scholarly journals Comprehensive Analysis of the Expression and Prognosis for MMPs in Human Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Jing Yu ◽  
Zhen He ◽  
Xiaowen He ◽  
Zhanhao Luo ◽  
Lei Lian ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Expression Patterns ◽  
Progression Free Survival ◽  
Tumor Stage ◽  
Clinicopathological Parameters ◽  
Online Tool ◽  
Protein Levels ◽  
Precision Therapy ◽  
Public Dataset ◽  
Pathway Analyses

BackgroundPrevious study implicated that genes of matrix metalloproteinase (MMP) family play an important role in tumor invasion, neoangiogenesis, and metastasis. However, the diverse expression patterns and prognostic values of 24 MMPs in colorectal cancer are yet to be analyzed.MethodsIn this study, by integrating public database and our data, we first investigated the expression levels and protein levels of MMPs in patients with colorectal cancer. Then, by using TCGA and GEO datasets, we evaluated the association of MMPs with clinicopathological parameters and prognosis of colorectal cancer. Finally, by using the cBioPortal online tool, we analyzed the alterations of MMPs and did the network and pathway analyses for MMPs and their nearby genes.ResultsWe found that, MMP1, MMP3, MMP7, MMP9–MMP12, and MMP14 were consistently upregulated in public dataset and our samples. Whereas, MMP28 was consistently downregulated in public dataset and our samples. In the clinicopathological analyses, upregulated MMP11, MMP14, MMP16, MMP17, MMP19, and MMP23B were significantly associated with a higher tumor stage. In the survival analyses, upregulated MMP11, MMP14, MMP17, and MMP19 were significantly associated with a shorter progression-free survival (PFS) time and a shorter relapse-free (RFS) time.DiscussionThis study implied that MMP11, MMP14, MMP17, and MMP19 are potential targets of precision therapy for patients with colorectal cancer.

FAK expression as a prognostic marker in colorectal cancer: A single institution study of 298 patients.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 623-623 ◽  
Author(s):  
Lindy Davis ◽  
Felicia Lenzo ◽  
Lourdes Ylagan ◽  
Angela Omilian ◽  
Kristopher Attwood ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Internal Control ◽  
Primary Tumor ◽  
Expression Patterns ◽  
Tumor Stage ◽  
Therapeutic Window ◽  
Single Institution ◽  
Normal Colon ◽  
Primary Tumors

623 Background: Focal adhesion kinase (FAK) is an attractive therapeutic target in solid cancers, but there is no method for patient selection based on FAK expression nor biomarker for therapeutic response. Previous FAK expression studies were not standardized and showed varying correlations. This single-institution study aims to define FAK expression patterns in colorectal cancer (CRC) and correlate with patient outcomes and expression in other solid cancers. Methods: We analyzed 635 samples from 298 patients (pt) with CRC using tissue microarrays (TMAs) stained for FAK and scored 0-3 by a single pathologist. The TMAs contained samples of 298 primary tumors with 290 matching normal tissue and 47 matching metastases. As an internal control, we examined FAK and outcomes in 135 breast cancer pt and 145 melanoma pt. FAK expression and pt outcomes were evaluated using Kruskal-Wallis exact and Wilcoxon signed-rank tests. Results: FAK expression correlated with aggressive phenotype in CRC primaries. Matching normal colon had lower FAK than primaries (Mean FAK 0.61 vs 1.87, p < 0.001). Higher primary tumor FAK was associated with higher tumor stage; the 88 T1-2 primaries had a mean FAK 1.54, compared to FAK 2.06 in the 99 T3-4 tumors (p < 0.001). There was no difference in FAK among Stage II-IV pt, nor between mean FAK in the primaries (1.87) versus metastases (1.73). When FAK was dichotomized as high vs low (high = FAK > 2), high primary tumor FAK was associated with shorter overall survival (OS). Median OS was 91 months (95% CI 73-130) in high FAK (n = 122 pt) vs 155 months (95% CI 124-196) in low FAK (n = 176 pt), p = 0.007. The OS rates at 5 and 10 years in high FAK were 65% and 43%, vs 79% and 61% in low FAK. FAK in CRC metastases did not correlate with OS (p = 0.945). In contrast, when CRC was compared to breast cancer and melanoma, FAK did not show the same correlations in outcome. Conclusions: For the first time, by standardizing FAK quantification, we have identified that FAK expression in the primary correlates with outcome in CRC. These data may have implications in selection of patients for adjuvant therapy. Normal colon and earlier stage CRC had lower FAK expression compared to more advanced stages, suggesting a therapeutic window for FAK as a target.

