Review
Thrombomodulin: tumour biology and prognostic implications

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Summary

Background

Thrombomodulin (TM) is an endothelial receptor that exerts anti-coagulant, anti-fibrinolytic, and anti-inflammatory activity by inhibiting thrombin and cellular adhesion. There is growing evidence that TM plays a role in tumour behaviour.

Methods

The electronic literature (1966–2004) was reviewed with a specific focus on tumour biology.

Results

TM is expressed on both the endothelium and tumour cells in several cancers. Loss of expression denotes a more malignant profile with poorer prognosis. Loss of TM is mediated by hypoxia, endotoxin, and various cytokines, while up-regulation can be achieved by pharmacological manipulation (e.g. pentoxyfylline and statins).

Conclusion

Originally described as an endothelial anticoagulant, TM plays a key role in tumour biology and prognostics, and provides a potential therapeutic target in impeding cancer spread.

Introduction

Thrombomodulin (TM) was first described as an integral component of the haemostatic pathway in 1981.1 Constitutively expressed on the vascular and lymphatic endothelium, TM interacts with thrombin to form a high-affinity complex that inhibits thrombin activity (fibrin formation) and accelerates protein C activation.2, 3 In addition to this anticoagulant function, TM reduces fibrinolysis by activating thrombin-activatable fibrinolysis inhibitor (TAFI) in plasma.4 Thus, induced TM deficiency (genetic knock-out in mice) results in a hypercoagulable state with risk of arterial thrombotic disease.5

Soluble molecules of TM, released from endothelial cell surfaces, are found in plasma and urine where higher levels indicate injury and/or enhanced turnover of the endothelium.6, 7, 8 It is not surprising, therefore, that smokers display increased serum soluble TM concentrations that correlate with activated protein C levels, number of cigarettes smoked (per day), duration of smoking (years), degree of endothelial damage, and risk of thrombosis.9, 10 Serum TM elevations, by neutrophil-mediated proteolytic/oxidative cleavage or hypoxia-induced shedding from the endothelium, parallel the activity of inflammatory diseases (e.g. vasculidites and ulcerative colitis), ischaemia-reperfusion injuries (i.e. vascular, cardiac, and transplant surgery), and atherosclerotic complications (e.g. in hypertension, smoking, and diabetes).11, 12, 13, 14, 15, 16 Clinical use of exogenous soluble infusions is approaching with recent report that administration of human urinary TM limited ischaemic injury, reperfusion sequelae, and systemic coagulopathy in a canine model of hepatic surgery.17

Early literature focused on TM as a placental surface protein (termed at the time fetomodulin) where it was identified as a marker of fetal endodermal differentiation essential for survival.18, 19 However, since it was recognized that embryonic lethality was independent of its anticoagulant activity3 the role of TM in tumour biology has drawn clinical interest. The key points in this genesis are presented here with a focus on future directions in cancer care.

Section snippets

The role of thrombomodulin in tumour biology

In 1987, TM was identified as a marker of invasive malignancy in vascular tumours.20 This led to further investigation that linked TM to prognosis in many tumour types including those of embryonal, epithelial and lymphatic origin.21, 22, 23, 24 Since, it is found in the placental syncytiotrophoblast of the placenta, TM was examined in chorionic diseases of the uterus and stomach.25 The finding that it is expressed in uterine choriocarcinoma but not in gastric choriocarcinoma suggests that it

Thrombomodulin and squamous cell carcinoma

Perhaps the most striking evidence for the biological role of TM in carcinogenesis is in squamous epithelium. Initially, TM was proposed to be associated with keratinocyte differentiation as it was identified in all cell layers except the basal and upper granular levels.23 Following this, TM localisation was studied in normal and dysplastic oral epithelium and it was established that TM expression is not significantly different in normal epithelium, lichen planus and mild dysplasia.26 However,

Thrombomodulin and intercellular reactions

E-cadherin is an adhesion molecule that preserves epithelial structural integrity and whose loss denotes enhanced invasive potential of cancers in many tissue types.32 In an analogous fashion, loss of TM expression is associated with a poor prognosis.33 The cell-to-cell adhesion properties of TM underpin its role in limiting metastatic behaviour independent of its anticoagulant function.10 This adhesive function is reliant on the calcium-dependent, lectin-like domain of TM that inhibits

Manipulating thrombomodulin expression in cancer

The regulation of TM is complex and vascular endothelial growth factor (VEGF), which may be tumour-derived or released following major surgery, induces endothelial TM and protein C during angiogenesis.38 Perhaps of more interest to surgeons, because of the potential to reverse negative characteristics of primary tumours and inhibit circulating cancer cell-endothelial interactions, two pharmacological substances upregulate membrane expression of TM. Pentoxifylline increases TM expression in

Conclusions

Thrombomodulin plays a key role in tumour biology and prognostics. The opportunities afforded by inducers of thrombomodulin expression provide potential therapies to improve tumour behaviour and impede transendothelial spread of cancer.

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  • Cited by (32)

    • Thrombomodulin (TM) in tumor cell differentiation and periphery blood immune microenvironment in oral squamous cell carcinoma

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      TM is a cell surface glycoprotein which is widely expressed in a variety of cell types. Apart from being an endogenous anticoagulant, TM also plays critical modulatory roles in inflammation [13], thrombosis [14], and carcinogenesis [15]. Recent evidence has revealed that TM is expressed in some cancer cells and affects cancer cell growth and metastasis [6,16–18].

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      Several studies discover down-regulation of TM in a variety of malignant tumors [3–5]. Noticeably, reduction of TM expression is correlated with poor prognosis of the cancer patients [8,9]. For example, decreased expression of TM is associated with tumor cell invasiveness and poor prognosis in lung cancer [10].

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