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

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3561 ◽

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.

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miR-93 regulates epithelial-to-mesenchymal transition process in metastatic colorectal cancer by targeting EphA4

Annals of Oncology ◽

10.1093/annonc/mdx393.095 ◽

2017 ◽

Vol 28 ◽

pp. v193

Author(s):

S. Gao

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Epithelial To Mesenchymal Transition ◽

Transition Process ◽

Mesenchymal Transition

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miR93 regulates epithelial-to-mesenchymal transition process in metastatic colorectal cancer by targeting EphA4

Annals of Oncology ◽

10.1093/annonc/mdx679.002 ◽

2017 ◽

Vol 28 ◽

pp. x173-x174

Author(s):

S. Gao ◽

B. Jiang ◽

H. Liu ◽

S. Hou ◽

L. Wu ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Epithelial To Mesenchymal Transition ◽

Transition Process ◽

Mesenchymal Transition

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Pyrvinium pamoate inhibits cell proliferation through ROS-mediated AKT-dependent signaling pathway in colorectal cancer

Medical Oncology ◽

10.1007/s12032-021-01472-3 ◽

2021 ◽

Vol 38 (2) ◽

Author(s):

Wenqian Zheng ◽

Jinhui Hu ◽

Yiming Lv ◽

Bingjun Bai ◽

Lina Shan ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Proliferation ◽

Signaling Pathway ◽

Epithelial To Mesenchymal Transition ◽

Flow Cytometric Analysis ◽

Inhibitory Effect ◽

Dependent Manner ◽

Mesenchymal Transition ◽

Dependent Signaling Pathway ◽

Pyrvinium Pamoate

AbstractThe use of the anthelmintic drug pyrvinium pamoate (PP) in cancer therapy has been extensively investigated in the last decade. PP has been shown to have an inhibitory effect in colorectal cancer (CRC), but the underlying mechanism remains elusive. We aimed to investigate the antitumor activity and mechanisms of PP in CRC. In the present study, we used CCK-8 assays, colony formation assays, and western blotting to reveal that PP effectively suppressed CRC cell proliferation and the AKT-dependent signaling pathway in a concentration-dependent and time-dependent manner. Flow cytometric analysis and fluorescence microscopy demonstrated that PP increased intracellular reactive oxygen species (ROS) accumulation. We found that the inhibitory effect of PP on cell proliferation and AKT protein expression induced by PP could be partially reversed by N-acetyl-l-cysteine (NAC), an ROS scavenger. In addition, the results also demonstrated that PP inhibited cell migration by modulating epithelial-to-mesenchymal transition (EMT)-related proteins, including E-cadherin and vimentin. In conclusion, our data suggested that PP effectively inhibited cell proliferation through the ROS-mediated AKT-dependent signaling pathway in CRC, further providing evidence for the use of PP as an antitumor agent.

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

10.21203/rs.3.rs-45689/v1 ◽

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.

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