Tumor associated macrophages to predict the efficacy of bevacizumab plus chemotherapy in patients with advanced colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15103-e15103
Author(s):  
Hakan Akbulut ◽  
Fatma Sena Dost Gunay ◽  
Bilge Ayca Kirmizi ◽  
Elif Berna Koksoy ◽  
Arzu Ensari ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Combination Chemotherapy ◽  
Tumor Tissue ◽  
Advanced Colorectal Cancer ◽  
Univariate Analysis ◽  
Neuroendocrine Differentiation ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Clinicopathological Parameters ◽  
Histologic Subtype

e15103 Background: The tumor-associated macrophage (TAM) is one of the major components of tumor microenvironment. Neuroendocrine differentiation (NED) of the tumor has been linked to poor prognosis. We aimed to investigate the role of TAM infiltration and NED in tumor tissue on the efficacy of bevacizumab plus chemotherapy in patients with advanced colorectal cancer. Methods: A total of 123 consecutive patients with advanced colorectal cancer treated with bevacizumab plus either irinotecan or oxaliplatin-based combination chemotherapy were included in the study. Along with clinicopathological parameters including age, tumor location (right versus left colon), pretreatment CEA level, KRAS mutation status, tumor grade, histologic subtype (mucinous vs non-mucinous), the presence of NED and the level of TAM infiltration were studied as covariates for survival analysis. The patients with at least 2% or more staining with either synaptophysin or chromogranin A were regarded as NED positive. The +2 or less staining with anti-CD68 was regarded as low for TAM infiltration and +3 or +4 staining as high. The overall (OS) and progression-free survival (PFS) times were calculated from the start of bevacizumab. Results: Thirty-five percent of the patients were given bevacizumab in the first line setting, the others mainly at the second line. The chemo backbone was FOLFIRI in 75% of the patients. The median OS was 15,1 and PFS 7,1 months. The ratio of NED negative and TAM infiltration low patients were 73,9% and 13,8 %, respectively. The univariate analysis yielded only the NED and higher TAM infiltration as the significant factors for PFS. However, only NED was significant for PFS in the multivariate analysis (HR:0.542). The left-sided tumors and the low levels of TAM infiltration were the favorable factors for OS in the univariate analysis. However, the TAM level was the only independent factor predicting the OS (26,7±8,8 vs 14,1±1,7 months, respectively; HR: 0,301). Conclusions: Our results suggest that the TAM infiltration in the tumor tissue could be used as a predictive marker of efficacy of bevacizumab plus combination chemotherapy in patients with advanced colorectal cancer.

scholarly journals Osteopontin Overexpression Induced Tumor Progression and Chemoresistance to Oxaliplatin through Induction of Stem-Like Properties in Human Colorectal Cancer

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Lui Ng ◽  
Timothy Wan ◽  
Ariel Chow ◽  
Deepak Iyer ◽  
Johnny Man ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cell ◽  
Poor Prognosis ◽  
Cancer Metastasis ◽  
Tumor Stage ◽  
Clinicopathological Parameters ◽  
Stem Cell Markers ◽  
Cell Markers ◽  
Response To Chemotherapy

Colorectal cancer (CRC) is one of the most common and fatal malignancies worldwide. The poor prognosis of colorectal cancer patients is due to development of chemoresistance and cancer metastasis. Recently osteopontin (OPN) has been associated with stem-like properties in colorectal cancer. This study further examined the clinicopathological significance of OPN in CRC and its effect on chemoresistance and transcription of stem cell markers. We examined the transcription level of OPN in 84 CRC patients and correlated the expression with their clinicopathological parameters. The associations of OPN overexpression with transcription of stem cell markers and response to chemotherapy in DLD1-OPN overexpressing clones and CRC patients were also investigated. Our results showed that OPN was significantly overexpressed in CRC, and its overexpression correlated with tumor stage and poor prognosis. Overexpression of CRC induced OCT4 and SOX2 expressionin vitroand correlated with SOX2 overexpression in CRC patients. In addition, DLD1-OPN overexpressing cells showed enhanced ability to survive upon oxaliplatin treatment, and OPN expression was higher in CRC patients who were resistant to oxaliplatin-involved chemotherapy treatment. Thus, CRC cells overexpressing OPN demonstrated stem-like properties and OPN inhibition is a potential therapeutic approach to combat CRC progression and chemoresistance.

scholarly journals Expressions of TWIST1 and CD105 markers in colorectal cancer patients and their association with metastatic potential and prognosis

