The Activation of Prothrombin Seems to Play an Earlier Role than the Complement System in the Progression of Colorectal Cancer: A Mass Spectrometry Evaluation

Colorectal cancer (CRC) is the second cause of death in men and the third in women. This work deals with the study of the low molecular weight protein fraction of sera from patients who underwent surgery for CRC and who were followed for several years thereafter. MALDI-TOF MS was used to identify serum peptidome profiles of healthy controls, non-metastatic CRC patients and metastatic CRC patients. A multiple regression model was applied to signals preliminarily selected by SAM analysis to take into account the age and gender differences between the groups. We found that, while a signal m/z 2021.08, corresponding to the C3f fragment of the complement system, appears significantly increased only in serum from metastatic CRC patients, a m/z 1561.72 signal, identified as a prothrombin fragment, has a significantly increased abundance in serum from non-metastatic patients as well. The findings were also validated by a bootstrap resampling procedure. The present results provide the basis for further studies on large cohorts of patients in order to confirm C3f and prothrombin as potential serum biomarkers. Thus, new and non-invasive tests might be developed to improve the classification of colorectal cancer.

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Complement System: Promoter or Suppressor of Cancer Progression?

Antibodies ◽

10.3390/antib9040057 ◽

2020 ◽

Vol 9 (4) ◽

pp. 57

Author(s):

Margot Revel ◽

Marie V. Daugan ◽

Catherine Sautés-Fridman ◽

Wolf H. Fridman ◽

Lubka T. Roumenina

Keyword(s):

Cancer Progression ◽

Complement System ◽

Current Knowledge ◽

Prognostic Impact ◽

Cancer Type ◽

Human Cancers ◽

Cancer Types ◽

The Complement System

Constituent of innate immunity, complement is present in the tumor microenvironment. The functions of complement include clearance of pathogens and maintenance of homeostasis, and as such could contribute to an anti-tumoral role in the context of certain cancers. However, multiple lines of evidence show that in many cancers, complement has pro-tumoral actions. The large number of complement molecules (over 30), the diversity of their functions (related or not to the complement cascade), and the variety of cancer types make the complement-cancer topic a very complex matter that has just started to be unraveled. With this review we highlight the context-dependent role of complement in cancer. Recent studies revealed that depending of the cancer type, complement can be pro or anti-tumoral and, even for the same type of cancer, different models presented opposite effects. We aim to clarify the current knowledge of the role of complement in human cancers and the insights from mouse models. Using our classification of human cancers based on the prognostic impact of the overexpression of complement genes, we emphasize the strong potential for therapeutic targeting the complement system in selected subgroups of cancer patients.

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Low molecular weight protein tyrosine phosphatase (LMWPTP) upregulation mediates malignant potential in colorectal cancer

Oncotarget ◽

10.18632/oncotarget.3224 ◽

2015 ◽

Vol 6 (10) ◽

pp. 8300-8312 ◽

Cited By ~ 21

Author(s):

Elmer Hoekstra ◽

Liudmila L. Kodach ◽

Asha M. Das ◽

Roberta R. Ruela-de-Sousa ◽

Carmen V. Ferreira ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Weight ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Malignant Potential ◽

Low Molecular Weight ◽

Molecular Weight Protein ◽

Protein Tyrosine ◽

Weight Protein ◽

Low Molecular Weight Protein

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Vemurafenib downmodulates aggressiveness mediators of colorectal cancer (CRC): Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP), Protein Tyrosine Phosphatase 1B (PTP1B) and Transforming Growth Factor β (TGFβ)

Biological Chemistry ◽

10.1515/hsz-2020-0124 ◽

2020 ◽

Vol 401 (9) ◽

pp. 1063-1069 ◽

Cited By ~ 1

Author(s):

Helon Guimarães Cordeiro ◽

Alessandra Valéria de Sousa Faria ◽

Carmen Veríssima Ferreira-Halder

Keyword(s):

