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VWF and Cancer: A String Quartet of Problems

VWF and Cancer: A String Quartet of Problems

VWF Form and Function: About the Piece

Von Willebrand Factor (VWF) is a complex multimeric glycoprotein critical in normal haemostatic function. VWF contributes to haemostasis in two main roles firstly as a carrier for procoagulant factor VIII and secondly, to recruit and adhere to platelets at sites of vascular injury (Lenting et al. 2015). Under physiological conditions, VWF biosynthesis is restricted to endothelial cells (EC), megakaryocytes and platelets. EC store VWF in specialised granules known as Weibel-Palade bodies (WPB) and constitutively secrete VWF into the plasma, while in contrast, megakaryocytes and platelets store VWF in α-granules and release VWF upon activation (Mayadas & Wagner 1991). VWF release from EC can also be induced when stimulated resulting in a greater rate of VWF secretion (de Wit & van Mourik 2001).

Importantly, VWF is secreted by EC in a highly multimeric string-like form known as Ultra-Large VWF (UL-VWF) (Mayadas & Wagner 1991; Lenting et al. 2015). The multimeric composition of VWF is a key determinant of its activity. VWF strings can unwind via circulatory stresses, exposing further binding sites along the structure including platelet binding site GPIbα, P-selectin and collagen (Li et al. 2004; Arya et al. 2002). Interestingly, these UL-VWF strings are broken down by a VWF-cleaving protease A Disintegrin And Metalloproteinase with Thrombospondin Type 1 Motif, 13 (ADAMTS13) that results in the production of less biologically active multimers known as low molecular weight multimers (LMWM) before being cleared from the circulation (Schwameis et al. 2015).

VWF in the Tumour Microenvironment: Conducting from the Front

Successful cancer development is a multifactorial process requiring specific alterations to the tumour cells that can directly enhance cancer proliferation. This is done by targeting the hallmarks of cancer, these hallmarks include avoiding immune destruction, inducing angiogenesis for nutrient supply, sustaining proliferative signalling and eventually invasion and subsequent metastasis to secondary sites (Hanahan & Weinberg 2011). Haematogenous factors are heavily associated with the developmental processes of tumour proliferation, as these factors are located at the precipice of tumour advancement and are a fundamental aspect of the tumour microenvironment. In fact, Armand Trousseau identified the involvement of haematogenous factors in cancer progression as early as 1865 (Trousseau 1865). Therefore, given its roles in angiogenesis (Starke et al. 2011), cell proliferation (Ishihara et al. 2019), inflammation (Chen & Chung 2018) and immune recruitment (Pendu et al. 2006), VWF constitutes an ideal candidate for tumour dysregulation with mounting evidence suggesting VWF does play a role in cancer development.

Indeed, VWF serum levels have been shown to be elevated in a variety of cancers, including breastprostate and colorectal cancers with the greatest increases associated with metastatic disease (Rӧhsig et al. 2001; Damin et al. 2002; Ablin et al. 1988). Furthermore, increased VWF concentrations have been shown to localise at the tumour stroma in colon cancer (Cahlin et al. 2008). Correspondingly, lung cancer patients with elevated VWF levels in cancerous tissues were not found in adjacent healthy lung tissues (Y. Xu et al. 2017). Moreover, localised deposition of VWF at the tumour stroma is a result of tumour cell mediation, studies have demonstrated that the basal secretome of multiple cancer types when co-cultured over EC layers resulted in increased VWF expression (Karagiannis et al. 2014; Y. Xu et al. 2017; Kerk et al. 2010; Aird et al. 1997). Cumulatively, these data place VWF at the stroma within the tumour microenvironment. The tumour microenvironment is the site of tumour proliferation, metastasis and angiogenesis and the subsequent localisation of VWF within this milieu offers it the ability to influence tumour development and associated pathologies (Candido & Hagemann 2013). The release of VWF into the microenvironment results in four main complications including angiogenic dysregulation, inflammation, metastasis and coagulopathies that work in concert with another to promote tumour progression.

