Renal Metastasis of Adenocarcinoma of the Colon

Purpose. Despite the recent progress in diagnosis and treatment for colorectal cancer (CRC), prognosis of CRC patients still remains poor. Metastatic recurrence is the major causes of cancer-related death in CRC patients, and recent progress in treatment options, especially technical advances in invasive treatment for metastatic lesion, have improved the prognosis of CRC patients with metastasis. Furthermore, almost half of patients that receive chemotherapy derive no clinical benefit, though all are exposed to these severe toxic and expensive therapeutic regimens in patients with metastatic CRC patients. In view of these underlying issues, for improvement of patient's prognosis, there is a keen interest in developing robust biomarkers that can identify the subset of patients who can benefit from intensive post-treatment surveillance protocols for early detection of recurrence, and prompt decision of appropriate treatment protocol. Herein, we systemically and comprehensively evaluated differentially levels of serum cytokines using array-based techniques to identify novel and reliable serum biomarker to predict metastasis and poor outcome in CRC. Methods. The study design included an initial dual screening phases, and followed by a subsequent clinical validation phase in this study.In discovery phase, we examined cytokine profiling using preoperative serum from two different CRC cohorts (n = 30) to identify differentially expressed serum cytokines in CRC patients with metastasis. In validation phase, serum levels of MCP-4 were assessed in 194 CRC patients by enzyme-linked immunosorbent assay, and their relationships with clinicopathological findings, including recurrence and survival, were investigated. Results. In discovery phase, three cytokines (elevated: MCP-4, ENA-78; decreased:Ckb8-1) were overlapped as a differentially expressed cytokines in serum from CRC patients with metastasis compared those without metastasis. High serum MCP-4 was significantly associated with older age (p = 0.033), advanced T stage (p = 0.029), distant metastasis (p = 0.011) and UICC stage classification (p = 0.006). Cox regression analysis showed that elevated MCP-4 was a significant and independent prognostic factor of disease free survival (HR:2.6, 95%CI:1.0-6.7) and overall survival (HR:2.7, 95%CI:1.3-5.9) in all CRC patients. Furthermore, logistic regression analysis revealed that high serum MCP-4 level was an independent marker in predicting distant metastasis in CRC (OR:3.8, 95%CI:1.3-10.9). Conclusion. Our comprehensive study highlights the clinical feasibility of serum MCP-4 as a prognostic and predictive biomarker for distant metastasis and recurrence in CRC patients. Quantification of serum MCP-4 concentration might support the early detection/prediction of recurrence and may contribute to the prediction of clinical outcomes in CRC. Citation Format: Yoshinaga Okugawa, Yuji Toiyama, Koji Tanaka, Mikio Kawamura, Takahito Kitajima, Tadanobu Shimura, Hiroki Imaoka, Hiroyuki Fujikawa, Susumu Saigusa, Yasuhiro Inoue, Motoyoshi Tanaka, Yasuhiko Mohri, Chikao Miki, Ajay Goel, Masato Kusunoki. Elevated serum monocyte chemotactic protein 4 (MCP4) as a novel noninvasive prognostic and predictive biomarker for detection of metastasis in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5016.

BackgroundTumour deposits are a prognostic factor for overall survival and distant metastasis in lymph node-negative colorectal cancer. However, the current TNM staging system does not account for the presence of tumour deposits in lymph node-positive colorectal cancer, or for the presence of multiple deposits. This study aimed to investigate the prognostic effect of tumour deposit count in patients with colorectal cancer.MethodsPatients who underwent curative surgery for colorectal cancer between 2016 and 2019 were identified nationwide from the Swedish Colorectal Cancer Registry. Patients with undisclosed tumour deposit status/count and stage IV disease were excluded. Univariable and multivariable Cox regression analyses were used to assess the prognostic effect of tumour deposit count on overall survival and distant metastasis adjusted for age, sex, neoadjuvant treatment, and number of positive lymph nodes.ResultsOf 18 913 patients assessed, 14 154 patients were analysed with tumour deposits (TDs) present in 1702 (12%) patients. Patients were stratified by tumour deposit count (0, 1, 2, 3, 4, and ≥5 TDs). Increased tumour deposit count was associated with decreased 5-year overall survival (79%, 70%, 61%, 66%, 50%, 49%) and increased 5-year risk for distant metastasis (14%, 26%, 35%, 41%, 48%, 54%) respectively. Tumour deposit count remained an independent negative prognostic factor after multivariable Cox regression analysis.ConclusionTumour deposit count is a negative prognostic predictor of both overall survival and distant metastasis in colorectal cancer, independent of positive lymph nodes or neoadjuvant treatment. These findings suggest that tumour deposit count should be integrated into the TNM staging regardless of lymph nodes status to improve prognostic accuracy.

