Prognostic Factor In Colorectal Cancer Research Articles

Intraepithelial tumour infiltrating lymphocytes are associated with absence of tumour budding and immature/myxoid desmoplastic reaction, and with better recurrence-free survival in stages I-III colorectal cancer.

Tumour budding (TB), desmoplastic reaction (DR) and intraepithelial tumour infiltrating lymphocytes (iTILs) are recently recognised prognostic factors in colorectal cancer (CRC). In this study, we evaluated their significance and relationship to each other and their cumulative effect on survival. A total of 372 stages I-III CRC cases from 2013 to 2016 were included. Low TB was identified in 302 (81%) cases, immature/myxoid DR in 67 (18%) cases and iTILs in 130 (35.0%) cases. iTILs was associated with low budding (P=0.0247), non-myxoid DR (P=0.0004), poorly differentiated histology (P=0.0015), absence of perineural invasion (P=0.0367) and loss of mismatch repair proteins (P=0.0002). Absence of iTILs and presence of immature/myxoid DR were associated with a worse recurrence-free survival (RFS) [hazard ratio (HR)=2.191, 95% confidence interval (CI)=1.232-3.895; and HR=5.706, 95% CI=3.632-8.964, respectively]. A competing risk analysis showed statistically significant prognostic groups combining iTILs and TB (P<0.0001). Cases with iTILs and low TB were associated with better RFS compared to cases without iTILs and with intermediate/high TB (HR=0.214, 95% CI=0.109-0.421). Similarly, combining iTILs and DR revealed statistically significant prognostic groups (P<0.0001). Cases with iTILs and a non-myxoid DR had better RFS compared to cases without iTILs and immature/myxoid DR (HR =0.113, 95% CI=0.056-0.230). On multivariate cause-specific analysis, patients' age (P=0.0045), iTILs (P=0.0345), DR (P<0.0001) and pTNM prognostic groups (P<0.0001) were associated with RFS. Our study validates the association of iTILs and DR as independent prognostic finding in CRC, and propose a prognostic model using the combinations of iTILs with TB and stromal reaction in CRC.

VGLL4 with low YAP expression is associated with favorable prognosis in colorectal cancer.

The Hippo pathway is a tumor suppressive pathway regulating Yes-associated protein-TEA domain-containing sequence-specific transcription factor (YAP-TEAD) complex. VGLL (Vestigial-like) proteins are transcriptional cofactors competing with YAP for TEAD binding and interfering oncogenic activity of YAP-TEAD complex. We evaluated the expression of VGLL4, YAP, and TEAD4 and assessed their correlations with clinicopathologic factors and prognostic effects in 295 colorectal cancers. VGLL4 was positive in 164 (55.6%) cases and correlated with small tumor size, low pT classification, and absence of lymph node metastasis. YAP and TEAD4 were highly expressed in 138 (46.8%) cases and 144 (48.8%) cases, respectively, and high expressions were associated with presence of lymphovascular invasion and lymph node metastasis, or distant metastasis. VGLL4 expression was significantly correlated with low YAP expression (p<0.001) and had significantly better overall survival than negative expression (p<0.001). High YAP (HR, 2.108; 95% confidence interval, 1.239-3.584; p=0.006) and TEAD4 (1.724; 1.021-2.912; p=0.042) expressions were associated with poor overall survivals. The combined VGLL4pos YAPlow expression showed the best overall survival than other groups (p<0.001). VGLL4 expression (0.381; 0.212-0.683; p=0.001) and combined VGLL4pos YAPlow expression (0.227; 0.108-0.475; p<0.001) were independent good prognostic factors in colorectal cancers. The expressions of VGLL4, YAP, and TEAD4 can be used as prognostic markers in colorectal cancer patients.

LncRNA ADAMTS9-AS1, as prognostic marker, promotes cell proliferation and EMT in colorectal cancer.

