Published online before print September 4, 2008, doi: 10.1161/ATVBAHA.108.175083
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© 2008 American Heart Association, Inc.
Integrative Physiology/Experimental Medicine |
Contribution of Host-Derived Tissue Factor to Tumor Neovascularization
From the Henderson Research Centre (J.Y., L.M., C.M., J.I.W., J.R.), McMaster University, Hamilton, ON, Canada; the University of Toronto (J.Y.), ON, Canada; Centocor Inc (G.M.A.) Radnor, Pa; the Department of Pharmacology, Toxicology and Therapeutics (J.P.L.) University of Kansas Medical Center, Kansas City, Kansas; the Department of Hematology (G.B.), Washington University School of Medicine, St. Louis, Mo; the Department of Medicine (N.M.), University of North Carolina- Chapel Hill; and the Montreal Children’s Hospital (J.R.), McGill University, QC, Canada.
Correspondence to Janusz Rak, Montreal Children’s Hospital Research Institute, Place Toulon, 4060 Ste Catherine West, PT-232, Montreal, Quebec, H3Z 2Z3, Canada. E-mail janusz.rak{at}mcgill.ca
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Abstract |
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Objective— The role of host-derived tissue factor (TF) in tumor growth, angiogenesis, and metastasis has hitherto been unclear and was investigated in this study.
Methods and Results— We compared tumor growth, vascularity, and responses to cyclophosphamide (CTX) of tumors in wild-type (wt) mice, or in animals with TF levels reduced by 99% (low-TF mice). Global growth rate of 3 different types of transplantable tumors (LLC, B16F1, and ES teratoma) or metastasis were unchanged in low-TF mice. However, several unexpected tumor/context-specific alterations were observed in these mice, including: (1) reduced tumor blood vessel size in B16F1 tumors; (2) larger spleen size and greater tolerance to CTX toxicity in the LLC model; (3) aborted tumor growth after inoculation of TF-deficient tumor cells (ES TF–/–) in low-TF mice. TF-deficient tumor cells grew readily in mice with normal TF levels and attracted exclusively host-related blood vessels (without vasculogenic mimicry). We postulate that this complementarity may result from tumor-vascular transfer of TF-containing microvesicles, as we observed such transfer using human cancer cells (A431) and mouse endothelial cells, both in vitro and in vivo.
Conclusions— Our study points to an important but context-dependent role of host TF in tumor formation, angiogenesis and therapy.
Tumor angiogenesis in animals with low levels of TF (low-TF mice) has not been studied. We report that reduced levels of host-related TF impaired growth of TF-deficient teratomas, but not TF-proficient tumors. We suggest that TF can be shared between tumor and host cells via microvesicles.
Key Words: angiogenesis • tissue factor • tumor • microvesicles • cyclophosphamide
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Introduction |
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Several experimental studies point to the antitumor effects of genetic and pharmacological blockade of the coagulation system including tumor-cell associated tissue factor (TF),1,2 and often through interference with angiogenesis.3–6 However, other reports suggest that TF expression by cancer cells is of little (or no) consequence for tumor aggressiveness.7,8 For instance, experiments with murine embryonic stem (ES) cells with either intact (TF+/–) or disrupted (TF–/–) TF gene originally led Toomey et al to conclude that subcutaneous teratomas could be efficiently generated irrespectively of the TF status of tumor forming (ES) cells.7 A possible explanation of this conundrum could lie in the observation that TF may be expressed by various subsets of host cells often present in the tumor mass, including stromal fibroblasts, inflammatory cells, and the endothelium, all likely involved in regulation of angiogenesis,9 but this possibility has not been explored directly.
See accompanying article on page 1885
The effects of TF on vascular cells could be mediated through localized procoagulant effects of this receptor, irrespectively of its cellular source, leading to the generation of factor Xa and thrombin, followed by the deposition of fibrin and activated platelets.2,10 However, the effects of TF could also be more cell autonomous in nature, and driven by changes in intracellular signaling.11 In this case the coexpression of TF and protease activated receptors (PARs) could trigger signals mediated by thrombin (via PAR-1), or by TF/VIIa complex,11–13 including interactions between the cytoplasmic tail of TF and PAR-2 receptor in endothelial cells.14 Interestingly, deletion of the latter TF domain in transgenic mice altered (increased) their vascular responses in the context of tumors and developing retina.14 However, the angiogenic consequences associated with the obliteration of the entire TF molecule in the host compartment of a growing tumor are still to be examined.