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Fahimeh Fattahi ◽  
Leili Saeednejad Zanjani ◽  
Somayeh Vafaei ◽  
Zohreh Habibi Shams ◽  
Jafar Kiani ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endothelial Cells ◽  
Epithelial Cells ◽  
Tumor Cells ◽  
Progression Free Survival ◽  
Distant Metastases ◽  
Clinicopathological Parameters ◽  
Tissue Samples ◽  
Mesenchymal Transition ◽  
Nuclear Expression

Abstract Background TWIST1 and CD105, which contribute to tumor malignancy, are overexpressed in cancers. Accordingly, TWIST1 enhances epithelial-to-mesenchymal transition (EMT) and promotes the formation of cancer stem cells (CSCs). Also, CD105 is a neoangiogenesis marker in endothelial cells, which is introduced as a CSC marker in tumoral epithelial cells in several types of cancers. The present study was aimed to investigate expressions of TWIST1 and CD105 in colorectal cancer (CRC) patients. Methods Expressions of TWIST1 and CD105 in 250 CRC tissue samples were evaluated using immunohistochemistry on tissue microarrays (TMAs). In this regard, TWIST1 expression was investigated in the subcellular locations (cytoplasm and nucleus), while CD105 was mapped in endothelial cells and cytoplasmic tumor cells of CRC tissues. The association between the expression of these markers and clinicopathological parameters, as well as survival outcomes were analyzed. Results Results indicate a statistically significant association between higher nuclear expression levels of TWIST1 and distant metastases in CRC (P = 0.040) patients. In addition, it was shown that the increased nuclear expression of TWIST1 had a poor prognostic value for disease-specific survival (DSS) and progression-free survival (PFS) (P = 0.042, P = 0.043, respectively) in patients with CRC. Moreover, analysis of CD105 expression level has revealed that there is a statistically significant association between the increased expression of CD105 in tumoral epithelial cells and more advanced TNM stage (P = 0.050). Conclusions Our results demonstrate that nuclear TWIST1 and cytoplasmic CD105 expressions in tumor cells had associations with more aggressive tumor behavior and more advanced diseases in CRC cases.

scholarly journals B7-H4 Expression is Upregulated by PKCδ Activation and Contributes to PKCδ-Induced Cell Mobility in Colorectal Cancer

2021 ◽  
Author(s):  
Bin Zhou ◽  
Youwei Lu ◽  
Zhiming Zhao ◽  
Tongguo Shi ◽  
Hongya Wu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Expression Patterns ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Colorectal Tumour ◽  
Protein Levels ◽  
Cell Mobility ◽  
Unknown Protein ◽  
Poor Differentiation

Abstract Background B7-H4 is overexpressed in colorectal cancer (CRC) and plays important roles in tumour growth and immunosuppression. However, the exact mechanism that regulates B7-H4 expression remains largely unknown. Protein kinase δ (PKCδ) plays a significant role in a range of cancers, including CRC. Here, we investigated whether PKCδ regulates the expression of B7-H4 in CRC.Methods By using immunohistochemical and immunofluorescence (IF) staining, we analysed the expression of B7-H4 and phospho-PKCδ (p-PKCδ) in 225 colorectal tumour samples, and the clinical significance of these expression patterns was determined. In vitro experiments were performed with the CRC cell lines HCT116 and SW620 to detect the effect of PKCδ activation on B7-H4 expression.Results B7-H4 expression was significantly correlated with p-PKCδ expression (r=0.378, P<0.001) in tumour tissues. The co-expression of p-PKCδ and B7-H4 was significantly associ­ated with moderate/poor differentiation (P=0.024), lymph node metastasis (P=0.001) and an advanced Dukes’ stage (P=0.002). Western blot analysis showed that TPA increased B7-H4 levels in a concentration-dependent manner and rottlerin also abrogated TPA-induced B7-H4 enhancement. The expression of B7-H4 and p-STAT3 were significantly reduced by PKCδ-specific siRNA. Moreover, STAT3 inhibitor cryptotanshinone significantly decreased B7-H4 protein levels in HCT116 cells. Knockdown of B7-H4 or PKCδ expression suppressed cell migration and mobility.Conclusion B7-H4 expression was significantly correlated with p-PKCδ expression in CRC samples. B7-H4 expression was upregulated by STAT3 activation via PKCδ and played roles in PKCδ-induced cancer cell mobility and metastasis.

scholarly journals Clinical Significance of Serum Glutamine Level in Patients with Colorectal Cancer