The long non-coding RNA antisense 1 ADAMTS9-AS1 has been reported to predict the survival in several tumors, including bladder cancer and breast cancer. However, the clinical significance and biological behaviors of ADAMTS9-AS1 in colorectal cancer (CRC) have not been reported yet. In this study, the expression of ADAMTS9-AS1 was measured in CRC tissues and cell lines using quantitative real-time PCR analysis. The clinical significance of ADAMTS9-AS1 was evaluated with Chi-squared test, Kaplan-Meier method and Cox regression analysis in CRC patients. CCK8 assay, colony formation assay, flow cytometry and transwell assay were used to explore the biological function of ADAMTS9-AS1 knockdown in CRC cell lines (SW1116 and HT29). We further explore the role of ADAMTS9-AS1 in vivo though xenograft tumor assay. Our data showed that ADAMTS9-AS1 expression level was significantly up-regulated in CRC tissues and cell lines compared with corresponding controls. High ADAMTS9-AS1 level was associated with TNM stage, lymph node invasion and worse survival prognosis. Depletion of ADAMTS9-AS1 significantly suppressed cell proliferation, G1/S transition, migration and invasion, as well as suppressed CDK4/Cyclin D1 and epithelial-mesenchymal transition (EMT). To sum up, these findings illustrated that ADAMTS9-AS1 might be a promising therapeutic target and prognostic factor for CRC.

504P Primary tumour location impacts oncological outcome of patients with resected colorectal liver metastases

Primary tumour location has emerged as a prognostic factor for colorectal cancer. Approximately 38% of patients will develop liver metastases, yet evidence on the impact of sidedness after resection is lacking.

Monocyte-to-lymphocyte ratio as a prognostic factor in peripheral whole blood samples of colorectal cancer patients.

BACKGROUNDColorectal cancer is the third most common malignancy worldwide. Therefore, it is critically important to identify new useful markers that can be easily obtained in routine practice. Inflammation is a crucial issue in the pathogenesis and development of cancer.AIMTo evaluate the prognostic value of absolute monocyte count, monocyte to lymphocyte ratio (MLR), the combination of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (NLR-PLR), and combined platelet and neutrophil-to-lymphocyte ratio (PLT-NLR) in peripheral blood samples of patients with colorectal cancer undergoing surgery.METHODSWe conducted a retrospective study of 160 patients with colorectal cancer who underwent surgery, and 42 healthy controls. The status of absolute monocyte count, MLR, NLR-PLR and PLT-NLR was calculated on the basis of blood samples obtained before and after surgery. Haematologic factors were examined in correlation with the type of tumour growth, tumour size, histological type, percentage of mucinous component, grade of malignancy, Tumour-Node-Metastasis stage, venous, lymphatic and perineural invasion of cancer cells, status of lymph node invasion and the presence of cancer cell deposits. The Kaplan-Meier method and the long-rank test were used to compare survival curves. To determine independent prognostic factors, univariate and multivariate Cox proportional hazards regression models were applied.RESULTSThe PLT-NLR status was correlated with tumour size and the presence of perineural invasion (P = 0.015; P = -0.174, P = 0.037). Moreover, high NLR-PLR and PLR-NLR ratios in the blood samples obtained after surgery were positively associated with histological type of cancer and percentage of the mucinous component (NLR-PLR: P = 0.002; P = 0.009; PLR-NLR status: P = 0.002; P = 0.007). The analysis of 5-year disease-free survival showed that the MLR of whole blood obtained after surgery [HR = 2.903, 95%CI: (1.368-6.158), P = 0.005] and the status of lymph node metastasis [HR = 0.813, 95%CI: (0.653-1.013), P = 0.050] were independent prognostic factors in colorectal cancer patients.CONCLUSIONThe postoperative MLR in whole blood samples can be used as an independent prognostic factor in patients diagnosed with colorectal cancer.

Prognosis of Synchronous Colorectal Liver Metastases After Simultaneous Curative-Intent Surgery According to Primary Tumor Location and KRAS Mutational Status.

