tissue factor proangiogenic signaling in cancer progression

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Thrombosis Research 129, Supplement 1 (2012) S127S131

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Tissue factor proangiogenic signaling in cancer progression

Florence Schaffner, Naho Yokota, Wolfram Ruf*Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA, USA

A R T I C L E I N F O A B S T R A C T

Keywords:Tissue factorProtease activated receptorAngiogenensisCoagulation factor VIIMetastasisProtein C receptor

Cancer progression from a dormant, non-vascularized benign tumor to metastatic disease is a multiple stepsprocess that critically depends on contributions from the hemostatic system. Tissue factor (TF), protease ac-tivated receptors (PARs), factor VIIa, and the endothelial protein C receptor (EPCR) are expressed by tumorcells as well as the host compartment. These components of the hemostatic system regulate tumor growth,angiogenesis and metastasis. Here we review the evidence that TF-dependent signaling is the major driver of primary tumor growth, whereas TF-initiated coagulation and interactions of procoagulant tumor cells withthe host compartments initiate multiple pathways that support and regulate the efficiency of metastatic tu-mor dissemination.

2012 Elsevier Ltd. All rights reserved.

1. Tissue factor procoagulant activity in hematogenousmetastasis

Coagulation is an important step of tumor dissemination andtissue factor (TF) on tumor cells is the key initiator of the coagula-tion activation in experimental lung metastasis [1]. Reconstitution

of TF-decient cells with procoagulant TF [24], modulation of TF activity by antibody [1] and inhibitors including tissue factorpathway inhibitor (TFPI) [5,6], or TF knock-down [7] demonstratethat TF is crucial for the survival of metastatic cells arrested in themicrocirculation. The TF-VIIa complex activates coagulation [4] andgenerates thrombin that is a central mediator for successful tumorcell implantation in pulmonary metastasis models [8]. Thrombinactivates platelet through protease activator receptor (PAR) 4 inmice [9]. Activated platelets use surface assembled bronectinand von Willebrand factor (VWF) as an adhesive bridge to tumorcells [10] and thrombin-generated brin further stabilizes tumorcell-associated clots. Platelets and brin protect tumor cells fromnatural killer (NK) cell-mediated attack and thus assure the survivalof metastatic cells after arrest at the endothelial interface [2,11

13]. Recent studies show that these initial interactions of tumorcells with the endothelium are regulated at multiple levels by thehemostatic system.

2. Regulation of thrombin thresholds at the endothelialinterface

Thrombin not only promotes clot formation, but is also cru-cial for the anticoagulant pathway upon binding to endothelial

* Correspondence to: Wolfram Ruf, Department of Immunology and MicrobialScience, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla,CA 92037, USA. Tel.: +1 858-784-2748; fax: +1 858-784-8480.

E-mail address: [email protected] (W. Ruf).

0049-3848/$ see front matter 2012 Elsevier Ltd. All rights reserved.

cell-expressed thrombomodulin (TM). The TM-thrombin complexgenerates activated protein C (aPC) facilitated by binding of PCto the endothelial protein C receptor (EPCR). The anticoagulantsystem, specically TM, aPC, and EPCR, has recently been shownto play important regulatory roles in tumor metastasis [1416].TM mutant mice (TM Pro ) have a single amino acid substitution

(Glu404 /Pro) and exhibit 1,000-fold decreased PC activation and100-fold reduced binding affinity for thrombin [17]. The resulting

combined loss of local thrombin neutralization and diminished aPCgeneration results in a dramatically increased metastasis in TM Pro

mice that is dependent on tumor cell TF, circulating prothrombin,as well as platelets [14].

