Marker Of Colorectal Cancer Progression Research Articles

DNA methylation biomarkers for predicting lymph node metastasis in colorectal cancer.

Colorectal cancer is one of the most common cancers worldwide. Lymph node metastasis is an important marker of colorectal cancer progression and plays a key role in the evaluation of patient prognosis. Accurate preoperative assessment of lymph node metastasis is crucial for devising appropriate treatment plans. However, current clinical imaging methods have limitations in many aspects. Therefore, the discovery of a method for accurately predicting lymph node metastasis is crucial clinical decision-making. DNA methylation is a common epigenetic modification that can regulate gene expression, which also has an important impact on the development of colorectal cancer. It is considered to be a promising biomarker with good specificity and stability and has promising application in predicting lymph node metastasis in patients with colorectal cancer. This article reviews the characteristics and limitations of currently available methods for predicting lymph node metastasis in patients with colorectal cancer and discusses the role of DNA methylation as a biomarker.

Deregulation of cancer-stem-cell-associated miRNAs in tissues and sera of colorectal cancer patients.

Colorectal cancer (CRC) is a deadly tumour in Western countries characterized by high cellular/molecular heterogeneity. Cancer stem cells (CSC) act in cancer recurrence, drug-resistance and in metastatic epithelial-to-mesenchymal transition. microRNAs (miRNAs) contribute to cancer is increasing, and miRNA roles in CSC phenotype and fate and their utility as CRC biomarkers have also been reported. Here, we investigated miR-21, miR-221, miR-18a, miR-210, miR-31, miR-34a, miR-10b and miR-16 expression in experimental ALDH+ and CD44+/CD326+ colorectal CSCs obtained from the human CRC cell lines HCT-116, HT-29 and T-84. Then, we moved our analysis in cancer tissue (CT), healthy tissue (HT) and serum (S) of adult CRC patients (n=12), determining relationships with clinical parameters (age, sex, metastasis, biochemical serum markers). Specific miRNA patterns were evident in vitro (normal, monolayers and CSCs) and in patients’ samples stratified by TNM stage (LOW vs HIGH) or metastasis (Met vs no-Met). miR-21, miR-210, miR-34a upregulation ad miR-16 dowregulation associated with the CSCs phenotype. miR-31b robustly overexpressed in monolayers and CSCs, and in CT ad S of HIGH grade and Met patients, suggesting a role as marker of CRC progression and metastasis. miR-18a upregulated in all cancer models and associated to CSC phenotype, and to metastasis and age in patients. miR-10b downregulated in CT and S of LOW/HIGH grade and no-Met patients. Our results identify miRNAs useful as colorectal CSC biomarker and that miR-21, miR-210, miR-10b and miR-31b are promising markers of CRC. A specific role of miR-18a as metastatic CRC serum biomarker in adult patients was also highlighted.

Genetic variants in C‐type lectin genes are associated with colorectal cancer susceptibility and clinical outcome

Inflammatory responses play a vital role at different stages of colorectal carcinogenesis. C-type lectins mediate inflammatory/immune responses and participate in immune escape of pathogens and tumors. Our study aimed to evaluate the correlation between polymorphisms in three C-type lectin genes, CD209, MBL2 and REG4, and colorectal cancer (CRC) risk and clinical outcome. We genotyped 15 potentially functional single nucleotide polymorphisms (SNPs) and assessed their associations with CRC risk in a case-control study of 1353 CRC cases and 767 healthy controls from the Czech Republic. We also analyzed these SNPs in relation to overall and event-free survival in 414 patients. Two CD209 SNPs were associated with CRC risk after adjustment for multiple comparison. Minor allele carriers of the promoter SNP rs2287886 had an increased risk of CRC (OR 1.30, 95% CI 1.08-1.56), while minor allele carriers of the 3'UTR SNP, rs7248637, had a decreased risk (OR 0.74, 95% CI 0.60-0.91). Multivariate survival analyses, including age, gender, TNM stage and grade, showed that patients without distant metastasis at the time of diagnosis and carrying the rs2994809 T allele had a decreased overall and event-free survival (HR 2.11, 95% CI 1.20-3.72 and HR 2.00, 95% CI 1.18-3.39, respectively). We show that SNPs in CD209 may affect CRC risk, while a SNP in REG4 may be a useful marker for CRC progression.

The Role Of Raf-1 Kinase Inhibitory Protein (RKIP) In Colorectal Cancer Liver Metastasis

Introduction: Colorectal cancer (CRC) remains the second most frequent cause of cancer-related mortality in the United States. The majority of these deaths are secondary to metastatic disease. Emerging data suggest the idea that RKIP is a metastasis suppressor. The loss of RKIP expression has been reported to be a marker of CRC progression and metastasis. Despite this correlation, the mechanism of RKIP inhibition of CRC metastasis remains undefined. We hypothesize that RKIP expression directly inhibits cell invasion and metastasis by regulating the MAPK/ERK signaling pathway.

