Coagulative System Activation and Fibrinolytic System Inhibition Activities Arise From Tumoral Draining Vein in Colon Carcinoma

García-Avello, Ángel; Álvarez, Julio Galindo; Martínez-Molina, Enrique; Cesar-Perez, J.; Navarro, José Luís

doi:10.1016/s0049-3848(01)00383-8

Cited by 15 publications

(11 citation statements)

References 14 publications

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“…After controlling for other vascular risk factors and cancer characteristics, our analysis found that patients with GI cancer were 4 times more likely to develop embolic infarcts. This proneness to embolic infarction is probably due to activities of adenocarcinoma, such as induction of hypercoagulability and non-bacterial thrombotic endocarditis [18,19,20]. However, our further analysis showed no direct relationship between adenocarcinoma alone and embolic infarction.…”

Section: Discussionmentioning

confidence: 62%

Patterns of Acute Cerebral Infarcts in Patients with Active Malignancy Using Diffusion-Weighted Imaging

2009

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Background and Purpose: It is still controversial whether the nature of cerebral infarcts differs between cancer patients and the general population. The aim of this study is to delineate the characteristics of acute cerebral infarction in patients with active malignancy using diffusion-weighted imaging (DWI). Materials and Methods: Seventy consecutive patients with both active malignancy and acute cerebral infarction (confirmed by DWI) were retrospectively included. These 70 were divided into 3 groups on the basis of infarct pattern: embolic infarction, large artery disease, and lacunar infarction. Medical records were reviewed in detail for demographic data, cancer information, vascular risk factors, and prognosis. Results: Two thirds of cancer patients had multiple infarcts, and 30% of infarcts were located infratentorially. Embolic infarction, large artery disease, and lacunar infarction occurred in 60, 31, and 9% of cancer patients, respectively. Gastrointestinal (GI) cancer was significantly related to embolic infarction (odds ratio 4.64, p = 0.04). The 3-month mortality rates were higher in patients with rather than without cancer metastasis (68 vs. 8%; p < 0.001). Conclusions: Cerebral infarcts in cancer patients tended to be embolic and multiple. Patients with GI cancer were particularly susceptible to embolic infarction.

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Section: Discussionmentioning

confidence: 62%

Patterns of Acute Cerebral Infarcts in Patients with Active Malignancy Using Diffusion-Weighted Imaging

2009

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“…Thrombin generation is probably the direct result of the overactivation of the coagulation system, a widely described abnormality in various cancer patients32 including those with colon cancer 18, 19. Thus, plasma thrombin can cross the leaky local microvasculature34 from the draining veins of colon tumors35 to reach the solid tumors. Other studies showed that the tumor itself in colon adenocarcinoma produces thrombin‐like activity, as assessed by platelet aggregation assay 36.…”

Section: Discussionmentioning

confidence: 99%

Aberrant expression of proteinase‐activated receptor 4 promotes colon cancer cell proliferation through a persistent signaling that involves Src and ErbB‐2 kinase

Gratio

Walker

Lehy

et al. 2009

Intl Journal of Cancer

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Thrombin is now recognized as an important factor in many cancers. Here, we examined the expression and role of the recently discovered thrombin receptor PAR4, in human colon cancer cells. PAR4 mRNA was found in 10 out of 14 (71%) human colon cancer cell lines tested but not in epithelial cells isolated from normal human colon. This finding is in line with immunostaining results of PAR4 in human colon tumors and its absence in normal human colonic mucosa. Investigation of the functional significance of the aberrant expression of PAR4 in colon cancer cells revealed (i) a prompt increase in intracellular calcium concentration on challenge with PAR4-specific agonist AP4 (100 lM) and (ii) marked mitogenic response (2.5-fold increase in cell number) in a dose-dependent manner on treatment with AP4 (0.1-300 lM). Analysis of the signaling pathways downstream of PAR4 activation in HT29 cells showed (i) a sustained phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2) and (ii) the involvement of epidermal growth factor receptor B-2 (ErbB-2) but not of epidermal growth factor receptor in PAR4-induced mitogen-activated protein kinase activation. Tyrphostin AG1478, the ErbB inhibitor, reversed the action of AP4 on ERK1/2 and ErbB-2 phosphorylation and HT29 cell growth. Finally, the Src inhibitor PP2 abrogated ErbB-2 and ERK phosphorylation and HT29 cell proliferation, suggesting the essential role of Src activity in PAR4-induced phosphorylation of ErbB-2. These data highlight the role of PAR4 as a new important player in the control of colon tumors and underline the critical role of ErbB-2 transactivation. ' 2008 Wiley-Liss, Inc.Key words: colon cancer; thrombin; protease; receptor /PAR4; signal transduction; proliferation; ErbB-2; EGFR The progression from normal colonic mucosa to malignant tumor is a multistep process whereby genetic alterations in prooncogenes and/or tumor suppressor genes can lead to aberrant growth. 1,2 Proteases have long been associated with colon cancer progression because of their ability to degrade extracellular matrices, which facilitates invasion and metastasis. 3 However, recent studies have shown that these enzymes target diverse substrates and favor all steps of tumor evolution. 4 Recently, the traditional view of the role of proteases in tumor growth and progression has significantly changed. Besides their contribution to cancer progression by degrading extracellular matrix proteins, it is now clear that a subclass of proteases serve as signal molecules controlling cell functions through specific membrane receptors, the proteaseactivated receptors (PARs). 5,6 This new class of receptors belongs to the superfamily of the serpentine G protein-coupled receptors (GPCRs). The PARs are activated by low subnanomolar concentrations of serine proteases that cleave a single peptide bond in the N-terminal extracellular domain of the receptor. The resulting new N-terminal domain serves as a receptor agonist. 5,6 This intramolecular ligand binds to the core of the receptor and initiates sig...

