rNAPc2, a Novel Inhibitor of Tissue Factor/Factor VIIa Complex, Suppresses Lung Metastasis and Synergizes with 5-FU or Bevacizumab in Mouse Models of Colorectal Cancer.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 904-904
Author(s):  
Jingsong Zhao ◽  
Gerard Aguilar ◽  
Steven R. Deitcher ◽  
Walter Funk ◽  
Arie Abo
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Tissue Factor ◽  
Therapeutic Potential ◽  
Factor Viia ◽  
Specific Inhibitor ◽  
Colorectal Tumor ◽  
Tumor Xenograft ◽  
Dosing Regimens ◽  
Colorectal Cancer Patients

Abstract Recombinant nematode anticoagulant protein c2 (rNAPc2) is a specific inhibitor of tissue factor (TF)/factor VIIa complex with novel anti-metastasis, anti-angiogenesis, and anti-thrombosis activities. rNAPc2 has been previously shown to inhibit both the primary growth and metastasis of murine B16 melanoma and Lewis lung carcinoma in mice. TF is highly expressed in human colorectal tumors and the level of TF expression positively correlates with the progression of malignancy. To explore the therapeutic potential of rNAPc2 during tumor growth and progression, we tested rNAPc2 efficacy in experimental colorectal cancer in mice. Both primary and metastatic colorectal tumor models were used in the current study and rNAPc2 was given to mice via daily intraperitoneal injections. Administration of rNAPc2 inhibited pulmonary metastasis in mice systemically disseminated with CT26 murine colon carcinoma cells in a dose-dependent fashion, as measured by either number of lung surface metastases or lung mass. While rNAPc2 treatment alone moderately reduced primary tumor growth, combining rNAPc2 with the cytotoxic agent 5-fluorouracil (5-FU) resulted in synergistic growth inhibition of HCT116 human colorectal tumor xenografts in nude mice. Likewise, rNAPc2 further reduced tumor growth in HCT116 human colorectal tumor xenograft-bearing mice receiving bevacizumab (humanized anti-vascular endothelial growth factor monoclonal antibody). The doses and dosing regimens of rNAPc2 used in these murine models of colorectal cancer were well tolerated by recipient mice without major complications of hemorrhage or any other adverse effects. In conclusion, the synergistic tumor inhibitory activity of rNAPc2 in pre-clinical colorectal cancer models suggests that rNAPc2 may be an effective anti-tumor agent in human colorectal cancer patients to potentiate chemo- or anti-angiogenic therapies.

rNAPc2, a Novel Inhibitor of Tissue Factor/Factor VIIa Complex, Inhibits Tumor Growth and Metastasis in Mouse Models of Colorectal Cancer.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 923-923
Author(s):  
Jingsong Zhao ◽  
Gerard Aguilar ◽  
Michael Imperiale ◽  
Walter Funk ◽  
Arie Abo
Keyword(s):  
Colorectal Cancer ◽  
Tumor Growth ◽  
Tissue Factor ◽  
Nude Mice ◽  
Factor Viia ◽  
Colorectal Tumor ◽  
Disease Stage ◽  
Major Hemorrhage ◽  
Tumor Xenografts ◽  
Tumor Growth And Metastasis

Abstract Recombinant nematode anticoagulant protein c2 (rNAPc2) is a specific inhibitor of tissue factor (TF)/factor VIIa complex with novel anti-metastatic, anti-angiogenic, and anti-thrombotic activities. TF is highly expressed in human colorectal tumors and the level of TF expression positively correlates with disease stage and inversely correlates with survival. To explore the therapeutic potential of rNAPc2 during tumor growth and metastasis, we tested rNAPc2 efficacy in experimental colorectal cancers in mice. Administration of rNAPc2 inhibited pulmonary metastasis in mice systemically disseminated with CT26 murine colon carcinoma cells in a dose-dependent fashion, as measured by either number of lung surface metastases or lung mass. While rNAPc2 treatment alone moderately reduced primary tumor growth, combining rNAPc2 with the cytotoxic agent 5-fluorouracil (5-FU) resulted in synergistic growth inhibition of HCT116 human colorectal tumor xenografts in nude mice. Likewise, rNAPc2 further reduced tumor growth in HCT116 human colorectal tumor xenograft-bearing mice receiving bevacizumab (humanized anti-vascular endothelial growth factor monoclonal antibody). Using CD31 and Ki67 immunohistochemisty, we found that rNAPc2 synergized with either 5-FU or bevacizumab in inhibiting microvessel density and tumor cell proliferation in HCT116 human colorectal tumor xenografts. Furthermore, rNAPc2 synergized with CPT-11 in inhibiting hepatic metastasis in nude mice with portal vein injection of HCT116 human colorectal tumor cells. Long-term administration of rNAPc2 also significantly suppressed formation of intestinal adenomas and adenocarcinomas in ApcMin/+ mice. The dosing regimens of rNAPc2 used in these studies were well tolerated up to a three-month period by recipient mice without major hemorrhage or other adverse effects. In conclusion, the synergistic tumor inhibitory activity of rNAPc2 in pre-clinical colorectal cancer models suggests that rNAPc2 may be an effective anti-tumor agent in human colorectal cancer patients to potentiate chemo- or anti-angiogenic therapies.

