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Cancer and Coagulation; Focusing on Tissue Factor and Heparanase

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From Molecular to Modular Tumor Therapy

Part of the book series: The Tumor Microenvironment ((TTME,volume 3))

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Abstract

Cancer patients have a pro-thrombotic state due to the ability of cancer cells to activate the coagulation system and to interact with haemostatic cells, thus tilting the balance between pro- and anti-coagulants. Tissue factor (TF), the main initiator of blood coagulation, is a transmembrane receptor that is expressed constitutively in tumors. TF also plays a role in cellular signalling, contributing to tumor growth and metastasis. The only known endogenous modulator of blood coagulation initiated by TF is tissue factor pathway inhibitor (TFPI) – a plasma Kunitz-type serine protease inhibitor. Growing evidence suggest involvement of tumor derived substrates, including heparanase, in activation of the coagulation system. Heparanase is an endo-β-D-glucuronidase that cleaves heparan sulfate chains on cell surfaces and in the extracellular matrix, activity that closely ­correlates with cell invasion, angiogenesis and tumor metastasis. Recently we demonstrated that heparanase is involved in the regulation of the hemostatic ­system. Heparanase was found to up-regulate the tissue factor and interact with TFPI on the cell surface, leading to dissociation of TFPI from the cell ­membrane and increased cell surface coagulation activity. Taking into account the prometastatic and pro-angiogenic functions of heparanase, its overexpression in human malignancies and abundance in platelets, its involvement in the coagulation machinery is an intriguing novel arena for further research. Thus, inhibition of factors participating in blood coagulation may potentially reduce thrombotic complications and tumor growth.

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Abbreviations

TF:

Tissue factor

PC:

Protein C

PS:

Protein S

TFPI:

Tissue factor pathway inhibitor

VEGF:

Vascular endothelial growth factor

TNF α:

Tumor necrosis factor alpha

FGF:

Fibroblast growth factor

PDGF:

Platelet derived growth factor

EGR1:

Early growth response 1

MAPK:

Mitogen-activated protein kinase

JNK:

c-jun Terminal NH2-kinase

PKC:

Protein kinase C

NF:

Nuclear factor

ECM:

Extracellular matrix

TGF:

Transforming growth factor

HUVEC:

Human umbilical vein endothelial cell

MMP:

Matrix metalloproteinase

HS:

Heparan sulfate

HSPG:

Heparan sulfate proteoglycan

TSP-1:

Thrombospondin-1

GPI:

Glycosyl phosphatidylinositol

AML:

Acute myeloid leukemia

CLL:

Chronic lymphatic leukemia

CML:

Chronic myeloid leukemia

ALL:

Acute lymphoblastic leukemia

LMWH:

Low molecular weight heparin

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  1. Thrombosis and Hemostasis Unit, Department of Hematology, Rambam Medical Center, Haifa, Israel

    Yona Nadir

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    Albrecht Reichle

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Nadir, Y. (2010). Cancer and Coagulation; Focusing on Tissue Factor and Heparanase. In: Reichle, A. (eds) From Molecular to Modular Tumor Therapy. The Tumor Microenvironment, vol 3. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9531-2_4

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