In this regard, studies on host-related TF have been hampered by the embryonic lethality associated with TF gene disruption in mice, and with limitations of the available mouse-specific pharmacological antagonists of this receptor. Moreover, such agents tend to target selectively some (procoagulant), but not all biological activities of TF,15 eg, may not obliterate TF-dependent signaling.11 One way to circumvent these difficulties is to take advantage of a unique strain of mice, in which the endogenous mouse TF gene (mTF) is substituted with a human minigene (hTF) giving rise to the expression of a severely hypomorphic TF phenotype (low-TF mice).16 Homozygous low-TF mice (mTF–/–/hTF+/+) are viable, but unlike their wild-type (mTF+/+) or heterozygous (mTF+/–/hTF+/–) counterparts express only 1% of the expected TF activity, encoded exclusively by the hTF sequence.16 We chose low-TF mice to examine the effects of host-TF on tumor angiogenesis.
Here we show that the growth of three different types of TF-expressing transplantable tumors was unchanged in low-TF mice, as compared to that in their TF-proficient counterparts. However, host TF does exert a number of context-dependent effects, including on blood vessel size in some but not all tumors. Importantly, in the absence of tumor-related TF the growth of tumors in low-TF mice was completely aborted. We propose that TF plays a crucial role in tumor formation, and it can be shared between tumor and host compartment through exchange of membrane microvesicles.
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Materials and Methods |
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Cells and Culture Conditions
Lewis Lung Carcinoma (LLC), B16F1 melanoma, and A431 human squamous cell carcinoma cells were purchased from American Type Tissue Collection (ATCC, Manassas, Va). The cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM; HyClone) supplemented with 10% fetal bovine serum (FBS; Invitrogen). Mouse brain endothelial cells (MBE) were cultured on 1% gelatin coated dishes in EGM2 medium, as previously described.17,18 The labeling of A431 cell surface and related microvesicles with the PKH26 dye (Sigma) was conducted as previously described.6,19 MTF+/– and TF–/– ES cells were generated as detailed elsewhere,7 as were the wild-type ES cells (R1) and their LacZ (C16) and YFP (YC5)-tagged derivatives, a generous gift of Dr Andras Nagy, University of Toronto.20 All ES cells were maintained on gelatinized (0.1%) culture plates in the presence of mitomycin C treated fibroblasts (MEFs; DR4 from American Tissue Culture Collection, Manassas, Va) containing 2ME, nonessential amino acids, leukemia inhibitory factor (LIF/ESGRO, Millipore; 500 U), 15% pretested fetal bovine serum (Hyclone), and with frequent feeding and subculturing. The cells were passaged several times without MEFs before injection into mice.20
Northern Analysis
Expression of TF transcripts was analyzed as described earlier.6 The membranes were examined using the Typhoon 9410 Phosphoimager (Amersham Biosciences) and autoradiographed.
Mice
Low-TF mice were described previously.16 For tumor studies the mice were backcrossed into either C57BL/6 (LLC, B16F1), or (ES-teratoma) severe combined immunodeficiency (SCID) background.
Tumor Generation and Analysis
Tumorigenic cells were collected and injected subcutaneously in 0.1 mL of phosphate buffered saline (PBS), at the following predetermined numbers: 7 to 10x105 (LLC), 2x106 (B16F1) and 107 (ES cells) under isoflurane anesthesia (1% to 3%). Tumor growth was monitored as described earlier.20 All in vivo experiments were approved by the institutional Animal Care Committees at McMaster and McGill Universities and in accordance with the Canadian Council of Animal Care (CCAC) guidelines.
Therapy
Cyclophosphamide (CTX; Procytox, ASTA Medica Ltd) was used according to previously published maximal tolerated dose (MTD) and low dose/metronomic (LD) protocols.21 Under the MTD regimen the drug was injected at 150 mg/kg on days 2, 4, and 6 after tumor cell inoculation, and then on days 23, 25, and 27. Increase in mortality occurred after the first round of injections. For metronomic (LD) therapy the drug was injected at the dose of 150 mg/kg on day 2 after tumor inoculation and then daily at 25 mg/kg.21 A monoclonal antihuman TF antibody (TF8–5G9; Centocor Inc.; 5 mg/kg) or vehicle was injected intraperitoneally into low-TF mice (hTF) harboring LLC tumors (mTF) 3 times a week beginning on day 2 post tumor cell inoculation.