scholarly journals Gene Expression Signature-Based Approach Identifies Antifungal Drug Ciclopirox As a Novel Inhibitor of HMGA2 in Colorectal Cancer

Biomolecules ◽  
2019 ◽  
Vol 9 (11) ◽  
pp. 688 ◽  
Author(s):  
Yu-Min Huang ◽  
Chia-Hsiung Cheng ◽  
Shiow-Lin Pan ◽  
Pei-Ming Yang ◽  
Ding-Yen Lin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Cell Cycle ◽  
Therapeutic Potential ◽  
Specific Inhibitor ◽  
Gene Expression Signature ◽  
Hsp90 Inhibitor ◽  
Response To Therapy ◽  
Mesenchymal Transition ◽  
Potential Inhibitor

Human high-mobility group A2 (HMGA2) encodes for a non-histone chromatin protein which influences a variety of biological processes, including the cell cycle process, apoptosis, the DNA damage repair process, and epithelial–mesenchymal transition. The accumulated evidence suggests that high expression of HMGA2 is related to tumor progression, poor prognosis, and a poor response to therapy. Thus, HMGA2 is an important molecular target for many types of malignancies. Our recent studies revealed the positive connections between heat shock protein 90 (Hsp90) and HMGA2 and that the Hsp90 inhibitor has therapeutic potential to inhibit HMGA2-triggered tumorigenesis. However, 43% of patients suffered visual disturbances in a phase I trial of the second-generation Hsp90 inhibitor, NVP-AUY922. To identify a specific inhibitor to target HMGA2, the Gene Expression Omnibus (GEO) database and the Library of Integrated Network-based Cellular Signatures (LINCS) L1000platform were both analyzed. We identified the approved small-molecule antifungal agent ciclopirox (CPX) as a novel potential inhibitor of HMGA2. In addition, CPX induces cytotoxicity of colorectal cancer (CRC) cells by induction of cell cycle arrest and apoptosis in vitro and in vivo through direct interaction with the AT-hook motif (a small DNA-binding protein motif) of HMGA2. In conclusion, this study is the first to report that CPX is a novel potential inhibitor of HMGA2 using a drug-repurposing approach, which can provide a potential therapeutic intervention in CRC patients.

Effects of Chemotherapy on Extracellular Vesicles and Coagulation Activation in Colorectal Cancer Patients: A Pilot Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1425-1425
Author(s):  
Ludwig Traby ◽  
Hannah C. Puhr ◽  
Marietta Kollars ◽  
Kammer Michael ◽  
Gerald Prager ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Venous Thromboembolism ◽  
Pilot Study ◽  
Cancer Patients ◽  
Tissue Factor ◽  
Extracellular Vesicles ◽  
Advanced Colorectal Cancer ◽  
Coagulation Activation ◽  
Colorectal Cancer Patients ◽  
D Dimer