Tumor location and KRAS mutational status have emerged as prognostic factors of colorectal cancer. We aimed to define the prognostic impact of primary tumor location and KRAS mutational status among synchronous colorectal liver metastases (CRLM) patients who underwent simultaneous curative-intent surgery (SCIS). We compared the clinicopathologic characteristics and long-term outcomes of 227 patients who underwent SCIS for synchronous CRLM, according to tumor location and KRAS mutational status. We cross-classified tumor location and KRAS mutational status and compared survival outcomes between the four resulting patient groups. Forty-one patients (18.1%) had right-sided (RS) tumors and 186 (81.9%) had left-sided (LS) tumors. One-third of tumors (78/227) harbored KRAS mutations. The KRAS mutant-type (KRAS-mt) was more commonly observed among RS tumors than among LS tumors [21/41 (51.2%) vs. 57/186 (30.6%), p = 0.012]. Median follow-up time was 43.4months. Patients with RS tumors had shorter survival times than those with LS tumors [median disease-free survival (DFS): RS, 9.9months vs. LS, 12.1months, p = 0.003; median overall survival (OS): RS, 49.7months vs. LS, 88.8months, p = 0.039]. RS tumors were a negative prognostic factor for DFS [hazard ratio (HR) 1.878, p = 0.001] and OS (HR 1.660, p = 0.060). RS KRAS-mt and LS KRAS wild-type (KRAS-wt) tumors had the worst and best oncological outcomes, respectively. Tumor location has a prognostic impact in patients who underwent SCIS for CRLM, and RS KRAS-mt tumors yielded the worst oncological outcome. These results may allow for more tailored multimodality treatments.

Prognostic Significance of Immune Cell Populations Identified by Machine Learning in Colorectal Cancer Using Routine Hematoxylin and Eosin-Stained Sections.

Although high T-cell density is a well-established favorable prognostic factor in colorectal cancer, the prognostic significance of tumor-associated plasma cells, neutrophils, and eosinophils is less well-defined. We computationally processed digital images of hematoxylin and eosin (H&E)-stained sections to identify lymphocytes, plasma cells, neutrophils, and eosinophils in tumor intraepithelial and stromal areas of 934 colorectal cancers in two prospective cohort studies. Multivariable Cox proportional hazards regression was used to compute mortality HR according to cell density quartiles. The spatial patterns of immune cell infiltration were studied using the GTumor:Immune cell function, which estimates the likelihood of any tumor cell in a sample having at least one neighboring immune cell of the specified type within a certain radius. Validation studies were performed on an independent cohort of 570 colorectal cancers. Immune cell densities measured by the automated classifier demonstrated high correlation with densities both from manual counts and those obtained from an independently trained automated classifier (Spearman's ρ 0.71-0.96). High densities of stromal lymphocytes and eosinophils were associated with better cancer-specific survival [P trend < 0.001; multivariable HR (4th vs 1st quartile of eosinophils), 0.49; 95% confidence interval, 0.34-0.71]. High GTumor:Lymphocyte area under the curve (AUC0,20μm; P trend = 0.002) and high GTumor:Eosinophil AUC0,20μm (P trend < 0.001) also showed associations with better cancer-specific survival. High stromal eosinophil density was also associated with better cancer-specific survival in the validation cohort (P trend < 0.001). These findings highlight the potential for machine learning assessment of H&E-stained sections to provide robust, quantitative tumor-immune biomarkers for precision medicine.

Abstract 1520: RAB31 triggers oxaliplatin resistance in colorectal cancer via epithelial-mesenchymal transition