Diminished activation of the anticoagulant pathway is at leastin part responsible for the enhanced metastasis in TM Pro mice.Although EPCR is expressed by tumor cells [1820], transgenicoverexpression of endothelial cell EPCR in the host compartmentor treatment with recombinant aPC markedly reduce experimentalmetastasis in liver and lung [16], whereas inhibition of endogenousaPC increases metastasis [15]. Interestingly, when the anticoagulantactivity of the endogenous aPC is blocked, brin depletion has

only a minimal effect on metastasis [13], indicating that a hyper-thrombotic state diminishes the contributions of certain thrombintargets to successful tumor cell implantation at metastatic sites.EPCR-aPC-PAR1 signaling promotes endothelial barrier stabilizationthrough sphingosine 1 phosphate receptor 1 cross-activation andthrombin-PAR1 signaling can disrupt endothelial barrier integrity[21,22]. Therefore, regulation of barrier function may contributeto the anti-metastatic effects of aPC [15,23]. However, PAR1-deciency, which in the mouse circulatory system mainly affectsendothelial thrombin signaling, does not alter metastasis [9]. Fur-ther studies are needed to fully understand the precise mechanismsby which a prothombotic state enhances metastasis.


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3. Multicellular interactions contribute to successful tumor cellmetastasis

Substantial evidence indicates that the initial recruitment of platelets by tumor cells has broader effects on multiple cell typesin the metastatic niche. Coagulation activation not only generatesa protective barrier against immune surveillance, but facilitatesthe initial steps of tumor cell extravasation [24,25]. Plateletsdirectly stimulate tumor growth and inuence angiogenesis byreleasing a variety of growth factors and chemokines stored in theirgranules [26,27]. The aggregates of activated platelets and tumorcells arrested at the endothelium furthermore recruit leukocytesinvolving mechanisms of tethering and adhesion typically employedin inammation. These interactions are supported by selectins,integrins, platelet receptors, and soluble and extracellular matrixproteins.

Selectins, a family of transmembrane cell adhesion moleculesexpressed by platelets (P-selectin), endothelial cells (P- and E-selectin), and leukocytes (L-selectin), mediate the initial attachmentof circulating tumor cells on the endothelium and the subsequentrecruitment of leukocytes [28]. Tumor cells can express selectinligands, such as P-selectin glycoprotein (PSGL)-1, mucins, and CD44that further contribute to tumor cell-platelet interaction and alsodirectly trigger clot formation [29]. Experimental metastasis issignicantly reduced in the absence of P- or L-selectin on hostcells, while no attenuation of metastasis was observed in E-selectindecient mice [3036]. However, mice overexpressing E selectin inliver redirects metastasis from lungs to liver [37]. The combinedabsence of P- and L- selectin further reduced metastasis, indicatingbroad roles of blood- and endothelial cell-expressed selectins insupporting multicellular aggregate formation at sites of metastasis[33].

Selectins mediate initial tethering that is followed by integrin-mediated rm cell adhesion. Key integrins supporting multicellularaggregates in the metastatic process are IIb3 on platelets [38,39],v3 on tumor cells [40], and M2 on leukocytes. Platelet P-

selectin ligation of PSGL-1 on leukocyte activate integrin M2which plays an important role in mediating leukocyte interactionswith tumor cells involving brinogen and brin bridging to in-tegrin v3 and ICAM-1 [41,42]. Interaction between ICAM-1 onmelanoma cells and 2 integrins on leukocyte facilitates adhesionto the endothelium and subsequent extravasation in in vitro models[43].

Selectin-dependent interaction between tumor cells, platelets,and leukocytes induces the activation of endothelial cells to re-lease the C-C motif chemokine 5 (CCL5), which recruits monocytesto support metastasis [44]. The important role of leukocyte re-cruitment to sites of metastasis is further demonstrated by thepro-metastatic effect of the chemokine CCL2 (MCP-1) that canbe derived from either stromal or tumor cells. CCL2 leads to

the recruitment of inammatory monocytes, which express thechemokine CCL2 receptor CCR2, as well as to the association of macrophages with metastasizing tumor cells [45]. These stud-ies provide initial evidence that tumor cell-initiated formation of micro-thrombi supports complex heterotypic cellular interactionscontributing to successful metastatic tumor cell dissemination.