Abstract Introduction Venous thromboembolism is a frequent complication in cancer patients and results in a considerable morbidity and mortality. The underlying mechanisms leading to the increased thrombotic risk are yet poorly understood. We have previously shown that levels of extracellular vesicles (EV) are elevated in patients with colorectal cancer compared to healthy control individuals (Hron et al, Thromb Haemost 2007;97:119-123). EV originate from blood or endothelial cells, or from the underlying tumor itself. They may contribute to coagulation activation and propagation by exposing tissue factor and by providing a surface for the interaction of coagulation factors. In that study, the number of EV was also positively correlated with levels of D-dimer, a fibrin split product and marker of coagulation activation. We hypothesize that number of EV and levels of D-dimer decline with decreasing tumor load during antineoplastic treatment. Therefore, the study aims at evaluating the long-term effect of chemotherapy on hemostatic system activation in patients with advanced colorectal cancer. Methods We conducted a pilot study including patients receiving chemotherapy because of advanced colorectal cancer. All chemotherapy regimens were based on 5-fluorouracilcombined with either oxaliplatin or irinotecan without or with an antibody (bevacizumab in 72%, cetuximab in 11%, and ramucirumab in 5% of patients, respectively). Patients were followed for 3 chemotherapy cycles. The study was approved by the local ethics committee, was conducted according to the Declaration of Helsinki and informed consent was obtained from all study patients. Venous blood was sampled at each cycle immediately before chemotherapy and was centrifuged at 2600 g for 15 minutes. The number of EV was assessed by flow cytometry using a FACSCalibur® flow cytometer with CellQuest™ software (Becton Dickinson) immediately after blood collection and centrifugation in fresh plasma. EV were defined by size (forward scatter, <1 µm) and annexin V binding. Tissue factor positive EV were characterized by an anti-CD142 antibody. Plasma was then frozen and stored at -80°C and was used for determination of markers of coagulation activation (D-dimer, prothrombin fragment f1.2) by commercially available ELISA kits. All outcome variables were log-transformed due to skewed distributions. The paired t-test was used to compare baseline (before the 1st chemotherapy) levels with measurements obtained from the 2nd and 3rd blood sampling. In order to provide a clearer legibility, all data is presented in absolute numbers and all values are given as median (quartiles) if not otherwise stated. Results 18 patients completed 3 cycles of chemotherapy. Their mean (± SD) age was 60.5 (± 12.2) years and 14 (78%) were men. None of the patients developed venous thromboembolism. Table 1 shows the levels of coagulation activation markers and the number of EV at baseline and before the 2nd and 3rd cycle of chemotherapy, respectively. D-dimer levels were 1.22 (0.42-2.31) µg mL-1 at baseline and significantly decreased over the course of treatment. D-dimer levels did not correlate with the number of EV either at baseline or at later time points. The number of EV decreased from 474 (312-617) x 103 mL-1 at baseline to 359 (239-474) x 103 mL-1 before the 3rd cycle. The proportion of tissue factor positive EV was small at baseline and throughout treatment. Levels of prothrombin fragment f1.2 did not change during treatment and did not correlate with number of EV at any time point. Conclusions In patients with advanced colorectal cancer chemotherapy attenuates coagulation activation as indicated by a decline of D-dimer levels and number of EV. These findings warrant further studies in a larger patient population and longer observation time. Table 1 Number of extracellular vesicles (EV) and markers of coagulation activation in plasma of colorectal cancer patients before and during chemotherapy Table 1. Number of extracellular vesicles (EV) and markers of coagulation activation in plasma of colorectal cancer patients before and during chemotherapy Disclosures No relevant conflicts of interest to declare.

scholarly journals A specific Upregulated lncRNA in Colorectal Cancer Promotes Cancer Progression by Modulating miR-185-5p/CCND2 Axis

2021 ◽  
Author(s):  
Junshu Li ◽  
Yanhong Ji ◽  
Na Chen ◽  
Huiling Wang ◽  
Chao Fang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Network Analysis ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Gene Mutations ◽  
Disease Free Survival ◽  
Luciferase Reporter ◽  
Colorectal Cancer Patients

Abstract BackgroundAdenomatous polyposis coli (APC) gene mutations were found in most colorectal cancer patients and functioned as an important inducer of tumorigenesis. Long non-coding RNA (lncRNA) plays a crucial role in the pathogenesis of various diseases, including colorectal cancer (CRC). Here we investigated the role of SURC which is specific upregulated in CRC progression. MethodsBased on the previous microarray results, weighted correlation network analysis (WGCNA) and lncRNA-mRNA co-expression network analysis were used to identify a lncRNA (SURC) and found it was specific up-regulated in CRC patients by qPCR and FISH staining. Chromatin immunoprecipitation (ChIP) assay was used to demonstrate the regulatory effect and mechanism of APC mutation on SURC expression. The effects of SURC on proliferation and cell cycle were determined by in vitro and in vivo experiments. Chromatin Isolation by RNA Purification (CHIRP) and luciferase reporter assay were carried out to illustrate the interaction between SURC, miR-185-5p and CCND2.ResultsWe found that SURC was specific up-regulated in CRC, but not in other solid tumor, when compared with normal adjacent tissues. High expression of SURC correlates with poorer disease-free survival and overall survival of CRC patients. Mutated APC protein resulted in stabilization of β-catenin in CRC, which promotes the transcription of SURC via binding to its promoter. Knockdown of SURC impaired CRC cell proliferation, colony formation and CRC tumor growth. Mechanistically, after transcription, SURC was transferred to cytoplasm and inhibits miR-185-5p expression via binding to miR-185-5p and inhibiting the synthesis of miR-185-5p from pri-miR-185-5p, which results in CCND2 expression.ConclusionCollectively, these results indicated that SURC promoted CRC tumor growth via interacting with miR-185-5p and regulating the activity of miR-185-5p/CCND2 axis which would be a novel diagnosis and prognosis prediction target for CRC.