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 898 ◽  
Author(s):  
Hang Huong Ling ◽  
Yi-Ping Pan ◽  
Chung-Wei Fan ◽  
Wen-Ko Tseng ◽  
Jen-Seng Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Significance ◽  
Progression Free Survival ◽  
Clinicopathological Characteristics ◽  
Prognostic Scores ◽  
Baseline Serum ◽  
Glutamine Level ◽  
Independent Prognostic Marker ◽  
Protein Levels ◽  
Pretreatment Serum

Limited studies have assessed the associations of pretreatment serum glutamine level with clinicopathological characteristics and prognosis of colorectal cancer (CRC) patients. This study focuses on clarifying the clinical significance of baseline serum glutamine level in CRC patients. We retrospectively examine 123 patients with newly diagnosed CRC between 2009 and 2011. The associations of pretreatment serum glutamine level with clinicopathological characteristics, proinflammatory cytokines, overall survival (OS), and progression-free survival (PFS) were analyzed. We executed univariate and multivariate analyses to assess the associations between serum glutamine level and clinicopathological variables able to predict survival. Low glutamine levels were associated with older age, advanced stage, decreased albumin levels, elevated carcinoembryonic antigen levels, higher C-reactive protein levels, higher modified Glasgow prognostic scores, and higher proinflammatory cytokine levels. Furthermore, patients with low glutamine levels had poorer OS and PFS than those with high glutamine levels (p < 0.001 for both). In multivariate analysis, pretreatment glutamine level independently predicted OS (p = 0.016) and PFS (p = 0.037) in CRC patients. Pretreatment serum glutamine level constitutes an independent prognostic marker to predict survival and progression in CRC patients.

scholarly journals Neonatal Nav1.5 Protein Expression in Human Colorectal Cancer: Immunohistochemical Characterization and Clinical Evaluation

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3832
Author(s):  
Elena Lastraioli ◽  
Scott P. Fraser ◽  
R. Mine Guzel ◽  
Jessica Iorio ◽  
Lapo Bencini ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Protein Expression ◽  
Expression Patterns ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Normal Mucosa ◽  
Free Survival ◽  
Human Carcinomas ◽  
Clinical Biomarker ◽  
High Level

Voltage-gated Na+ channels (VGSCs) are expressed widely in human carcinomas and play a significant role in promoting cellular invasiveness and metastasis. However, human tissue-based studies and clinical characterization are lacking. In several carcinomas, including colorectal cancer (CRCa), the predominant VGSC is the neonatal splice variant of Nav1.5 (nNav1.5). The present study was designed to determine the expression patterns and clinical relevance of nNav1.5 protein in human CRCa tissues from patients with available clinicopathological history. The immunohistochemistry was made possible by the use of a polyclonal antibody (NESOpAb) specific for nNav1.5. The analysis showed that, compared with normal mucosa, nNav1.5 expression occurred in CRCa samples (i) at levels that were significantly higher and (ii) with a pattern that was more delineated (i.e., apical/basal or mixed). A surprisingly high level of nNav1.5 protein expression also occurred in adenomas, but this was mainly intracellular and diffuse. nNav1.5 showed a statistically significant association with TNM stage, highest expression being associated with TNM IV and metastatic status. Interestingly, nNav1.5 expression co-occurred with other biomarkers associated with metastasis, including hERG1, KCa3.1, VEGF-A, Glut1, and EGFR. Finally, univariate analysis showed that nNav1.5 expression had an impact on progression-free survival. We conclude (i) that nNav1.5 could represent a novel clinical biomarker (‘companion diagnostic’) useful to better stratify CRCa patients and (ii) that since nNav1.5 expression is functional, it could form the basis of anti-metastatic therapies including in combination with standard treatments.

scholarly journals The Expression Profiles and Clinical Significance of PKM2 and Notch1 in Colorectal Cancer

2021 ◽  
Author(s):  
Jia Wang ◽  
Meijuan Sun ◽  
Wenlong Du ◽  
Yuanxian Guo ◽  
Jiebin Pan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Western Blot ◽  
Expression Profiles ◽  
Immunohistochemical Analysis ◽  
Tumor Stage ◽  
Expression Levels ◽  
Protein Levels ◽  
Disease Occurrence ◽  
Mrna And Protein Expression ◽  
And Migration