Abstract Colorectal tumorigenesis during Epithelial-Mesenchymal transition (EMT) is associated with cancer metastasis and drug resistance. The small G-proteins family has been implicated in the regulation of cell cytoskeleton, cell movement, and vesicle transport. Small G-proteins family is divided into five main families. The Rab protein family is a member of the Ras superfamily of small G-proteins. We analyzed all probes of the Rab family members from microarray datasets and RNA-sequencing. We further calculated the EMT scores by using an algorithm. Our results showed that the RAB31 expression levels of the three probes are positively correlated with EMT score (Pearson rho=0.72, 0.71 and 0.68, respectively). Compared with other family members, RAB31 had most significantly value in colorectal cancer cell lines. We established several two-way model with cDNA and shRNAs of RAB31, respectively. Furthermore, we observed that the expression of epithelial type marker CDH1 was inhibited, and mesenchymal type markers SNAI1 and SNAI2 were upregulated in RAB31 overexpression models. Moreover, we found that the protein level of RAB31 was correlated with several clinicopathological parameters (N status, M status) and disease-free survival in tissue arrays through immunohistochemistry staining. According to The Cancer Genome Atlas Program (TCGA) and online meta-database, high RNA level of RAB31 was consistent in colorectal cancer (HR=1.38, n=466 and HR=1.29, n=482) and correlated with poor prognosis of patients. In addition, we identified that RAB31 may associated with IC50 of oxaliplatin and EGFR trafficking. We concluded that RAB31 regulates the sensitivity of oxaliplatin, an additional chemotherapy strategy and an independent prognostic factor for colorectal cancer. Citation Format: Chi-Long Chen, Yu-Chan Chang, Michael Hsiao. RAB31 triggers oxaliplatin resistance in colorectal cancer via epithelial-mesenchymal transition [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1520.

Prognostic relevance of neuroendocrine differentiation in colorectal cancer: a population-based, propensity score matching study.

Neuroendocrine differentiation (NED) may serve as a prognostic factor in colorectal cancer; however, the prognostic relevance of NED remains controversial. The aim of the present study was to determine whether NED influenced the survival of patients in colorectal cancer while exploring its potential interactions with other clinicopathological features. Patients with primary stage I to IV colorectal adenocarcinoma ranging between 2010 and 2015 were identified using the Surveillance, Epidemiology, and End Results database. The Kaplan-Meier technique, Cox proportional hazards model, propensity score matching, and stratification analyses were employed in this study. A total of 94,291 patients (including 101 patients with NED and 94,190 patients without NED) were included. In the univariable analyses, NED was found to be correlated with a significantly poorer overall survival (hazard ratio (HR) of death = 3.09, 95% CI 2.42-3.95, P < 0.001) and cancer-specific survival (HR of death = 3.77, 95% CI 2.94-4.83, P < 0.001). Moreover, NED remained independently correlated with overall survival (HR of death = 1.84, 95% CI 1.34-2.51, P < 0.001) and cancer-specific survival (HR of death = 2.01, 95% CI 1.45-2.79, P < 0.001) after adjusting in multivariable and propensity score analyses. Furthermore, further stratification analyses indicated that the influence of NED on survival was not affected by tumor location, differentiation, T stage, and distant metastasis status; however, it was found to be associated with lymph node metastasis. NED is associated with poor survival outcomes among colorectal cancer patients, especially in those with positive lymph nodes.

Poorly differentiated clusters in colorectal cancer: a current review and implications for future practice.

Poorly differentiated clusters (PDC), defined as small groups of ≥5 tumour cells without glandular differentiation, have gained recent attention as a promising prognostic factor in colorectal cancer (CRC). Numerous studies have shown PDC to be significantly associated with other adverse histopathological features and worse clinical outcomes. PDC may hold particular promise in stage II colon cancer, where risk stratification plays a critical role in patient selection for adjuvant chemotherapy. In addition, emerging evidence suggests that PDC can predict lymph node metastasis in endoscopically resected pT1 CRC, potentially helping the selection of patients for oncological resection. In 'head-to-head' comparisons, PDC grade has consistently outperformed conventional histological grading systems both in terms of risk stratification and reproducibility. With a number of large-scale studies now available, this review evaluates the evidence regarding the prognostic significance of PDC, considers its relationship with other emerging invasive front prognostic markers (such as tumour budding and stroma type), assesses its 'practice readiness', addressing issues such as interobserver reproducibility, scoring methodologies and special histological subtypes (e.g. micropapillary and mucinous carcinoma), and draws attention to ongoing challenges and areas in need of further study. Finally, emerging data on the role of PDC in non-colorectal cancers are briefly considered.