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“…16 Second, elevation of the levels of thrombin/anti-thrombin complexes as well as thrombin fragments has been found in the blood of patients with colon cancer 14 in particular in the draining veins of colon tumors. 17 Third, it has been clearly demonstrated that colon cancer cells aggregate platelets by generation of thrombin activity. 18,19 Although activation of the thrombin pathway is probably a consequence of the disease, activation of coagulation during the disease processes could, in turn, contribute to pathogenesis of colon cancer.…”

Section: (Am J Pathol 2003 162:1503-1513)mentioning

confidence: 99%

Aberrant Expression and Activation of the Thrombin Receptor Protease-Activated Receptor-1 Induces Cell Proliferation and Motility in Human Colon Cancer Cells

Darmoul

Gratio

Devaud

et al. 2003

The American Journal of Pathology

186

173

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The traditional view on the role of serine proteases in tumor biology has changed with the recent discovery of a family of protease-activated receptors (PARs). In this study we explored the expression and functional role of the thrombin receptor PAR-1 in human colon cancer cells. Reverse transcriptase-polymerase chain reaction analysis showed that PAR-1 mRNAs are present in 11 of 14 human colon cancer cell lines tested but not in normal human colonic epithelial cells. This is in line with the immunolocalization of PAR-1 in human colon tumors and its absence in normal human colonic mucosa. The functional significance of the aberrant expression of PAR-1 in colon cancer cells was then investigated. We found that 1) a prompt increase in intracellular calcium concentration was observed on thrombin (10 nmol/L) or PAR-1 agonist AP1 (100 micro mol/L) challenge of HT29 cells; 2) HT29 quiescent cells treated with thrombin (0.01 to 20 nmol/L) or AP1 (1 to 300 micro mol/L) exhibited dramatic mitogenic responses (3.5-fold increase in cell number). Proliferative effects of thrombin or AP1 were also observed in other colon cancer cell lines expressing PAR-1. This effect was reversed by the MEK inhibitor PD98059 in consonance with the ability of thrombin or AP1 to induce phosphorylation of p42/p44 extracellular-regulated protein kinases. 3) PAR-1 activation by thrombin or AP1 led to a two-fold increase in cell motility of wounded HT29-D4. Our results demonstrate for the first time the aberrant expression of the functional thrombin receptor PAR-1 in colon cancers and its important involvement in cell proliferation and motility. Thrombin should now be considered as a growth factor for human colon cancer.

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Coagulative System Activation and Fibrinolytic System Inhibition Activities Arise From Tumoral Draining Vein in Colon Carcinoma

Cited by 15 publications

References 14 publications

Patterns of Acute Cerebral Infarcts in Patients with Active Malignancy Using Diffusion-Weighted Imaging

Patterns of Acute Cerebral Infarcts in Patients with Active Malignancy Using Diffusion-Weighted Imaging

Aberrant expression of proteinase‐activated receptor 4 promotes colon cancer cell proliferation through a persistent signaling that involves Src and ErbB‐2 kinase

Aberrant Expression and Activation of the Thrombin Receptor Protease-Activated Receptor-1 Induces Cell Proliferation and Motility in Human Colon Cancer Cells

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