Relationship of Src activity and prior oxaliplatin on outcomes after hepatectomy for metastatic colorectal cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3561-3561
Author(s):  
Van Karlyle Morris ◽  
Nila Parikh ◽  
Michael J. Overman ◽  
Zhi-Qin Jiang ◽  
Dipen M Maru ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Automated Image Analysis ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Nonreceptor Tyrosine Kinase ◽  
Mesenchymal Transition ◽  
Before And After

3561 Background: The nonreceptor tyrosine kinase Src regulates pathways critical to tumor proliferation, chemoresistance, and epithelial-to-mesenchymal transition. In vitro, Src is activated after acute oxaliplatin exposure and in acquired oxaliplatin resistance, but not after 5-FU alone. Activation of Src and its substrate FAK in metastatic colorectal cancer treated with oxaliplatin has not been studied in human specimens. Methods: Samples from 170 hepatic resections from two cohorts of patients with metastatic colorectal cancer were examined by IHC for expression of activated Src (pSrc) and FAK (total and pFAK). In the first cohort (n=50), tissue was collected at consecutive hepatic resections before and after oxaliplatin. Patients in the second cohort (n=120) were compared based on whether or not oxaliplatin was administered after resection. IHC was graded semi-quantitatively, 0 to 4 based on intensity (first cohort), and by automated image analysis (second cohort). Results: In the first cohort, pFAK expression increased after oxaliplatin exposure (mean IHC score 2.04 vs. 1.18, p<0.01). In the second cohort, Src activation was correlated with pFAK expression (p<0.01). Patients pretreated with oxaliplatin demonstrated increased expression of activated FAK (p=0.02) compared to 5-FU alone or irinotecan regimens. There was a weak association between total Src expression and the number of oxaliplatin cycles (p=0.06). Among patients in the second cohort, five-year relapse-free survival was inversely related to levels of pFAK (21.1%, 16.5%, and 7.4% for low, medium, and high levels of pFAK, respectively; p=0.02) and of pSrc (19.6%, 13.6%, and 8.2% for low, medium, and high levels of pSrc, respectively; p= 0.01). Conclusions: Patients treated with neoadjuvant oxaliplatin demonstrated increased Src signaling in liver metastases, a finding associated with worse relapse-free survival. These results are consistent with prior in vitro studies correlating oxaliplatin exposure with Src pathway activation and support the idea that inhibition of Src, when used in combination with platinum chemotherapy, warrants further investigation in patients with metastatic colorectal cancer.

scholarly journals Lessons to Learn for Adequate Targeted Therapy Development in Metastatic Colorectal Cancer Patients

2021 ◽  
Vol 22 (9) ◽  
pp. 5019
Author(s):  
Helena Oliveres ◽  
David Pesántez ◽  
Joan Maurel
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Tyrosine Kinases ◽  
Epithelial To Mesenchymal Transition ◽  
Acquired Resistance ◽  
Post Translational Modification ◽  
Mesenchymal Transition ◽  
Igf1r Signaling ◽  
Colorectal Cancer Patients

Insulin-like growth factor 1 receptor (IGF1R) is a receptor tyrosine kinase that regulates cell growth and proliferation. Upregulation of the IGF1R pathway constitutes a common paradigm shared with other receptor tyrosine kinases such as EGFR, HER2, and MET in different cancer types, including colon cancer. The main IGF1R signaling pathways are PI3K-AKT and MAPK-MEK. However, different processes, such as post-translational modification (SUMOylation), epithelial-to-mesenchymal transition (EMT), and microenvironment complexity, can also contribute to intrinsic and acquired resistance. Here, we discuss new strategies for adequate drug development in metastatic colorectal cancer patients.

Tanshinone IIA Inhibits Epithelial-to-mesenchymal Transition Through Regulating β-arrestin1 Mediated β-catenin Signaling Pathway in Colorectal Cancer

2020 ◽  
Author(s):  
Qing Song ◽  
Liu Yang ◽  
Zhifen Han ◽  
Xinnan Wu ◽  
Ruixiao Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Western Blot ◽  
Signaling Pathway ◽  
Lung Metastasis ◽  
Nude Mice ◽  
Epithelial To Mesenchymal Transition ◽  
Tanshinone Iia ◽  
Mesenchymal Transition