Experimental Metastasis
A single cell suspension of 105 LLC cells per 0.2 mL PBS was injected into the prewarmed dilated lateral tail veins of the respective wild-type or low-TF syngeneic C56BL/6 mice, as indicated. Mice were euthanized after 28 days and autopsied. Lungs were excised preserved in Bouin fixative, and surface nodules were counted under a dissecting microscope, as described.22
Tissue Staining
Microvasculature of tumors was assessed by immunostaining for endothelial (CD31/PECAM; CD105/endoglin), or pericyte markers (
SMA), as described elsewhere.23
Data Analysis
The experiments were repeated 2 to 5 times, mostly 3 times, with similar results. The number of experimental mice per group in all in vivo studies varied between 4 to 10 for each experiment. The results were expressed as mean±SD for each group. Unpaired Student t tests were used to examine the differences between groups. Probability values <0.05 were considered significant unless otherwise stated.
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Results |
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Host TF and Blood Vessel Patterning in Melanoma
In syngeneic mice, B16F1 mouse melanoma cells form rapidly growing tumors containing cuffs of viable malignant parenchyma clustering around distinctly large (15 to 30 µm) blood vessels, in which endothelial layers are covered with well-differentiated pericytes, as determined by staining for CD31/PECAM (or CD105/endoglin) and alpha smooth muscle actin (
SMA), respectively (Figure 1A). These host cells are known to express TF.13 Injection of B16F1 cells into mice with intact TF levels (mTF+/–) or into their hypomorphic, low-TF counterparts resulted in indistinguishable rate of tumor formation (Figure 1B), however the tumor vascular microarchitecture has undergone a significant rearrangement (Figure 1C). Thus, in low-TF mice tumor blood vessels were still covered with pericytes, but for the most part were considerably smaller in size (mostly <15 µm in diameter) than those in TF-proficient mice (both mTF+/+ and mTF+/–).
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Unchanged Growth, Vascularity, and Metastasis of LLC in Low-TF Mice
Similarly to B16F1 melanoma, LLC cells form aggressive tumors in vivo, but with vastly different vascular patterns. A defining feature in this case is the absence of large vessels and a dense network of small capillaries (<15 µm), largely devoid of SMA-reactive pericytes (Figure 2A). Although the TF content of LLC tumors increases in vivo, possibly with some contribution of host TF (Figure 2B), the latter does not influence LLC progression or angiogenesis, as tumor growth, experimental metastasis and vascular patterns were virtually identical in wild type (mTF+/+), heterozygous (mTF+/–), and low-TF mice (Figure 2C and 2D, data not shown). Tumor growth remained unchanged even when tumor-bearing low-TF mice were treated with an antihuman TF antibody (TF8–5G9), which would selectively obliterate the residual host TF (encoded by the hTF transgene), but not tumor/LLC-related (mouse) TF16 (Figure 2C).
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Host-Related TF Modulates Toxic Side Effects of Cyclophosphamide
Anticancer agents often trigger procoagulant events.24 We asked whether host TF may play a role in this context, or in responses to other prototypic therapies such as administration of cyclophosphamide (CTX) at maximal tolerated doses (MTD), or at antiangiogenic/metronomic, low doses (LD), both previously validated in the LLC model.21 As shown in Figure 3A, the responses of LLC tumors to MTD or LD protocols of CTX were unaffected by the host TF status. Interestingly, MTD therapy led to some mortality, but only in TF-proficient (mTF+/–) tumor bearing mice and not in their low-TF counterparts (Figure 3B). Moreover, we observed that untreated low TF (SCID) mice exhibit markedly larger spleens than their mTF+/+ or mTF+/– controls (Figure 3C and 3D). This was also the case in LLC tumor bearing mice, where low TF hosts contained more extensive lymphocytic infiltrates in areas surrounding white pulp. While CTX treatment reduced spleen size and cellularity in all mice, low TF mice retained greater amounts of spleen mass and white pulp nodules (Figure 3E through 3I). Interestingly, these mice also had reduced fibrin deposition in their kidney (not shown). This may suggest that low levels of host TF may have a protective role against some of the side effects of anticancer therapy, likely through a combination of coagulation-dependent and hematopoietic effects that remain to be elucidated.
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0.05; (E) and morphology (F through I) in LLC bearing mice 24 hours after the last dose of MTD CTX vs controls. Noticeable are lymphocytic infiltrates (ly) in low TF mice with retention of white pulp (wp) – H&E staining.