Racism Is a Modifiable Risk Factor: Relationships Among Race, Ethnicity, and Colorectal Cancer Outcomes

目的 探讨结直肠癌肝转移患者血清中 CD44和 CD54含量与结直肠癌肝转移发生发展的关系,寻找一个稳定的早期诊断结直肠癌肝转移的生物学指标.方法应用酶联免疫吸附测定方法( ELISA)检测 38例结直肠癌和 21例结直肠癌肝转移患者以及 40例健康成人(正常对照组)的血清 CD44和 CD54含量, 并比较血清中 CD44和 CD54含量在治疗前后的变化.结果结直肠癌肝转移组和结直肠癌组血清中 CD44和 CD54含量明显高于正常对照组,且结直肠癌肝转移组较结直肠癌组含量也明显增高.结直肠癌肝转移组和结直肠癌组治疗后的血清 CD44和 CD54含量比治疗前下降.结论 CD44和 CD54可以作为临床早期诊断结直肠癌肝转移的生物学指标,同时也可以作为监测结直肠癌和结直肠癌肝转移预后的客观指标.

Introduction: Colorectal cancer is the third most common cancer in the North America with a 5-year survival rate of ∼65%. A portion of the inter-patient variability in disease outcome in colorectal cancer patients is attributed to inherited and somatic genetic factors. Identification of these genetic factors helps implementing personalized medicare to improve the chances of cure in patients. While numerous research articles have investigated the genetic basis of clinical outcome in colorectal cancer, there has not been a central resource, such as a public database, that compiles these findings in a systematic, comprehensive and concise way. Here we describe the dbCPCO, a database of genetic factors investigated in relation to clinicopathological characteristics and clinical outcome (i.e. treatment response and toxicity, prognosis and survival) in colorectal cancer. Methods: Literature reports were retrieved from PUBMED. The data that met the inclusion criteria were compiled in a relational database and posted in a dedicated website. Results: The genetic factors included the inherited genetic polymorphisms, somatic and germline mutations in both nuclear and mitochondrial DNA. As of November 2009, the dbCPCO website posts 610 scientific findings on >300 polymorphisms, somatic and germline mutations from 146 genes tested for correlation with clinicopathological and/or clinical outcome in colorectal cancer. Conclusion: The dbCPCO is a unique and comprehensive database that compiles literature findings on the genetic basis of disease phenotype and clinical outcome in colorectal cancer and will be instrumental in expediting personalized medicine and further research in this disease. The dbCPCO is updated periodically and is freely available for the scientific and medical community at http://www.med.mun.ca/cpco/Default.aspx. 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 92.