Colorectal Cancer ◽

Protein Tyrosine Phosphatase ◽

Transforming Growth Factor ◽

Tyrosine Phosphatase ◽

Low Molecular Weight ◽

Protein Tyrosine Phosphatase 1B ◽

Molecular Weight Protein ◽

Protein Tyrosine ◽

Weight Protein ◽

Low Molecular Weight Protein

AbstractColorectal Cancer (CRC) therapy confronts challenges as chemoresistance and side effects. Therefore, drugs with antitumor properties that downmodulate aggressiveness mediators are required. Studies have shown the relevance of Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP), Protein Tyrosine Phosphatase 1B (PTP1B), and Transforming Growth Factor β (TGFβ) in mediating proliferation, chemoresistance, and metastasis. In this study, we aimed to investigate the responsiveness of colorectal cancer lines (HT29 and HCT116) towards Vemurafenib and whether this treatment could modulate these aggressiveness mediators. Cytotoxicity Assays (MTT and Trypan Exclusion Test) were performed to evaluate the viability of HT29 and HCT116 cells treated with Vemurafenib. Western blotting was performed to analyze the amount and/or the activity of mediators (LMWPTP, PTP1B, TGFβ, SMAD3), and the immunoprecipitation was performed to evaluate LMWPTP activity. This study brought up novel aspects of Vemurafenib action in colorectal cancer, which can decrease the activity of protein tyrosine phosphatases (LMWPTP and PTP1B) and the TGFβ pathway, making them important in the CRC aggressiveness. By downmodulating colorectal cancer hallmarks, Vemurafenib appears as an interesting candidate for CRC therapeutic protocols.

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Sa1694 Low Molecular Weight Protein Tyrosine Phosphatase (LMW-PTP) Is Upregulated in Primary Colorectal Cancer and Affects Cancer Signaling Pathways

Gastroenterology ◽

10.1016/s0016-5085(13)61007-0 ◽

2013 ◽

Vol 144 (5) ◽

pp. S-285

Author(s):

Elmer Hoekstra ◽

Liudmila L. Kodach ◽

James C. Hardwick ◽

Ernst J. Kuipers ◽

Marco J. Bruno ◽

...

Keyword(s):

Colorectal Cancer ◽

Molecular Weight ◽

Signaling Pathways ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Low Molecular Weight ◽

Molecular Weight Protein ◽

Primary Colorectal Cancer ◽

Weight Protein ◽

Low Molecular Weight Protein

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Novel spectroscopic biomarkers are applicable in non-invasive early detection and staging classification of colorectal cancer

Neoplasma ◽

10.4149/neo_2020_200506n494 ◽

2020 ◽

Author(s):

M. MISKOVICOVA ◽

V. FRYBA ◽

L. PETRUZELKA ◽

V. SETNICKA ◽

A. SYNYTSYA ◽

...

Keyword(s):

Colorectal Cancer ◽

Early Detection ◽

Non Invasive ◽

Staging Classification

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Protein S and C4b-Binding Protein: Components Involved in the Regulation of the Protein C Anticoagulant System

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646373 ◽

1991 ◽

Vol 66 (01) ◽

pp. 049-061 ◽

Cited By ~ 233

Author(s):

Björn Dahlbäck

Keyword(s):

Vitamin K ◽

Complement System ◽

Protein C ◽

Protein S ◽

High Affinity ◽

Anticoagulant System ◽

Dependent Protein ◽

The Complement System ◽

Β Chain ◽

Dependent Domain

SummaryThe protein C anticoagulant system provides important control of the blood coagulation cascade. The key protein is protein C, a vitamin K-dependent zymogen which is activated to a serine protease by the thrombin-thrombomodulin complex on endothelial cells. Activated protein C functions by degrading the phospholipid-bound coagulation factors Va and VIIIa. Protein S is a cofactor in these reactions. It is a vitamin K-dependent protein with multiple domains. From the N-terminal it contains a vitamin K-dependent domain, a thrombin-sensitive region, four EGF)epidermal growth factor (EGF)-like domains and a C-terminal region homologous to the androgen binding proteins. Three different types of post-translationally modified amino acid residues are found in protein S, 11 γ-carboxy glutamic acid residues in the vitamin K-dependent domain, a β-hydroxylated aspartic acid in the first EGF-like domain and a β-hydroxylated asparagine in each of the other three EGF-like domains. The EGF-like domains contain very high affinity calcium binding sites, and calcium plays a structural and stabilising role. The importance of the anticoagulant properties of protein S is illustrated by the high incidence of thrombo-embolic events in individuals with heterozygous deficiency. Anticoagulation may not be the sole function of protein S, since both in vivo and in vitro, it forms a high affinity non-covalent complex with one of the regulatory proteins in the complement system, the C4b-binding protein (C4BP). The complexed form of protein S has no APC cofactor function. C4BP is a high molecular weight multimeric protein with a unique octopus-like structure. It is composed of seven identical α-chains and one β-chain. The α-and β-chains are linked by disulphide bridges. The cDNA cloning of the β-chain showed the α- and β-chains to be homologous and of common evolutionary origin. Both subunits are composed of multiple 60 amino acid long repeats (short complement or consensus repeats, SCR) and their genes are located in close proximity on chromosome 1, band 1q32. Available experimental data suggest the β-chain to contain the single protein S binding site on C4BP, whereas each of the α-chains contains a binding site for the complement protein, C4b. As C4BP lacking the β-chain is unable to bind protein S, the β-chain is required for protein S binding, but not for the assembly of the α-chains during biosynthesis. Protein S has a high affinity for negatively charged phospholipid membranes, and is instrumental in binding C4BP to negatively charged phospholipid. This constitutes a novel mechanism for control of the complement system on phospholipid surfaces. Recent findings have shown circulating C4BP to be involved in yet another calcium-dependent protein-protein interaction with a protein known as the serum amyloid P-component (SAP). The binding sites on C4BP for protein S and SAP are independent. SAP, which is a normal constituent in plasma and in tissue, is a so-called pentraxin being composed of 5 non-covalently bound 25 kDa subunits. It is homologous to C reactive protein (CRP) but its function is not yet known. The specific high affinity interactions between protein S, C4BP and SAP suggest the regulation of blood coagulation and that of the complement system to be closely linked.