Figure 1: VWF in the Microenvironment: A Symphony of Dysregulation. The release of VWF into the tumour stroma begins a cascade of integrative tumour promoting events. VWF can directly induce angiogenesis, inflammation, metastasis and instigate coagulopathies such as VTE. However, each element can interplay with one another with excessive inflammation able to create leaky vasculature for metastasis or induce excessive coagulation factors resulting in coagulopathies.

VWF in Inflammation: Re-stringing the Bow

Induction of inflammation by a tumour facilitates a number of roles critical for tumour advancement. The induction of inflammation results in infiltration of cells, subversion of immune surveillance and helps to propagate endothelial activation resulting in the release of UL-VWF into the local environment (Grivennikov et al. 2010). However, the released UL-VWF strings are highly adhesive and can further the inflammatory process. Concordantly, in Sepsis, thrombotic thrombocytic purpura (TTP) and malaria UL-VWF strings can, while under conditions of shear stress, tether platelets, red blood cells and leukocytes (Chung et al. 2016). Furthermore, VWF can recruit neutrophils and other polymorphonuclear leukocytes (PMN) in inflammatory conditions (Zhu et al. 2016; Petri et al. 2010). Interestingly, this effect is also seen in breast cancer as VWF can actively recruit mast cells, and treatment that results in lowered VWF serum levels diminishes this effect (Nome et al. 2019).

On top of recruiting immune cells to add to the inflammatory milieu, emerging evidence suggests that VWF may also serve directly as a pro-inflammatory agent. In the inflammatory condition of cutaneous inflammation the inflammatory phenotype was diminished by blocking VWF in mice (Hillgruber et al. 2014). Additionally, in an intracerebral haemorrhage model, VWF infusion resulted in elevating pro-inflammatory mediators including IL-6Il-1b and neutrophil induced factor myeloperoxidase (Zhu et al. 2016). Taken together, the evidence suggests VWF can directly modulate inflammatory processes. Consequently, it is tempting to speculate on the role of VWF as an inflammatory agent and whether recruiting and tethering immune cells self-propagates further endothelial stimulation and subsequent VWF release.

Angiogenesis and Cancer: Letting the Music Flow

The availability of blood vasculature in cancer progression is a fundamental step in providing the factors necessary for tumour growth. Angiogenesis is essential for the growth of tumours beyond 0.4mm in diameter (Ferrara 2002). Interestingly, VWF has long been regarded as a biomarker for neovascularisation as well as a measure of microvessel density in both healthy and diseased beds (Chandrachud et al. 1997). Concordantly, it has been elucidated that VWF is a negative regulator of angiogenesis with VWF-/- mice displaying increased vascularisation (Starke et al. 2011). Furthermore, in cerebral ischemia the presence of VWF inhibited angiogenesis, which could then be normalised by VWF (H. Xu et al. 2017).

However, paradoxically VWF has been described as having pro-angiogenic roles in other disease settings. For example, in hind limb ischemia VWF-/- mice displayed reduced angiogenesis and diminished blood flow in contrast to other diseases. Similarly, a recent study found that VWF deficient mice demonstrated decreased pro-angiogenic factors and that VWF acts as a carrier molecule for several growth factors. Consequently, the absence of VWF as a carrier for these growth factors delayed wound healing (Ishihara et al. 2019). Importantly, the role of VWF in a disease state seems to fall along a VWF-angiogenesis axis, for tumour development growing evidence suggests that VWF is pro-angiogenic. As evidenced by one study that demonstrated that ADAMTS13-/- mice, known to induce prolonged persistence of UL-VWF networks, resulted in increased vessel density, size and angiogenesis (Goertz et al. 2016). Furthermore, in glioblastoma patients higher serum VWF levels correlated with higher levels of mortality but increased angiogenic markers as measured by magnetic resonance imaging (MRI) (Navone et al. 2019).