The tumor microenvironment (TME), comprising of the inflammatory cell infiltrate and tumor-associated stroma, is an important and potentially modifiable determinant of outcome in colorectal cancer (CRC). However, identifying patients who may benefit from therapy targeting the TME prior to surgery is problematic. The aim of the present study was to examine the clinical utility and prognostic value of assessment of the TME utilising colonoscopic tumor biopsies. Using an automated scoring system (nuclear h-score) the density of CD3+ T-lymphocytes was quantified in preoperative tumor biopsies of 120 patients undergoing elective resection of stage I-III CRC and compared to automated assessment and manual, semi-quantitative assessment (high vs. low) of CD3+ density within the TME of surgically resected tumor specimens. The tumor-associated stroma was measured in both biopsies and resected specimens using tumor stroma percentage (TSP) and classified as low (<50%) or high (>50%). The relationship with cancer-specific survival (CSS) was examined on univariate and multivariate analysis. The median h-score for CD3+ density in colonoscopic biopsies and resected specimens was 58 (interquartile range 33-83) and 22 (13-38). Automated assessment of CD3+ density in biopsies and resected specimens was significantly correlated (r = 0.329, P<0.001). Using the median value as a threshold, biopsy CD3+ density was classified as high or low density; this was associated with manual assessment of CD3+ density within the invasive margin (P<0.01) and cancer stroma (P<0.001) and showed a trend towards an association with density within the cancer cell nests (P = 0.06). Assessment of TSP in biopsies was associated with full section TSP; biopsy TSP accurately predicted high full section TSP in 39% of patients and low TSP in 87% of cases (P = 0.001). High biopsy CD3+ density was associated with increased CSS (HR 0.39 95%CI 0.19-0.80, P = 0.01) and high biopsy TSP was associated with decreased CSS (HR 2.56, 95%I 1.30-5.04, P = 0.007) on univariate analysis. On multivariate analysis, biopsy CD3+ density (HR 0.44, 95%CI 0.21-0.92, P = 0.03) and TSP (HR 2.88, 95%CI 1.44-5.75, P = 0.003) were associated with CSS independent of TNM stage (P = 0.015), venous invasion (P = 0.029) and surgical margin involvement (P = 0.058). The results of the present study suggest that staging of the TME, and in particular CD3+ density and TSP, is feasible utilising colonoscopic tumor biopsies and may inform prognosis. This may allow for appropriate stratification of patients entering clinical trials targeting the tumor microenvironment of patients with colorectal cancer. Citation Format: James H. Park, David Mansouri, Clare Orange, Joanne Edwards, Paul G. Horgan, Donald C. McMillan, Campbell SD Roxburgh. Pre-operative assessment of the tumor microenvironment of patients undergoing resection of colorectal cancer is feasible using colonoscopic biopsies [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A142.

Optimizing Colorectal Cancer Screening by Getting FIT Right

Background: Metastasis is the major reason for high recurrence rates and poor survival among patients with colorectal cancer (CRC). However, the underlying molecular mechanism of CRC metastasis is unclear. This study aimed to investigate the role of forkhead box K2 (FOXK2), one of the most markedly increased FOX genes in CRC, and the mechanism by which it is deregulated in CRC metastasis.Methods: FOXK2 levels were analyzed in two independent human CRC cohorts (cohort I, n = 363; cohort II, n = 390). In vitro Transwell assays and in vivo lung and liver metastasis models were used to examine CRC cell migration, invasion and metastasis. Chromatin immunoprecipitation and luciferase reporter assays were used to measure the binding of transcription factors to the promoters of FOXK2, zinc finger E-box binding homeobox 1 (ZEB1) and epidermal growth factor receptor (EGFR). Cetuximab was utilized to treat FOXK2-mediated metastatic CRC.Results: FOXK2 was significantly upregulated in human CRC tissues, was correlated with more aggressive features and indicated a poor prognosis. FOXK2 overexpression promoted CRC migration, invasion and metastasis, while FOXK2 downregulation had the opposite effects. ZEB1 and EGFR were determined to be direct transcriptional targets of FOXK2 and were essential for FOXK2-mediated CRC metastasis. Moreover, activation of EGFR signaling by EGF enhanced FOXK2 expression via the extracellular regulated protein kinase (ERK) and nuclear factor (NF)-κB pathways. The EGFR monoclonal antibody cetuximab significantly inhibited FOXK2-promoted CRC metastasis. In clinical CRC tissues, FOXK2 expression was positively correlated with the expression of p65, ZEB1 and EGFR. CRC patients who coexpressed p65/FOXK2, FOXK2/ZEB1 and FOXK2/EGFR had poorer prognosis.Conclusions: FOXK2 serves as a prognostic biomarker in CRC. Cetuximab can block the EGF-NF-κB-FOXK2-EGFR feedback loop and suppress CRC metastasis.