Relationship of Preoperative Serum Uric Acid Level with Survival in Colorectal Cancer

To investigate the prognostic significance of uric acid level in colorectal cancer in addition to conventional factors in terms of survival. Observational Study. At the University of Health Sciences, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara, Turkey, between January 2012 and December 2019. Methodology: A total of selected 332 patients, who underwent surgery for colorectal cancer between 2012 and 2019, were retrospectively reviewed. Patients with a history of neoadjuvant therapy due to rectal cancer, GUT disease, renal failure, stage 4 disease, emergency surgery and severe preoperative infection, were excluded from the study. Peripheral blood samples were collected about a week before the operation. Serum uric acid (SUA) values were measured and recorded. Results: The patients comprised 198 males and 134 females with a mean age 62.2 ±11.7 years (14-91) years in total. Conventional surgery was performed in 228 patients, and laparoscopy in 104 patients. Uric acid level, number of pathological lymph nodes, number of pathological lymph nodes/total number of lymph nodes (LNO), perineural invasion, type of surgery and disease stage were found to be factors affecting the prognosis (p <0.05). Uric acid cut off value of 5.3 or higher was found to be statistically significant in terms of survival. Serum uric acid (SUA) value measured preoperatively was found to be a prognostic factor for colorectal cancer. Key Words: Serum uric acid (SUA), Colon cancer, Rectal cancer, Prognostic factor.

Leptin Overexpression as a Poor Prognostic Factor for Colorectal Cancer

Leptin acts as an adipocytokine functions via the leptin receptor, which stimulates growth, migration, and invasion of cancer cells. This study is aimed at identifying leptin as a prognostic factor in colorectal cancer (CRC). The differentially expressed genes with prognostic value in CRC tissues either with or without liver metastasis were assessed based on The Cancer Genomic Atlas (TCGA). Leptin was considered a candidate gene for further analysis. Its expression features of 206 CRC patients without liver metastasis and 201 patients with metastasis on tissue microarrays were assessed by immunochemical staining, and the effect of leptin on survival was assessed by Kaplan-Meier analyses. Overexpressed leptin indicated a poorer prognosis for CRC patients in overall survival (p < 0.05, log-rank test) based on the TCGA database. The leptin expression significantly correlated with metastasis stage (p < .010) and lymph node involvement (p < .010). Multivariate analysis also indicated that strong leptin expression was an independent adverse prognosticator in CRC (p = .017). Leptin may be valued as a prognostic marker could contribute to predicting a clinical outcome for patients with CRC.

CircFADS2: A potential prognostic biomarker of colorectal cancer.

Colorectal cancer (CRC) is the third most common malignancy worldwide with the second highest mortality rate. Although multidisciplinary cooperative therapies are helpful for improving the survival of CRC patients, the prognosis remains poor. Therefore, it is imperative to seek new biomarkers for the development of individualized treatment for each CRC patient. Circular RNA, an endogenous transcript with specific covalent closed loop, exhibits higher stability, conservation and expression abundance than the corresponding linear component and thus may be utilized as a promised biomarker. Although the majority of studies have focused on circular RNA expression profiling in various types of cancers, evidence supporting their critical role in the diagnosis and prognosis of CRC is limited. This study aimed to screen and identify novel circular RNA biomarkers of CRC by chip analysis and qPCR verification, and to highlight their potential as targets for CRC prognosis, and therapy.

Risk factors and predictors of lymph nodes metastasis and distant metastasis in newly diagnosed T1 colorectal cancer.

