as histological grade, depth of invasion, angioinvasion, staging, regional lymph node invasion, and PCNA expression. It was found that almost 88% of patients with stage I had high levels of Grx1 expression, while only 1% of patients with stage III exhibited high levels of Grx1 protein expression. Furthermore, the study discovered that high levels of Grx1 expression were present in samples of colon mucosa without any pathological changes. These results were supported by in vitro analysis conducted on colorectal cancer cell lines that corresponded to stages I, II, and III of colorectal cancer, using qRT-PCR and Western blot.
Summary
Background
It is generally accepted that angiogenesis is a complex and tightly regulated process characterized by the growth of blood vessels from existing vasculature. Activation of the ...Notch signalling pathway affects multiple aspects of vascular development. One of the components of the Notch signalling pathway, Delta-like ligand 4 (DLL4), has recently appeared as a critical regulator of tumour angiogenesis and thus as a promising therapeutic target.
Methods
This review article includes available data from peer-reviewed publications associated with the role of DLL4 in cancer angiogenesis. Searches were performed in PubMed, EMBASE, Google Scholar and Web of Science using the terms “tumour angiogenesis”, “DLL4”, “Notch signalling” and “anti-cancer therapy”.
Results
The survival curves of cancer patients revealed that the patients with high DLL4 expression levels had significantly shorter survival times than the patients with low DLL4 expression. Moreover, a positive correlation was also identified between DLL4 and VEGF receptorsʼ expression levels. It seems that inhibition of DLL4 may exert potent growth inhibitory effects on some tumours resistant to anti-VEGF therapies. A great number of blocking agents of DLL4/Notch signalling including anti-DLL4 antibodies, DNA vaccination, Notch antibodies and gamma-secretase inhibitors have been studied in preclinical tumour models.
Conclusion
DLL4 seems to be a promising target in anti-cancer therapy. Nevertheless, the careful evaluation of adverse effects on normal physiological processes in relation to therapeutic doses of anti-DLL4 drugs will be significant for advancement of DLL4 blocking agents in clinical oncology.
Several studies revealed that expression levels of glutathione peroxidase 1 (Gpx-1) can be associated with cancer development, mainly through its role in hydroperoxide scavenging by regulating ...intracellular reactive oxygen species (ROS) levels. Therefore, our aim was to investigate the expression of Gpx-1 protein in a population of Polish patients with colon adenocarcinoma in the absence of any therapy prior to radical surgery. The study was carried out using colon tissue from patients with adenocarcinoma of the colon confirmed by histopathological examination. Gpx-1 antibody was used to determine the immunohistochemical expression of Gpx-1. The Chi
test or Chi
test were used to analyse the associations between the immunohistochemical expression of Gpx-1 and clinical parameters. The relationship between Gpx-1 expression, and 5-year patient survival was examined using Kaplan-Meier analysis and the log-rank test. Intracellular localisation of Gpx-1 was detected by the use of transmission electron microscopy (TEM). Western blot analysis was used for the evaluation of Gpx-1 protein expression levels in cancer cell lines in vitro. Immunohistochemical study revealed that the high expression of Gpx-1 was associated with the tumour's histological grade, proliferating cell nuclear antigen (PCNA) immunohistochemical expression, depth of invasion, and angioinvasion (all
< 0.001) (4). The high immunohistochemical expression of Gpx-1 is correlated with poor prognosis of colon adenocarcinoma patients.
(1) Background: Colorectal cancer (CRC) is the third most common cancer in terms of incidence and mortality. Approximately 90% of all colorectal cancer cases are adenocarcinomas, originating from ...epithelial cells of the colorectal mucosa. Upregulated gene 4 (URG4) is an oncogene involved in cancer development. The aim of the study was to assess the immunohistochemical expression of URG4 protein expression in Polish patients with colon adenocarcinoma who were not treated with any therapy before radical surgery. (2) Methods: The study used colon tissue samples taken from people with a confirmed diagnosis of colorectal adenocarcinoma after a thorough histopathological examination. The associations between the immunohistochemical expression of URG4 and clinical parameters were analyzed by the Chi2 test or Chi2Yatesa test. The study conducted an analysis of the correlation between the expression of URG4 and the five-year survival rate of patients through the application of the Kaplan–Meier analysis and the log-rank statistical test. The intracellular localization of URG4 was identified through the utilization of transmission electron microscopy (TEM) methodology. (3) Results: In univariate Cox regression analyses, immuno-histochemical expression of URG4, grade of histological differentiation, depth of invasion, angioinvasion, PCNA expression, stage of disease and lymph node involvement were found to be significant prognostic factors. Within our patient cohort, it was observed that the degree of tumour differentiation and URG4 expression were found to be distinct prognostic factors in regard to the 5-year survival rates of those with colon adenocarcinoma. (4) Conclusions: High immunohistochemical expression of URG4 correlates with poor prognosis in patients with colon adenocarcinoma.
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