Abstract Background: Tanshinone IIA (Tan IIA) is a major active ingredient extracted from Salvia miltiorrhiza, which has been proved to inhibit metastasis of various cancers including colorectal cancer (CRC). However, the detailed mechanisms of Tan IIA against CRC metastasis are not well explored. Epithelial-to-mesenchymal transition (EMT) exerts an important regulatory role in CRC metastasis, and our previous mechanism studies demonstrated that β-arrestin1 could regulate CRC EMT partly through β-catenin signaling pathway. Therefore, in this work we investigated whether Tan IIA could regulate CRC EMT through β-arrestin1-mediated β-catenin signaling pathway in vivo and in vitro.Methods: The nude mice tail vein metastasis model was established to observe the effect of Tan IIA on CRC lung metastasis in vivo. The lung metastasis was evaluated by living animal imaging and hemaoxylin-eosin staining. The migratory ability of CRC cells in vitro were measured by transwell and wound healing assays. The protein expression and cellular localization of β-arrestin1 and β-catenin were characterized by immunofluorescence staining and western blot. The β-catenin signaling pathway related proteins and EMT associated proteins in CRC cells were detected by western blot and immunohistochemistry. Results: Our results showed that Tan IIA inhibited the lung metastases of CRC cells in vivo and extended the survival time of nude mice. In vitro, Tan IIA increased the expression of E-cadherin, decreased the secretion of Snail, N-cadherin and Vimentin, thus suppressed EMT and the migratory ability of CRC cells. Further study found the mechanism involving in Tan IIA regulating EMT and metastasis, referring to the suppression of β-arrestin1 expression, reduction of β-catenin nuclear localization, thereby the decreased activity of β-catenin signaling. Conclusion: Our data revealed a new mechanism of Tan IIA on the suppression of EMT and metastasis in CRC via β-arrestin1-mediated β-catenin signaling pathway, and provided support for Tan IIA as anti-metastatic agents in CRC.

scholarly journals Circulating inflammation signature predicts overall survival and relapse-free survival in metastatic colorectal cancer

2019 ◽  
Vol 120 (3) ◽  
pp. 340-345 ◽  
Author(s):  
Andreas Varkaris ◽  
Anastasia Katsiampoura ◽  
Jennifer S. Davis ◽  
Neeraj Shah ◽  
Michael Lam ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Metastatic Colorectal Cancer ◽  
Relapse Free Survival ◽  
Free Survival

scholarly journals Thrombomodulin Influences the Survival of Patients with Non-Metastatic Colorectal Cancer through Epithelial-To-Mesenchymal Transition (EMT)

PLoS ONE ◽  
2016 ◽  
Vol 11 (8) ◽  
pp. e0160550 ◽  
Author(s):  
Yu-Jia Chang ◽  
Ya-Wen Cheng ◽  
Ruo-Kai Lin ◽  
Chi-Chou Huang ◽  
William Tzu-Liang Chen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition

scholarly journals LncRNA TUG1 promotes the progression of colorectal cancer via the miR-138-5p/ZEB2 axis

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Zhenkun Yan ◽  
Miaomiao Bi ◽  
Qiyu Zhang ◽  
Yumei Song ◽  
Sen Hong
Keyword(s):  
Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Area Under The Curve ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Diagnosis And Prognosis ◽  
Non Coding Rna ◽  
Tissue Specimens

Abstract To explore the role of long-chain non-coding RNA (lncRNA) taurine up-regulated gene 1 (TUG1) in the development of colorectal cancer (CRC) via the miR-138-5p/zinc finger E-box-binding homeobox 2 (ZEB2) axis. Eighty-four CRC tissue specimens and 84 corresponding paracancerous tissue specimens were sampled from 84 patients with CRC admitted to the First Hospital of Jilin University from January 2018 to September 2019. The TUG1 expression in the specimens was determined, and its value in diagnosis and prognosis of CRC was analyzed. Additionally, constructed stable and transient overexpresison vectors and inhibition vectors were transfected into CRC cells. The MTT, transwell, and flow cytometry were adopted for analysis on the proliferation, invasion, and apoptosis of transfected cells, respectively, and a dual luciferase reporter (DLR) assay was carried out for correlation determination between TUG1 and miR-138-5p and between miR-138-5p and ZEB2. TUG1 was up-regulated in CRC, and serum TUG1 could be adopted as a diagnostic marker of CRC, with area-under-the-curve (AUC) larger than 0.8. In addition, siRNA-TUG1, shRNA-TUG1, miR-138-5p-mimics, and miR-138-5p-inhibitor were transfected into cells, and it turned out that overexpressing miR-138-5p and inhibiting ZEB2 exerted the same effects. The DLR assay revealed that TUG1 was able to targetedly regulate miR-138-5p, and miR-138-5p could targetedly regulate ZEB2, and in vitro experiments revealed that TUG1 could affect the epithelial-to-mesenchymal transition (EMT) of CRC via the miR-138-5p/ZEB2 axis. TUG1 could promote the development of CRC via the miR-138-5p/ZEB2 axis.

scholarly journals A Claudin-Based Molecular Signature Identifies High-Risk, Chemoresistant Colorectal Cancer Patients

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2211
Author(s):  
Saiprasad Gowrikumar ◽  
Mark Primeaux ◽  
Kristina Pravoverov ◽  
Chao Wu ◽  
Bryan C. Szeglin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Epithelial To Mesenchymal Transition ◽  
Standard Of Care ◽  
Integrated Approach ◽  
Molecular Signature ◽  
Molecular Characteristics ◽  
Mesenchymal Transition ◽  
Cancer Phenotypes