BackgroundLymph nodes metastasis (LNM) and distant metastasis (DM) are important prognostic factors in colorectal cancer (CRC) and determine the following treatment approaches. We aimed to find clinicopathological factors associated with LNM and DM, and analyze the prognosis of CRC patients with T1 stage.MethodsA total of 17 516 eligible patients with T1 CRC were retrospectively enrolled in the study based on the Surveillance, Epidemiology, and End Results (SEER) database during 2004‐2016. Logistic regression analysis was performed to identify risk factors for LNM and DM. Unadjusted and adjusted Cox proportional hazard models were used to identify prognostic factors for overall survival. We performed the cumulative incidence function (CIF) to further determine the prognostic role of LNM and DM in colorectal cancer‐specific death (CCSD). LNM, DM, and OS nomogram were constructed based on these models and evaluated by the C‐index and calibration plots for discrimination and accuracy, respectively. The clinical utility of the nomograms was measured by decision curve analyses (DCAs) and subgroups with different risk scores.ResultsTumor grade, mucinous adenocarcinoma, and age accounted for the first three largest proportion among the LNM nomogram scores (all, P < .001), whereas N stage, carcinoembryonic antigen (CEA), and tumor size occupied the largest percentage in DM nomogram (all, P < .001). OS nomogram was formulated to visually to predict 3‐, 5‐, and 10‐ year overall survivals for patients with T1 CRC. The calibration curves showed an effectively predictive accuracy of prediction nomograms, of which the C‐index were 0.666, 0.874, and 0.760 for good discrimination, respectively. DCAs and risk subgroups revealed the clinical effectiveness of these nomograms.ConclusionsNovel population‐based nomograms for T1 CRC patients could objectively and accurately predict the risk of LNM and DM, as well as OS for different stages. These predictive tools may help clinicians to make individual clinical decisions, before clinical management.

Transgelin is a poor prognostic factor associated with advanced colorectal cancer (CRC) stage promoting tumor growth and migration in a TGF\u03b2-dependent manner

Colorectal cancer (CRC) is the fourth most common cancer type globally. Investigating the signaling pathways that maintain cancer cell phenotype can identify new biomarkers for targeted therapy. Aberrant transforming growth factor-β (TGFβ) signaling has been implicated in CRC progression, however, the exact mechanism by which TGFβ exerts its function is still being unraveled. Herein, we investigated TAGLN expression, prognostic value, and its regulation by TGFβ in CRC. While TAGLN was generally found to be downregulated in CRC, elevated expression of TAGLN was associated with advanced CRC stage and predicted poor overall survival (hazard ratio (HR) = 1.8, log-rank test P-value = 0.014) and disease-free survival (HR = 1.6, log-rank test P-value = 0.046), hence implicating TAGLN as poor prognostic factor in CRC. Forced expression of TAGLN was associated with enhanced CRC cell proliferation, clonogenic growth, cell migration and in vivo tumor formation in immunocompromised mice, while targeted depletion of TAGLN exhibited opposing biological effects. Global gene expression profiling of TAGLN-overexpressing or TAGLN-deficient CRC cell lines revealed deregulation of multiple cancer-related genes and signaling pathways. Transmission electron microscopy (TEM) revealed ultrastructural changes due to loss of TAGLN, including disruption of actin cytoskeleton organization and aberrant actin filament distribution. Hierarchical clustering, principle component, and ingenuity pathway analyses revealed distinct molecular profile associated with TAGLNhigh CRC patients with remarkable activation of a number of mechanistic networks, including SMARCA4, TGFβ1, and P38 MAPK. The P38 MAPK was the top predicted upstream regulator network promoting cell movement through regulation of several intermediate molecules, including TGFβ1. Concordantly, functional categories associated with cellular movement and angiogenesis were also enriched in TAGLNhigh CRC, supporting a model for the molecular mechanisms linking TGFβ-induced upregulation of TAGLN and CRC tumor progression and suggesting TAGLN as potential prognostic marker associated with advanced CRC pathological stage.

S100 Staining Adds to the Prognostic Significance of the Combination of Perineural Invasion and Lymphovascular Invasion in Colorectal Cancer.