Abstract 562: Stromal TLR4 and IL 6 expression as potential prognostic inflammation-associated markers for colo-rectal cancer progression

Abstract Epidemiological studies suggest that chronic inflammatory conditions constitute pre-neoplastic conditions. To study how chronic inflammation could affect tumor growth and progression, we quantified the presence of inflammatory cells and expression of inflammatory cytokines by immunohistochemistry on archival tissue samples from 116 patients. We considered 13 cases of ulcerative colitis, 34 tubular or tubulo-villous adenomas with low or high grade dysplasia, and 53 infiltrating adenocarcinomas with T1, T2, T3, and T4 staging. Sixteen specimens of healthy mucosa resected along with the cancerous tissue were used as controls. We investigated expression of CD68 (macrophages), CD15 (neutrophils), CD31 (endothelial cells), Interleukin 6 (IL-6), Hepatocyte Growth Factor (HGF), and Toll-Like Receptor 4 (TLR-4). We considered 3 specific tissue compartments: epithelial, stromal and endothelial (vessel associated). Statistical differences between individual cell groups were determined using an unpaired two way t-test (Mann-Whitney). Progression from healthy tissue to ulcerative colitis was characterized by a massive inflammatory-angiogenic reaction, as for a significant increase in expression of inflammation markers, paralleled by down-regulation of a potential suppressive molecule, HGF. Subsequently, a progressive increase in cells expressing CD68, CD15, TLR-4, and IL6 were found in the passage from adenoma to adenocarcinoma. Adenocarcinoma patients that expressed high levels of TLR-4 in the stromal compartment had a significantly increased risk of relapse within 40 months. Moreover, in the subgroup of adenocarcinoma patients with a diagnosis of pT3 colon cancer (the most frequent pT), those with higher levels of TLR-4 in the tumor stroma showed increased risk for a relapse within 15 months. These data suggest that inflammation correlates with progression in colorectal cancer, and that TLR-4 represents a potential prognostic marker of colo-rectal cancer progression. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 562.

A System-Wide Investigation of the Dynamics of Wnt Signaling Reveals Novel Phases of Transcriptional Regulation

Aberrant Wnt signaling has been implicated in a wide variety of cancers and many components of the Wnt signaling network have now been identified. Much less is known, however, about how these proteins are coordinately regulated. Here, a broad, quantitative, and dynamic study of Wnt3a-mediated stimulation of HEK 293 cells revealed two phases of transcriptional regulation: an early phase in which signaling antagonists were downregulated, providing positive feedback, and a later phase in which many of these same antagonists were upregulated, attenuating signaling. The dynamic expression profiles of several response genes, including MYC and CTBP1, correlated significantly with proliferation and migration (P<0.05). Additionally, their levels tracked with the tumorigenicity of colon cancer cell lines and they were significantly overexpressed in colorectal adenocarcinomas (P<0.05). Our data highlight CtBP1 as a transcription factor that contributes to positive feedback during the early phases of Wnt signaling and serves as a novel marker for colorectal cancer progression.

Altered Expression and Localization of Creatine Kinase B, Heterogeneous Nuclear Ribonucleoprotein F, and High Mobility Group Box 1 Protein in the Nuclear Matrix Associated with Colon Cancer

Identification of biomarkers could lead to the development of effective screening tests for colorectal cancer. A previous study from our laboratory showed specific alterations of nuclear structure in colon cancer. In an effort to characterize these biomarkers, protein spots were selected from separations made by two-dimensional gel electrophoresis, which were analyzed by mass spectrometry. The sequences obtained from the isolated spots revealed that they have close similarity to creatine kinase B (CKB) isoforms, heterogeneous nuclear ribonucleoprotein F (hnRNP F) and high mobility group box 1 protein (HMGB1) isoforms. To determine the expression of these proteins in colon cancer, expression was studied in 9 tumor and matched adjacent normal pairs, 5 donor colons, 16 polyps, 4 metastatic liver lesions and matched adjacent normal pairs, and 3 liver donors. CKB and hnRNP F were expressed in 78% and 89% of colon tumors, respectively. hnRNP F had a higher frequency of expression than CKB in premalignant polyps. With the establishment of differential expression of the proteins in colon cancer, their subcellular localization was analyzed. The subcellular fractions studied both showed high protein levels of hnRNP F in colon tumors compared with normal colon tissues. Surprisingly, subcellular levels of CKB were decreased in colon tumors, suggesting that the observed high CKB levels in nuclear matrix extracts are caused by the enhanced localization of CKB to the nuclear matrix during colon tumorigenesis. These results suggest an involvement of hnRNP F and CKB in colorectal cancer. Additionally, they suggest that hnRNP F is a potential marker for colorectal cancer progression.

Clinical significance of serum vascular endothelial growth factor in colorectal cancer patients: correlation with clinicopathological factors and tumor markers.

Vascular endothelial growth factor (VEGF) is known as a potent inducer of angiogenesis in various human cancers. Serum VEGF concentrations of colorectal cancer patients was assessed for their clinical significance as a tumor marker. Serum samples were obtained at admission from 24 healthy volunteers and 111 patients with colorectal cancer. Preoperative serum VEGF concentrations, which are significantly higher than those of healthy controls, reflect clinical stage progression, depth of invasion, liver metastasis, lymph node metastasis and lymphatic invasion. Consequently, detection of VEGF could serve as a clinically useful marker for colorectal cancer progression and metastasis independent of other markers.

Matrilysin (matrix metalloproteinase-7) mRNA expression is a sensitive marker of colorectal cancer progression: [formula omitted], Y Ichikawa, T Chishima, N Takeuchi, H Yamaoka, K Miyazaki, Y Nagashima, M Mitsuhashi, T Akitaya, A Tarnawski, IJ Sarfeh, H Shimada. Yokohama City University, Hitachi Chem. Res. Ctr. CA, Hitachi Chem. Co. Japan, University of California, Irvine, CA

Matrilysin (matrix metalloproteinase-7) mRNA expression is a sensitive marker of colorectal cancer progression: [formula omitted], Y Ichikawa, T Chishima, N Takeuchi, H Yamaoka, K Miyazaki, Y Nagashima, M Mitsuhashi, T Akitaya, A Tarnawski, IJ Sarfeh, H Shimada. Yokohama City University, Hitachi Chem. Res. Ctr. CA, Hitachi Chem. Co. Japan, University of California, Irvine, CA