Identifying molecular characteristics that are associated with aggressive cancer phenotypes through gene expression profiling can help predict treatment responses and clinical outcomes. Claudins are deregulated in colorectal cancer (CRC). In CRC, increased claudin-1 expression results in epithelial-to-mesenchymal transition and metastasis, while claudin-7 functions as a tumor suppressor. In this study, we have developed a molecular signature based on claudin-1 and claudin-7 associated with poor patient survival and chemoresistance. This signature was validated using an integrated approach including publicly available datasets and CRC samples from patients who either responded or did not respond to standard-of-care treatment, CRC cell lines, and patient-derived rectal and colon tumoroids. Transcriptomic analysis from a patient dataset initially yielded 23 genes that were differentially expressed along with higher claudin-1 and decreased claudin-7. From this analysis, we selected a claudins-associated molecular signature including PIK3CA, SLC6A6, TMEM43, and ASAP-1 based on their importance in CRC. The upregulation of these genes and their protein products was validated using multiple CRC patient datasets, in vitro chemoresistant cell lines, and patient-derived tumoroid models. Additionally, blocking these genes improved 5-FU sensitivity in chemoresistant CRC cells. Our findings propose a new claudin-based molecular signature that associates with poor prognosis as well as characteristics of treatment-resistant CRC including chemoresistance, metastasis, and relapse.

Circular RNA hsa_circ_0001178 facilitates the invasion and metastasis of colorectal cancer through upregulating ZEB1 via sponging multiple miRNAs

2020 ◽  
Vol 401 (4) ◽  
pp. 487-496 ◽  
Author(s):  
Chunfeng Ren ◽  
Zhenmin Zhang ◽  
Shunhua Wang ◽  
Weitao Zhu ◽  
Peiguo Zheng ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Underlying Mechanism ◽  
Circular Rna ◽  
Mechanistic Study ◽  
Mesenchymal Transition ◽  
Promising Treatment

AbstractMetastasis is the main cause of increasing cancer morbidity and mortality. However, the underlying mechanism of cancer metastasis remains largely unknown. In the present study, we identified one circular RNA (circRNA) closely related to the metastasis of colorectal cancer (CRC), namely hsa_circ_0001178. CRC patients with high hsa_circ_0001178 were more prone to have metastatic clinical features, advanced TNM stage and adverse prognosis. Stable knockdown of hsa_circ_0001178 significantly weakened CRC cell migratory and invasive capabilities in vitro as well as lung and liver metastases in vivo. Mechanistic study revealed that hsa_circ_0001178 acted as a competing endogenous RNA (ceRNA) for miR-382/587/616 to upregulate ZEB1 (a key trigger of epithelial-to-mesenchymal transition), thereby promoting CRC metastatic dissemination. Of note, ZEB1 could also increase hsa_circ_0001178 expression via physically binding to hsa_circ_0001178 promoter region. Collectively, our data uncover the crucial role of hsa_circ_0001178 in CRC metastasis, and targeted therapy based on this positive feedback ceRNA axis may be a promising treatment for metastatic CRC patients.

MicroRNA regulation of radiation sensitivity in colorectal cancers.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 608-608
Author(s):  
Shushan Rajesh Rana ◽  
Katherine Kelley ◽  
Rebecca Ruhl ◽  
Charles R. Thomas ◽  
Vassiliki Liana Tsikitis ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Locally Advanced ◽  
Radiation Sensitivity ◽  
Colorectal Cancers ◽  
Specific Gene ◽  
Mesenchymal Transition

608 Background: Patients with locally advanced colorectal cancer (T3/T4/Node positive) receive neoadjuvant chemoradiation therapy (CRT) and subsequent surgery. While 10-25% of patients have complete response to CRT, the remaining patients undergo extensive tumor excision that leads to quality of life issues. Response to CRT is an independent predictor of overall survival highlighting the importance of improving CRT response rates. Several tumor intrinsic factors govern responses to CRT including specific gene expression programs. Emerging evidence suggests that microRNAs (miRs) modulate gene expression programs in response to radiation. Moreover, miR-processing machinery is frequently mutated in colorectal cancers (TCGA, 2016 provisional). miRs have been implicated in several pathological processes associated with colorectal cancer progression including cancer stemness and epithelial-to-mesenchymal transition (EMT). In this context, we hypothesized that differential expression of miRs regulates colorectal cancer radiation sensitivity and therefore can be used as a biomarker to predict therapeutic responses to radiation. Methods: To investigate the differences in miR profiles between rectal cancer patients that had either a pathological partial response (PR) or no response (NR), we isolated RNA from FFPE biopsies using the miRvana microRNA isolation kit (Life Technologies). We used the Nanostring miR profiling platform and obtained absolute counts for > 700 human miRs of which ~500 miRs were expressed above detection limits (cut-off of 20 counts after normalization to the top-100 miRs). We performed in vitro gain and loss of studies with miR transfections in human CRC cell lines with RNAimax reagent and used a luminescence-based assay for proliferation (Cell titer glo, Promega). We performed surviving fraction assays by seeding cells on 6 well plate and counting colonies stained with Methylene Blue. Results: We identified seventeen miRs that were differentially expressed. Among the most upregulated in this group, miR-451a, inhibited proliferation and colony formation in 2D and 3D assays in the presence of radiation. Conclusions: Our data suggests miRs may alter cell survival pathways and affect tumor radiosensitivity.

Sign in / Sign up

Export Citation Format

Share Document