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Stimulated Glanzmann’s Thrombasthenia Platelets Produce Microvesicles

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649978 ◽

1995 ◽

Vol 74 (06) ◽

pp. 1533-1540 ◽

Cited By ~ 23

Author(s):

Pål André Holme ◽

Nils Olav Solum ◽

Frank Brosstad ◽

Nils Egberg ◽

Tomas L Lindahl

Keyword(s):

Complement System ◽

Shape Change ◽

Annexin V ◽

Platelet Surface ◽

Glanzmann’S Thrombasthenia ◽

Large Numbers ◽

Glanzmann's Thrombasthenia ◽

Series Of Experiments ◽

The Complement System ◽

Number Of Particles

SummaryThe mechanism of formation of platelet-derived microvesicles remains controversial.The aim of the present work was to study the formation of microvesicles in view of a possible involvement of the GPIIb-IIIa complex, and of exposure of negatively charged phospholipids as procoagulant material on the platelet surface. This was studied in blood from three Glanzmann’s thrombasthenia patients lacking GPIIb-IIIa and healthy blood donors. MAb FN52 against CD9 which activates the complement system and produces microvesicles due to a membrane permeabilization, ADP (9.37 μM), and the thrombin receptor agonist peptide SFLLRN (100 μM) that activates platelets via G-proteins were used as inducers. In a series of experiments platelets were also preincubated with PGE1 (20 μM). The number of liberated microvesicles, as per cent of the total number of particles (including platelets), was measured using flow cytometry with FITC conjugated antibodies against GPIIIa or GPIb. Activation of GPIIb-IIIa was detected as binding of PAC-1, and exposure of aminophospholipids as binding of annexin V. With normal donors, activation of the complement system induced a reversible PAC-1 binding during shape change. A massive binding of annexin V was seen during shape change as an irreversible process, as well as formation of large numbers of microvesicles (60.6 ±2.7%) which continued after reversal of the PAC-1 binding. Preincubation with PGE1 did not prevent binding of annexin V, nor formation of microvesicles (49.5 ± 2.7%), but abolished shape change and PAC-1 binding after complement activation. Thrombasthenic platelets behaved like normal platelets after activation of complement except for lack of PAC-1 binding (also with regard to the effect of PGE1 and microvesicle formation). Stimulation of normal platelets with 100 μM SFLLRN gave 16.3 ± 1.2% microvesicles, and strong PAC-1 and annexin V binding. After preincubation with PGE1 neither PAC-1 nor annexin V binding, nor any significant amount of microvesicles could be detected. SFLLRN activation of the thrombasthenic platelets produced a small but significant number of microvesicles (6.4 ± 0.8%). Incubation of thrombasthenic platelets with SFLLRN after preincubation with PGE1, gave results identical to those of normal platelets. ADP activation of normal platelets gave PAC-1 binding, but no significant annexin V labelling, nor production of microvesicles. Thus, different inducers of the shedding of microvesicles seem to act by different mechanisms. For all inducers there was a strong correlation between the exposure of procoagulant surface and formation of microvesicles, suggesting that the mechanism of microvesicle formation is linked to the exposure of aminophospholipids. The results also show that the GPIIb-IIIa complex is not required for formation of microvesicles after activation of the complement system, but seems to be of importance, but not absolutely required, after stimulation with SFLLRN.

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