Abstract Background Studies have shown that pyruvate kinase M2 (PKM2) and Notch1 are highly expressed in colorectal cancer (CRC) tissues and have a certain relationship with disease occurrence and development. The expression levels of PKM2 and Notch1 are also related to the effect of chemotherapy and radiotherapy, which seriously influence the prognosis of CRC patients. Thus, both PKM2 and Notch1 have been identified as key targets of CRC treatment and research. However, correlations between PKM2 and Notch1 have not yet been established. Methods Immunohistochemical analysis was conducted to detect the expression of PKM2 and Notch1 in CRC tissues. The mRNA and protein expression levels of PKM2 and Notch1 in CRC cell lines were detected by quantitative real-time fluorescence polymerase chain reaction (qRT-PCR) and western blot analysis, respectively. Compound 3K and tangeretin (TGN) were used to inhibit the expression of PKM2 and Notch1, respectively. The proliferation and migration of cancer cells in each group were detected with the CCK-8 and wound healing assays. Results The Immunohistochemical analysis showed that PKM2 and Notch1 were highly expressed in CRC and related to tumor stage and lymph node metastasis. The qRTPCR and western blot results showed that PKM2 and Notch1 were notably upregulated in CRC cells both at the mRNA and protein levels. PKM2 and Notch1 form a positive feedback loop to promote the occurrence and development of CRC, and inhibition of PKM2 and Notch1 has a synergistic effect on the proliferative and invasive capabilities of CRC cells. Conclusion The combination of the PKM2 inhibitor compound 3K and the Notch1 inhibitor TGN presents a novel and effective strategy for treatment of CRC.

scholarly journals IDO1/COX2 Expression Is Associated With Poor Prognosis In Colorectal Cancer Liver Oligo-metastases

2020 ◽  
Author(s):  
Wenjuan Ma ◽  
Xing Wang ◽  
Lulu Wang ◽  
Tinglan Chen ◽  
Shanshan Hu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Biomarker ◽  
Cox Model ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Clinicopathological Parameters ◽  
Free Survival ◽  
Cell Responses ◽  
N Stage ◽  
Cox2 Expression

Abstract Background: IDO1 and COX2 have emerged as promising immunotherapy targets, and their inhibitors could enhance T cell responses to tumor cells. Whether IDO1 and COX2 expression in colorectal cancer (CRC) patients with liver oligometastases could be an independent predictor for overall survival (OS) and progression-free survival (PFS) is unclear. The purpose of this study was to investigate the correlation of IDO1 and COX2 expression with OS and PFS in CRC patients with liver oligometastases.Methods: The expression levels of IDO1 and COX2 were assessed by immunohistochemistry in 107 specimens from patients with liver oligometastases. The correlation between the expression of IDO1 and COX2 and the clinicopathological parameters and OS/PFS in patients was examined.Results: The expression level of IDO1/COX2 was significantly correlated with age and was not associated with gender, BMI, T stage, N stage, primary tumor size, liver metastasis size, CEA, CA19-9, CD3 TILs or CD8 TILs. In univariate analysis, we found that IDO1/COX2 expression, CEA and N stage all yielded significantly poor OS and PFS outcomes. In our multivariate Cox model, IDO1/COX2 coexpression, CEA and N stage were found to be significantly correlated with OS; IDO1/COX2 coexpression and CEA were significantly correlated with PFS.Conclusions: IDO1/COX2 coexpression has a pivotal role and may act as a potential prognostic biomarker for survival in CRC patients with liver oligometastases.

scholarly journals microRNA-451a regulates colorectal cancer radiosensitivity

2017 ◽  
Author(s):  
Rebecca Ruhl ◽  
Shushan Rana ◽  
Katherine Kelley ◽  
Cristina Espinosa-Diez ◽  
Clayton Hudson ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Xenograft Model ◽  
Standard Of Care ◽  
Tumor Stage ◽  
Radiation Sensitivity ◽  
Small Subset ◽  
Cancer Dataset ◽  
Protein Levels ◽  
Dose Fraction ◽  
Specific Mrnas

Colorectal cancer (CRC) is a leading cause of cancer-related death. The responses of CRC to standard of care adjuvant therapies such as radiation or chemotherapy are poorly understood. MicroRNAs (miRs) are small non-coding RNAs that affect gene expression programs in cells by downregulating specific mRNAs. In this study, we discovered a set of microRNAs upregulated rapidly in response to a single 2 Gy dose fraction of γ-radiation in a mouse colorectal carcinoma xenograft model. The most upregulated candidate in our signature, miR-451a inhibits tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes-CAB39, EMSY, MEX3C and EREG as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was decreased with tumor stage in a small subset of CRC patients. Finally, analysis of a TCGA colorectal cancer dataset reveals that the CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients and correlates with poorer overall survival. Taken together, our data indicates miR-451a influences the radiation sensitivity of colorectal carcinomas.

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