Ovarian metastases in colorectal carcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e14697-e14697
Author(s):  
Idris Yucel ◽  
Dilek Erdem ◽  
Bahiddin Yilmaz ◽  
Guzin Gonullu
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Menopausal Status ◽  
Colorectal Tumor ◽  
Ca 125 ◽  
Initial Symptom ◽  
Ovarian Metastases ◽  
Gynecological Examination ◽  
Colorectal Cancer Patients ◽  
Metachronous Metastases

e14697 Background: 5-30 % of all ovarian tumors are metastatic and only 3-14 % of them derive from gastrointestinal tract. The aim of this study is to determine the rate of colorectal cancer patients with ovarian metastases and also to identify the features in the management of these patients. Methods: 972 colorectal cancer patients admitted to our clinic between 01/2001 and 12/2011 were included in the study. Among these patients, only 9 had ovarian metastases. Age, menopausal status, initial symptom, operation status, localisation of colorectal tumor, stage at diagnosis, tumor grade, histopathological type, colorectal tumor-ovarian metastases interval, having synchronous or metachronous metastases, the place of metastases and concurrent metastatic disease were evaluated. SPSS 16 is used. Results: Mean age of patients was 45 years (range between 21-72 years). 66.7 % had premenopausal state. 55 % of them had right colon tumor. 5 patients had stage IV disease. 5 patients had synchronous metastases (55 %). Colorectal cancer-ovarian metastases interval was 6-49 months in the patients with metachronous metastases. Among patients; 5 had right and 1 had left ovarian metastases and 3 had metastases to both ovaries. 2 of 3 bilateral ovarian metastases were derived from right-sided tumors (66.6 %). 7 patients also had metastases to other different parts and most of those had peritoneal involvement (85.7 %). PFS was between 2 and 27 months. At the time of ovarian metastases, 7 patients had high CA 125 levels and 3 had high CEA levels. All patients with high levels of CA 125 during diagnosis continued to have high levels of CA 125 with ovarian metastases. Conclusions: Premenopausal patients seem to have higher risk of ovarian metastases. This study support that examining CA 125 levels in colorectal cancer patients who have abnormal findings in the gynecological examination preoperatively may help not to miss synchronous ovarian metastases.The finding of ovarian metastases should make consideration that the disease is disseminated. Ovaries should be examined preoperatively and it should be kept in mind that CA 125 levels may be a valuable marker in this setting.

scholarly journals The relationship between tissue factor and cancer progression: insights from bench and bedside

Blood ◽  
2012 ◽  
Vol 119 (4) ◽  
pp. 924-932 ◽  
Author(s):  
Yascha W. van den Berg ◽  
Susanne Osanto ◽  
Pieter H. Reitsma ◽  
Henri H. Versteeg
Keyword(s):  
Tumor Growth ◽  
Tissue Factor ◽  
Cancer Progression ◽  
Tumor Angiogenesis ◽  
Factor Viia ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Cancer Subtypes ◽  
Tumor Cell Behavior

Abstract It is now widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers, including pancreatic, colorectal, and gastric cancer, often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Reciprocally, components from the coagulation cascade also influence cancer progression. The primary initiator of coagulation, the transmembrane receptor tissue factor (TF), has gained considerable attention as a determinant of tumor progression. On complex formation with its ligand, coagulation factor VIIa, TF influences protease-activated receptor-dependent tumor cell behavior, and regulates integrin function, which facilitate tumor angiogenesis both in vitro and in mouse models. Furthermore, evidence exists that an alternatively spliced isoform of TF also affects tumor growth and tumor angiogenesis. In patient material, TF expression and TF cytoplasmic domain phosphorylation correlate with disease outcome in many, but not in all, cancer subtypes, suggesting that TF-dependent signal transduction events are a potential target for therapeutic intervention in selected types of cancer. In this review, we summarize our current understanding of the role of TF in tumor growth and metastasis, and speculate on anticancer therapy by targeting TF.