Colorectal cancer (CRC) is one of the leading cancer worldwide and alarmingly rising in India. Various lifestyle, clinicopathological and genetic risk factors of CRC have been reported. Individuals with risk factors are more likely to host cancer and are subjected to screening programs. CRC is the fourth most cancer in males and third most in females of the Kashmiri population. This study aims to find out the association and effect of lifestyle risk factors (Smoking and Diet), clinicopathological risk factors (Age, Gender, Metastatic status and Tumor site) and outcome of CRC. This research is a case study that included 222 patients registered in the Shree Maharaja Hari Singh (SMHS) hospital and Sher-i-Kashmir Institute of Medical Sciences, Soura (SKIMS) hospital of Kashmir valley. The information relevant to the aim of study for all CRC patients including various behavioral variables, clinicopathological variables were gathered and reviewed from patient medical records (files), histopathology studies, as well as details collected from patients or guardians (as some critical patients were not able to speak themselves) through personal interviews. The collected data also included symptoms such as abdominal pain, constipation, on and off fever, bleeding and weight loss which were gathered from registered records as well as from patients themselves. This entire study was carried out by the willingness of the patients as they were prior informed about this study. The relevant data particularly included dietary factors, smoking factors, age, gender, tumor site and metastatic status. The outcome of CRC was categorized into three groups: Disease Progression (DP), Partial Response (PR) and Disease-Free (DF); the criteria used for categorizing outcome groups DP, PR and DF were as follows: (1) The patients were categorized as a DF based on clinical examination, i.e., history and physical examination, radiologically, i.e., based on CACT abdomen/MRI PET tests and biochemically, i.e., based on examination of Tumor markers like CEA levels. (2) The patients were kept in the PR category whose disease status was found Stagnant and who showed a decrease in the volume of the tumor arrived at, based on three diagnostic techniques such as clinical, radiological and biochemical examination reports. (3) The patients were under DP whose Increased CEA level showed tumor burden and prognosis and an increase in the volume of the tumor with spread to nearby organs. Smoking (p =0.001), age (p = 7.599e–07), metastatic (p = 2.2e–16) and diet (p = 4.508e–07) showed a highly significant association with CRC outcomes. However, no difference was observed in gender and tumor site. The outcome groups (DP, PR, DF) were also different in mean and showed statistical significance (p = 0.0022). In addition, family-wise comparison in outcome groups was observed statistically significant in between G3 and G1 (i.e., disease-free group and disease progression group) and in G3–G2 (i.e., disease-free group and partial response group). Furthermore, the main effect of chosen risk factors was high in the disease progression group but overall no strong association of effect was found. Risk factors of CRC act as a big impediment during the treatment process leading more patients to disease progression and poor differentiation. More awareness about risk factors is needed to provide a clear picture of the role of risk factors in the development and treatment of CRC.

Objective To investigate the clinical features, diagnosis, treatment and prognosis of the renal secondary tumor. Methods From January 2000 to January 2014, the data from 31 patients, including 23 male patients and 8 female patients, with renal secondary tumors were analyzed retrospectively. Their mean age was 56 years old (ranging from 38 to 75 years old). The 31 renal secondary tumors rooted in lung cancer(n=14), lymphoma(n=5), colorectal cancer and gastric cancer(n=3), breast cancer(n=2), esophageal cancer(n=1), thyroid cancer(n=1), cervical cancer(n=1) and bladder cancer(n=1), respectively. There were 22 patients(71.0%) of renal metastasis accompany with other organs or lymph node metastasis. 9 cases (29%) suffered with independent renal metastasis and 21 cases (67.7%) suffered with unilateral renal metastasis. 5 cases(16.1%) were diagnosed as primary tumor with the renal metastasis at the same time, and the remaining 26 cases were found renal metastasis within 9 to 72 months after primary tumor (mean 30 months). There were only 5 patients (16.1%) with symptom. Ultrasound showed low echo range in 20 cases (65.6%) or uneven echo in 11 cases (34.4%). CT showed equal density (77.4%) in 24 cases or slightly low density shadow (22.6%)in 7 cases, most of which were endogenous, mild enhancement. 10 cases (32.3%) were bilateral renal metastasis , unilateral renal multiple metastases was found in 6 cases (19.4%), and single metastasis was noticed in 15 cases (48.4%). The average diameter of the renal metastasis was 2.7 cm (ranging from 0.9 to 6.8 cm). Except 4 cases gave up the treatment, the remaining 27 cases were accepted comprehensive therapy about the primary tumor. the 9 patients with renal metastasis only were treated with chemotherapy or targeted therapy for the advanced primary tumor. Among the 9 patients, 6 cases were undergone NSS or radical nephrectomy (RN) treatment. Results In 9 cases with only renal metastasis, 6 cases, treated by surgery, recovered well. Postoperative pathological and immunohistochemical results confirmed the renal metastasis. Up to January 2015, the follow-up duration ranged from 2 months to 60 months[mean (22.6±18.4) months]. The survival time ranged from 1 month to 51 months[mean (13.2±13.2) months]. Among 22 cases with multiple metastasis, 4 cases gave up treatment, whose average survival time was (2.0±1.4) months. However, the average survival time in remaining 18 cases was (11.1±4.7) months(P<0.05). In 9 cases with independent renal metastasis, the average survival time in 6 cases, accepted the procedure, was (26.2±18.6) months. While, the average survival time in remaining 3 non-surgical cases, was (10.3±4.0) months (P<0.05 ). Conclusions Renal secondary tumor was rare in clinic.Most cases have isolated lesion. Renal secondary tumor was advanced manifestation of the primary tumor, which could prolong the survival time according to the comprehensive treatment for the primary tumor. Surgical resection of the lesion before the comprehensive treatment could be chosen in the independent renal metastasis. Key words: Renal secondary tumor; Diagnosis; Treatment; Prognosis