4. Hemostatic mechanisms triggering early events in metastasis

The hemostatic system is not only pivotal for the nal stagesof metastatic homing, but plays critical roles in the initiation of metastasis. TF is upregulated in tumor cells selected for increasedintravasation into the blood stream from the highly vascularizedchicken chorioallantoic membrane (CAM) [46]. In these cells se-lected for more efficient metastasis in the CAM model, blockingTF by either RNA silencing or antibody inhibition of specically

TFs coagulation activity reduced tumor cell intravasation withoutimpairing primary tumor growth. The tumor microenvironment isconstantly exposed to components of the hemostatic systems due tothe abnormal architecture and hyperpermeability of tumor vessels.A recent study uncovered an intriguing role for platelet interactionswith tumor cells to promote early stages of metastasis. Activatedplatelets release large amounts of TGF which synergizes withdirect platelet-tumor cell contacts to activate TGF /Smad and NF-B pathways in cancer cells [47]. These signaling events promoteepithelial to mesenchymal transition of cancer cells, a key featureof more metastatic tumor cell populations. These studies documenta wide range of effects mediated by distinct components of thehemostatic system on early and late stages of tumor progressionand metastasis.

5. TF signaling in tumor angiogenesis

TF also supports primary tumor growth [4851]. Unlike the pro-coagulant roles of TF in metastasis, our studies show that the tumorgrowth promoting activities of TF are predominantly dependent ondirect cell signaling [52]. Tumor cells can ectopically synthesize VIIa,either constitutively or in response to hypoxia [53,54] and onco-genic growth factor receptors upregulate the entire complement of the upstream TF signaling complex [55]. The tumor cell-expressedTF-VIIa complex cleaves PAR2 to inuence important aspects of tumor progression, including survival, immune modulation andangiogenesis. TF-VIIa-PAR2 G protein-coupled receptor signaling in-duces pro-angiogenic factors, such as IL-8, CXCL1, or VEGF [5659]and growth factors for myeloid cells and macrophages [57].

TF-VIIa-PAR2 signaling is not necessarily restricted to autocrinetumor cell signaling. For example, glioblastoma cells express highlevels of TF that drives tumor progression [60,61]. In the hypoxictumor microenvironment, glioblastoma cells also release TF + microparticles that elicit TF-VIIa signaling in trans by targeting hypoxicendothelial cells that upregulate PAR2 [62]. Microparticle-inducedtrans-signaling specically induces endothelial cell expression of

HB-EGF that supports angiogenesis and activates the MET receptoron tumor cells to enhance their survival, proliferation and migration[63] and potentially induce a prothrombotic state [64]. Thus, TF-VIIa-PAR2 signaling contributes to tumor initiation and progressionunder hypoxia.

The critical role of TF-VIIa-PAR2 signaling in tumor angiogenesisis supported by genetic and pharmacological evidence. In thepolyoma middle T (PyMT) oncogene-driven model of spontaneousbreast cancer development, tumor progression occurs in the contextof an immune competent host and the angiogenic switch isdependent on the recruitment of immune cells and macrophagesto the tumor stroma [65]. PAR2-deciency results in delayed PyMTtumor development, low levels of the chemokine CXCL1 (KC) in thetumor stroma, and reduced counts of F4/80 positive macrophages

in early tumors compared to wild-type mice [66]. Reconstitutionexperiments of PAR2-decient tumor cells derived from these miceshowed that tumor cell autonomous TF-PAR2 signaling supportedCXCL1 induction in vitro and a more aggressive tumor growthphenotype in vivo [67].

In clinical breast cancer biopsies, upregulation of PAR2 andTF was associated with a marked phosphorylation of the TFcytoplasmic domain [68]. Only patients with phosphorylated TFhad a cancer relapse and genetic studies in mice showed thatPAR2 signaling was important for tumor cell TF cytoplasmic domainphosphorylation in vivo. Conrming that the TF cytoplasmic domainplayed an important role in tumor progression, PyMT tumordevelopment was delayed in mice lacking the TF cytoplasmicdomain similar to PAR2-decient animals [67]. Late stage tumors of TF cytoplasmic domain-deleted mice also displayed altered vesselarchitecture and reduced macrophages numbers in the tumor


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Conict of interest statement

Wolfram Ruf has pending patent applications on the use of antibodies described in this review.

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tissue factor proangiogenic signaling in cancer progression

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