VWF-Mediated Metastasis: Spreading the Music

Metastasis is the movement of primary tumour cells into a secondary site often involving the circulation for spread to distant organs. Given the pre-established idea that VWF can recruit, tether and promote the extravasation of leukocytes it is believed that cancer can hijack this VWF mechanism for its own secondary site invasion. As such, to utilise this function, it has been demonstrated that several non-endothelial tumour cells have acquired de novo VWF expression (Eppert et al. 2005). This tumour-derived expression was found in patient primary tumour biopsies and resulted in increased endothelial and platelet adhesion thereby enhancing metastasis of these cells (Mojiri et al. 2018; Yang et al. 2018).

Additionally, it is reported that VWF can bind to melanoma tumour cells both directly and also through platelet decoration to help draw tumour cells to the EC layer (Bauer et al. 2015). Concordantly, by blocking VWF ligand and platelet receptor, GPIbα, pulmonary metastasis and EC binding was reduced in lewis lung carcinoma cells (Qi et al. 2018). Moreover, it has been shown that VWF SiRNA silencing in gastric cancer also decreased metastasis (Yang et al. 2018). Finally, a study was able to reduce a colon adenocarcinoma tumour by 60% through with an anti-VWF antibody (Karpatkin et al. 1988). The studies suggest that VWF-mediated metastasis occurs by attaching to the tumour cells either with or without platelets to the EC layer.

Coagulopathies: The Crescendo

Cancer-Associated coagulopathies are a common side effect in cancer patients due to the over production of haematogenous factors (Burbury & MacManus 2018). As such, venous thromboembolism (VTE) is reported in up to 20% of cancer patients making it one of the leading causes of death (Khorana et al. 2007). Along with being central to arterial thrombosis and TTP development VWF has also been shown to be a major risk factor in cancer-associated VTE (Rietveld et al. 2019; Pepin et al. 2016; Schwameis et al. 2015; Obermeier et al. 2019). Furthermore, rising serum VWF levels are related to poorer overall survival and increased mortality in patients (Koh et al. 2011; Obermeier et al. 2019).

As such, low molecular weight heparins (LMWH), that function as anticoagulant agents, are used to treat cancer-associated VTE. Furthermore, LMWH have been shown to block prevent VWF release from EC and subsequent tumour invasion through the EC (Kerk et al. 2010; Bauer et al. 2015). However, another study by removing the anticoagulant properties of heparin displayed a reduction of tumour invasion due to the loss of adhesion to the EC layer (Sudha et al. 2012). Therefore, it is possible that the over expression of VWF used for the varying functions of cancer development could lead to venous occlusion and ultimately patient mortality.

VWF’s Swansong: Stealing the Show

There is now evidence to support a relationship between tumour size, metastasis and mortality with rising VWF serum levels. The data suggests that tumour cells can fine-tune the production of VWF through both EC activation and de novo VWF biosynthesis. Harmonious upregulation of VWF serum levels in the tumour microenvironment help to conduct the multi-faceted tumour promoting functions of VWF. These effects include potentially driving a self-proliferative inflammatory cycle, regulating angiogenesis in tumours and finally, promoting metastasis to distant sites. However, this effect can strike the wrong note and produce excessive VWF within the circulation culminating in a buildup of VWF, which can cause fatal thrombotic complications like VTE and TTP. Understanding how tumour cells can compose the growing VWF levels and conduct the various aspects of tumour development through VWF function could help in finding therapeutics to prevent tumour progression and cancer associated thrombosis. 

Figure 2: The Orchestration of VWF in Cancer: VWF levels increase in conjunction with tumour size and metastatic spread. Upon endothelial cell activation, VWF is released into the circulation or into the sub-endothelia. When within the tumour microenvironment VWF can enact many different functions. 1) Inducing Inflammation through immune recruitment and tethering 2) promoting angiogenesis and increasing blood supply to the tumour 3) tethering tumour cells and aiding invasion and distant metastasis. Finally, VWF levels can reach fatal levels and induce cancer-associated coagulopathies. 

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9th Oct 2019 Sean Patmore

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