We have read with great interest the recently published work by Lin et al (2014), which provides novel relevant findings about the tumour suppressor role of TAp63 via miR-133b downregulation in colorectal cancer (CRC). Of importance, the authors identified miR-133b as a transcriptional target of TAp63, and showed that the modulation of miR-133b expression is essential for the inhibitory effects of TAp63 in CRC cell migration and invasion. Moreover, they showed that TAp63 is expressed at low levels in CRC and proposed this alteration as a potential cause of miR-133b downregulation, which was previously described by our group in CRC cell lines and patient samples (Bandres et al, 2006). Furthermore, it has been reported that miR-133b has a tumour suppressor role inhibiting cell growth through modulation of the MET signalling pathway (Hu et al, 2010), and it has also been described that low expression level of miR-133b correlates with poor clinical outcome in CRC (Akcakaya et al, 2011). Notably, although the findings provided by Lin et al (2014) highlight the potential relevance of miR-133b deregulation in CRC progression and metastasis, this issue needs to be fully clarified. A recent publication pointed out that miR-133b contributes to increased CRC cell migration and invasion, and identified CXCR4 as a direct miR-133b target. In that work, Duan et al (2014) analysed 31 CRC patients observing miR-133b downregulation in 29 out of 31 tumour samples, and much lower expression in metastatic tumours. The authors proposed that miR-133b could be having a relevant role in CRC invasion and metastasis. However, only 13 out of the 31 CRC patients had metastatic disease (9 with lymph node metastasis and 4 with liver metastasis). Therefore, further studies confirming the role of miR-133b in the metastatic cohort are warranted. In this line of thinking, we analysed the potential role of miR-133b in CRC progression and metastasis. We quantified the expression pattern of 377 mature microRNAs using Taqman Low Density Arrays (TLDAs) panel A (Applied Biosystems, Grand Island, NY, USA) in primary and paired metastatic tissues from 17 CRC patients, 12 with liver metastasis and 5 with lung metastasis previously reviewed by a pathologist (FR) to further confirm the diagnosis. All samples were taken anonymously and the ethical committee and institutional review board approved the project. Analysis of relative gene expression data was performed using the 2−ΔCt method and U6B was used as internal control. Downregulation was considered when expression in the metastatic tissue showed at least three-fold decrease compared with its paired primary CRC tissue. Interestingly, we found miR-133b significantly downregulated in liver metastatic tissues compared with their paired primary CRC tissues (P<0.001). We observed that miR-133b was markedly downregulated in all the 12 CRC liver metastatic tissues analysed. Furthermore, we found lower miR-133b levels in lung metastasis compared with their paired primary CRC tissues although significance was not achieved in this case. In fact, we unexpectedly observed that only two out of the five CRC lung metastatic samples showed miR-133 downregulated and even in one of those cases miR-133b expression was found increased. Moreover, miR-133b showed almost five-fold lower expression levels in liver metastatic tissues compared with lung metastatic tissues. Altogether, we have confirmed the potential relevance of miR-133b in a larger cohort of CRC patients with liver metastasis and the proposed role for miR-133b in metastatic CRC. In addition, our results would indicate that miR-133b downregulation is more specific of liver CRC metastasis, which indicates that miR-133b might be having a potential role determining the metastatic niche, although further studies are warranted to clarify this issue.