Studies have suggested that perineural invasion (PNI) and lymphovascular invasion (LVI) serve as independent prognostic factors in colorectal cancer (CRC). Currently, little is known regarding the combination of PNI and LVI as prognostic factors, independent of stage. We hypothesized that this combination was a better prognostic marker than either PNI or LVI alone, and that S100 staining would detect PNI not seen with hematoxylin and eosin (H&E). Surgical pathology slides were retrospectively reviewed for 151 stages I to IV CRC patients who had surgery between January 1, 2008 and December 8, 2008 at 3 Hackensack Meridian Health hospitals in New Jersey. PNI and LVI were detected by H&E staining and a subset of 127 patient samples were additionally examined for PNI by S100 staining. Correlation between staining characteristics and patient outcomes was assessed using the Pearson χ tests and the Fisher exact tests. Survival was analyzed using Kaplan-Meier methods. Of the 151 cases reviewed, 30.5% were positive for PNI and 35.1% were positive for LVI by H&E. The use of S100 staining for PNI enabled its detection in 27 additional cases. Median time from patient diagnosis to death was significantly shorter for patients who were positive for both PNI and LVI (P<0.001). PNI and LVI were individual markers for poor survival in CRC patients and their combined presence had an even worse outcome. Failure to detect PNI on H&E can be overcome by S100 staining.

ASPP1 deficiency promotes epithelial-mesenchymal transition, invasion and metastasis in colorectal cancer

The apoptosis-stimulating protein of p53 (ASPP) family of proteins can regulate apoptosis by interacting with the p53 family and have been identified to play an important role in cancer progression. Previously, we have demonstrated that ASPP2 downregulation can promote invasion and migration by controlling β-catenin-dependent regulation of ZEB1, however, the role of ASPP1 in colorectal cancer (CRC) remains unclear. We analyzed data from The Cancer Genome Atlas (TCGA) and coupled this to in vitro experiments in CRC cell lines as well as to experimental pulmonary metastasis in vivo. Tissue microarrays of CRC patients with information of clinical-pathological parameters were also used to investigate the expression and function of ASPP1 in CRC. Here, we report that loss of ASPP1 is capable of enhancing migration and invasion in CRC, both in vivo and in vitro. We demonstrate that depletion of ASPP1 could activate expression of Snail2 via the NF-κB pathway and in turn, induce EMT; and this process is further exacerbated in RAS-mutated CRC. ASPP1 could be a prognostic factor in CRC, and the use of NF-κB inhibitors may provide new strategies for therapy against metastasis in ASPP1-depleted CRC patients.

Low Claudin-1 Expression Has Association with Deep Invading and Higher-Grade Colorectal Adenocarcinoma

BackgroundClaudin-1 is a tight junction protein in the cell that organizes paracellular permeability and epithelial polarity and maintains apical cell-to-cell adhesion. Deregulation of claudin-1 homeostasis will play pivotal role in tumorigenesis, migration, and metastasis of colorectal cancer through a complex signaling pathway. This study investigated the association of claudin-1 expression and clinicopathological factors in colorectal adenocarcinoma. Methods This study was a cross-sectional study of 43 colorectal cancer patients. Each clinicopathological parameter data was divided into 2 categories; depth of tumor invasion (T3, T4), degree of tumor differentiation (low, high grade), tumor location (right, left), sex (man, woman) and age (&lt;60, ≥60 y.o). Claudin-1 expression was examined by the immunohistochemistry method and evaluated by H-Score method. The H-score cut off was determined by the mean value of 148. The difference of claudin-1 expression score with tumor depth invasion and age was analyzed by Independent t-test, and then the degree of differentiation, tumor location and sex were analyzed by Mann-Whitney. All variables were analyzed by the Chi-square analysis with a significance value of P&lt;.05.ResultsThere was a significant mean difference of claudin-1 expression between T3 and T4 tumors (P=.041; 95% CI 1.7-75.1). Tumor with low expression of claudin-1 was 2.5 times more likely to be found in tumor with invasion depth T4 rather than T3 (P=.023; 95% CI 1.5-48). In addition, tumor with low expression of claudin-1 was 0.2 times more likely to be found in the high-grade tumor (P=.001; 95% CI 0.07-0.4). Claudin-1 expression was not statistically significant in different tumor locations, sex and age group. ConclusionThere was mean difference in claudin-1 expression between T3 and T4 tumors, and between low- and high-grade tumors. The low claudin-1 expression is associated with tumor depth invasion and poorly differentiated tumors. Therefore, the use of claudin-1 as an additional prognostic factor in colorectal cancer is proposed.