scholarly journals Isolation and Characterization of Two Novel Colorectal Cancer Cell Lines, Containing a Subpopulation with Potential Stem-Like Properties: Treatment Options by MYC/NMYC Inhibition

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2582
Author(s):  
Jan Schulte am Esch ◽  
Beatrice Ariane Windmöller ◽  
Johannes Hanewinkel ◽  
Jonathan Storm ◽  
Christine Förster ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Therapeutic Potential ◽  
Specific Inhibitor ◽  
Cancer Cell Lines ◽  
Colorectal Cancer Cell ◽  
Mesenchymal Transition ◽  
Isolation And Characterization ◽  
Colorectal Cancer Cell Lines

Cancer stem cells (CSC) are crucial mediators of cancer relapse. Here, we isolated two primary human colorectal cancer cell lines derived from a rectal neuroendocrine carcinoma (BKZ-2) and a colorectal adenocarcinoma (BKZ-3), both containing subpopulations with potential stem-like properties. Protein expression of CSC-markers prominin-1 and CD44 antigen was significantly higher for BKZ-2 and BKZ-3 in comparison to well-established colon carcinoma cell lines. High sphere-formation capacity further confirmed the existence of a subpopulation with potential stem-like phenotype. Epithelial–mesenchymal transition markers as well as immune checkpoint ligands were expressed more pronounced in BKZ-2. Both cell populations demonstrated N-myc proto-oncogene (NMYC) copy number gain. Myc proto-oncogene (MYC)/NMYC activity inhibitor all-trans retinoic acid (ATRA) significantly reduced the number of tumor spheres for both and the volume of BKZ-2 spheres. In contrast, the sphere volume of ATRA-treated BKZ-3 was increased, and only BKZ-2 cell proliferation was reduced in monolayer culture. Treatment with KJ-Pyr-9, a specific inhibitor of MYC/NMYC-myc-associated factor X interaction, decreased survival by the induction of apoptosis of both. In summary, here, we present the novel colorectal cancer cell lines BKZ-2 and BKZ-3 as promising cellular in vitro models for colorectal carcinomas and identify the MYC/NMYC molecular pathway involved in CSC-induced carcinogenesis with relevant therapeutic potential.

scholarly journals Tissue factor-dependent activation of tritium-labeled factor IX and factor X in human plasma

Blood ◽  
1984 ◽  
Vol 63 (6) ◽  
pp. 1338-1347 ◽  
Author(s):  
SA Morrison ◽  
J Jesty
Keyword(s):  
Human Plasma ◽  
Tissue Factor ◽  
Factor Viia ◽  
Stimulate Factor ◽  
Specific Inhibitor ◽  
Factor Xa ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X ◽  
Bovine Plasma

Recent investigations have suggested that the activation of factor IX by factor VII/tissue factor may be an important alternative route to the generation of factor Xa. Accordingly, we have compared the tissue factor-dependent activation of tritium-labeled factor IX and factor X in a human plasma system and have studied the role of proteases known to stimulate factor VII activity. Plasma was defibrinated by heating and depleted of its factors IX and X by passing it through antibody columns. Addition of human brain thromboplastin, Ca2+, and purified 3H- labeled factor X to the plasma resulted, after a short lag, in burst- like activation of the factor X, measured as the release of radiolabeled activation peptide. The progress of activation was slowed by both heparin and a specific inhibitor of factor Xa, suggesting a feedback role for this enzyme, but factor X activation could not be completely abolished by such inhibitors. In the case of 3H-factor IX activation, the rate also increased for approximately 3 min after addition of thromboplastin, but was not subsequently curtailed. A survey of proteases implicated as activators of factor VII in other settings showed that both factor Xa and (to a much smaller extent) factor IXa could accelerate the activation of factor IX. However, factor Xa was unique in obliterating activation when present at concentrations greater than approximately 1 nM. Heparin inhibited the tissue factor-dependent activation of factor IX almost completely, apparently through the effect of antithrombin on the feedback reactions of factors Xa and IXa on factor VII. These results suggest that a very tight, biphasic control of factor VII activity exists in human plasma, which is modulated mainly by factor Xa. Variation of the factor IX or factor X concentrations permitted kinetic parameters for each activation to be derived. At saturation of factor VIIa/tissue factor, factor IX activation was significantly more rapid than was previously found in bovine plasma under similar conditions. The activation of factor X at saturation was slightly more rapid than in bovine plasma, despite the presence of heparin.

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