We investigated laminin, an important extracellular matrix component, to elucidate mechanisms of invasion and metastasis in colorectal cancer, and whether preoperative serum laminin is a predictive marker of high-risk groups. We measured preoperative serum laminin levels using a two-step sandwich enzymeimmunassay (EIA) method in 205 patients with colorectal cancer, 109 with colon cancer and 96 with rectal cancer, 52 with hepatic metastases, and 153 with no hepatic metastases. Mean serum laminin in patients with colon cancer was 606.3+/-260.2 ng/ml, significantly higher than that of 258.0+/-92.0 ng/ml in normal controls (P<0.0001). The positive rate was higher at 89.3% for laminin vs. 38.0% for carcinoembryonic antigen (CEA) and 19.5% for CA19-9. Mean serum laminin in patients with hepatic metastases was 668.0+/-274.7 ng/ml, significantly higher than that of 585.2+/-252.5 ng/ml in patients without hepatic metastases (P=0.0472). Survival rates were significantly lower in the high (> or = 520 ng/ml) than in the low laminin group (<350 ng/ml; P=0.0451). Univariate and multivariate analysis, using Cox's proportional hazard regression model, showed serum laminin is an independent prognostic factor in colorectal cancer, along with hepatic, pulmonary and peritoneal metastases. Preoperative serum laminin levels are a useful predictive marker of high-risk groups in colorectal cancer.

BackgroundEmerging evidence has revealed miR-29 family as promising biomarkers for colorectal cancer (CRC), but their biomarker potential and molecular mechanisms remain poorly understood.MethodsWe performed a comprehensive meta-analysis to evaluate the biomarker performance of individual miR-29 and the related miRNA combination biomarkers. Meanwhile, we conducted an integrative bioinformatics analysis to unfold the underlying biological function of miR-29 and their relationship with CRC.ResultsUsing miR-29 expression to diagnose CRC produced 0.82 area under the curve, 70% sensitivity and 81% specificity while the combination biomarkers based on miR-29 enhanced the diagnostic power with an AUC of 0.86, a sensitivity of 78% and a specificity of 91%. For the prognosis evaluation, patients with higher expression of miR-29 had better survival outcome (pooled HR 0.78; 95% CI 0.56–1.07). In addition, miR-29 has also been identified as potential biomarker for predicting recurrence and metastasis in CRC. Then the genes regulated by the miR-29 family were retrieved and found closely associated with the molecular pathogenesis of CRC according to the gene ontology and pathway analysis. Furthermore, hub nodes and significant modules were identified from the protein–protein interaction network constructed with miR-29 family targets, which were also confirmed highly involved in the establishment and development of CRC.ConclusionsCurrent evidences suggest miR-29 family may become promising biomarkers for risk, recurrence, metastasis and survival outcome of CRC. Meanwhile our data highlight the potential clinical use of miRNA combination biomarkers. Nevertheless, further prospective studies are warranted before the application of the useful biomarkers in the clinical.

To clarify the clinical significance of the expression of vascular endothelial growth factor (VEGF) and its receptor, kinase domain-containing receptor (KDR) in colorectal cancer, we evaluated the relationship between the expression of VEGF and KDR, and the microvessel counts and clinicopathological factors in colorectal cancer. A total of 259 specimens from sequential colorectal cancer patients who had undergone surgery were examined by the avidin-biotin peroxidase complex method, using anti-human VEGF, anti-human KDR, and anti-human von Willebrand factor antibodies. The incidence of VEGF expression in the tumor cells of the patients with liver metastasis was significantly higher than that in the tumor cells of the patients without liver metastasis (67% vs 44%). The microvessel count at the tumor invasive edge in the patients whose tumor cells were positive for VEGF was significantly higher than that in the patients whose tumor cells were negative for VEGF (33.0 +/- 7.8 vs 28.0 +/- 7.9); the significant difference in microvessel counts was greater when there was a combination of VEGF and KDR expression. The overall survival rate of patients positive for VEGF was significantly (P = 0.0276) lower than that of those who were negative for VEGF. Although there was no significant difference (P = 0.0743) in the survival rates after potentially curative resection according to VEGF expression, the survival rate of the patients positive for both VEGF in tumor cells and KDR in endothelial cells was significantly (P = 0.0026) lower than that in the patients who were negative for VEGF and/or KDR. In addition, multivariate analysis revealed that the expression of both VEGF and KDR was an independent prognostic factor even after potentially curative resection. VEGF may be implicated in the definition of the malignant phenotype of colorectal cancer via tumor angiogenesis. VEGF and its receptor KDR expression in tumorous tissues could be useful prognostic factors in colorectal cancer.

Biological Implications and Clinical Potential of Metastasis-Related miRNA in Colorectal Cancer