Abnormal expression of ABCD3 is an independent prognostic factor for colorectal cancer.

ATP binding cassette subfamily D member 3 (ABCD3) is a member of the superfamily of ATP-binding cassette (ABC) transporters, which serve crucial roles in the process of tumor cell resistance to chemotherapy. The present study investigated the diagnostic and prognostic capabilities of ABCD3 in colorectal cancer (CRC) by bioinformatics analysis. Gene expression data and corresponding clinical information of patients with CRC were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The results demonstrated that ABCD3 mRNA level was decreased in CRC tissues compared with normal tissues following Wilcoxon test analysis. Furthermore, ABCD3 protein expression was significantly higher in normal colon tissues compared with colon adenocarcinoma tissues according to the Human Protein Atlas. In addition, the area under the Receiver Operating Characteristic curve based on comparison between the tumor and normal groups derived from TCGA and GEO databases demonstrated that the use of ABCD3 mRNA level may be used for the diagnosis of CRC. ABCD3 expression was significantly associated with clinical stage, T stage, and lymph node status following Kruskal-Wallis test or Wilcoxon rank sum test, logistic regression and χ2 test. Furthermore, the results from Kaplan-Meier survival analysis indicated that low ABCD3 mRNA expression had a poorer prognosis value compared with ABCD3 high expression in patients with CRC. In addition, results from univariate Cox regression analysis indicated that ABCD3 mRNA expression was associated with overall survival (OS), and results from multivariate Cox analysis indicated that ABCD3 mRNA expression may be considered an independent prognostic factor from other clinical factors, such as clinical stage, sex and age. The results from Gene Set Enrichment Analysis demonstrated that the ABCD3 high-expression phenotype was differentially enriched in five biological processes, including apoptosis, cell cycle, renal cell carcinoma, thyroid cancer and colorectal cancer. The findings from this study demonstrated that ABCD3 mRNA expression may be considered as a potential diagnostic and prognostic biomarker in patients with CRC. ABCD3 expression levels may participate in the regulation of cell apoptosis and cell cycle. In addition, GSEA analysis identified Kyoto Encyclopaedia of Genes and Genomes pathways for renal cell carcinoma, thyroid cancer and CRC involving ABCD3.

Prognostic factors for survival in colorectal cancer patients with brain metastases undergoing whole brain radiotherapy: multicenter retrospective study

Whole brain radiotherapy (WBRT) is a mainstay of the treatment for brain metastases (BM). We evaluated prognostic factors in colorectal cancer (CRC) patients undergoing WBRT for BM. The medical records of 106 CRC patients undergoing WBRT for BM between 2000 and 2014 at three institutions were reviewed. Patient and tumor factors were analyzed to identify the prognostic factors for overall survival (OS) calculated from the date of BM diagnosis to the date of death or last follow-up. Surgical resection of BM was performed in six patients. The dose of WBRT was 30 Gy, and boost radiotherapy or stereotactic radiosurgery (8–23 Gy) was given to 15 patients. Systemic therapy for BM was administered in one patient before WBRT and 26 patients after WBRT. The median follow-up time was 3.9 months (range, 0.4–114.1 months). The median OS time was 3.9 months, and the 1-year OS rate was 18.2%. Older age (>65 years), multiple BM (≥3), elevated level of carcinoembryonic antigen (CEA, >5 ng/ml) at BM diagnosis, and extracranial metastases were adverse prognostic factors for OS. Patient with 0–1 factor showed better OS (at 1 year, 76.9%) than patients with 2 factors (16.7%) or 3–4 factors (4.2%; p < 0.001). In conclusion, we evaluated age, the number of BM, CEA level, and extracranial metastases as the prognostic factors for OS in CRC patients undergoing WBRT. Our result might be useful to develop prognostic models predicting survival for patients whom WBRT is intended for.