Host TF Expression Is Essential for Growth of TF-Deficient Teratomas
In agreement with the aforementioned results, subcutaneous injection of TF-expressing and tumorigenic embryonic stem (ES) cells led to unperturbed formation of aggressive and angiogenic teratomas in both wild type and low-TF mice (Figure 4).23 In this case the mice were backcrossed to the SCID background to avoid immune rejection. It is of note that the model of ES teratoma afforded us a unique opportunity to interrogate TF depletion in both the host and tumor cell compartments simultaneously, eg, by including TF–/– ES cells7 and low-TF mice. Thus, we observed that both TF+/– and TF–/– ES cells grew as vascular teratomas in SCID mice with wild type levels of TF.7 Remarkably, this process was selectively aborted in the case of TF–/– ES cells (but not TF+/– cells) injected into low-TF SCID mice (Figure 4B). This result suggests that TF is essential for the malignant teratoma growth to occur, and this requirement can be met through TF contribution by either tumor, or host cells.
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ES Cell–Derived Teratomas Recruit Host Blood Vessels
The aforementioned result is novel and potentially important. However, totipotential capacity of ES cells to differentiate25 may imply that tumor blood vessels may in this case originate from tumor (ES) cells and not through recruitment of host endothelium, a phenomenon known as vasculogenic mimicry.26 Indeed, ES teratomas contain complex mixtures of histological elements including abnormal capillaries (Figure 4C through 4E). To unequivocally distinguish tumor (ES) and host (mouse)-derived elements we used several molecular tags, including: yellow and green fluorescent proteins (YFP and GFP), as well as beta galactosidase (LacZ; Figure 4C through 4H). Thus, TF-proficient (mTF+/+) ES cells (R1) tagged with LacZ were injected into untagged SCID mice, and we determined that all tumor-associated CD31-positive endothelial cells originated from the LacZ-negative host compartment (Figure 4F). We also generated teratomas from unlabeled ES cells that were injected into YFP/SCID mice harboring a constitutively expressed YFP transgene.23 Again, staining for CD105 and YFP revealed dual positivity (host origin) of all tumor-associated blood vessels (Figure 4G). Finally, YFP-labeled ES cells were used to generate tumors in untagged SCID mice and, again, we observed essentially no overlap between YFP and CD105 staining, except for a solitary blood vessel found in one section (Figure 4H). This enforces the notion that ES teratomas, like many other cancers, rely on recruitment of the host-derived vasculature, which may serve as a source of TF to support growth of TF–/– tumors shown in Figure 4B.
Endothelial Cell Uptake of Tumor-Related TF-Containing Microvesicles
The aforementioned experiments (Figure 4B) raise the possibility that TF activity may be shared between tumor and host cell compartments. One mechanism by which this could occur is through intercellular exchange of TF containing microvesicles (MVs).27–29 To test this, we used the human epithelial carcinoma cell line, A431, which produces ample amounts of TF (Figure 5A), which is also shed into conditioned medium as membrane MVs.28 To test whether this material could, indeed, be transferred to endothelial cells, the membranes of A431 cells were labeled with the fluorescent dye (PKH26) and their conditioned medium (containing MVs) was incubated with TF-negative mouse brain endothelial cells (MBEs). This led to a lasting acquisition by the latter cells of PKH26 fluorescence, human TF antigen expression (not shown), and TF-dependent procoagulant activity (Figure 5D), all derived from A431 tumor cells. These changes did not occur when A431-derived material was depleted from the MV fraction by high-speed centrifugation.28 Moreover, host blood vessels in A431 xenografts in SCID mice were positive for both human TF (Figure 5E through 5G) and endothelial markers (CD105), suggesting the intercellular transfer of TF taking place in vivo (Figure 5H).
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Discussion |
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In this study we report several new findings related to the role of host TF in tumor angiogenesis and progression. Notably, we provide evidence that TF expression may be essential for tumorigenesis, at least in some settings, because a simultaneous depletion of this receptor from both tumor and host compartments led to a complete arrest of tumor formation. The nature of this effect remains presently unknown, but may include thrombin-dependent or independent essential effects of TF on hemostasis or on signaling in endothelial, stromal, or tumor cells.11,13 In spite of this uncertainty, our results may reconcile the long-standing controversy, as to whether TF contributes to primary tumor growth and angiogenesis3–6,30,31 or is irrelevant for these processes.7,8 Using the same TF–/– ES cell lines7 that have originally led to the latter question we demonstrated that the removal of TF from cancer cells may, at least in some cases, be insufficient to block tumor formation, notably because of compensatory effects of the host-derived TF (and vice versa). We propose that this TF "sharing" between tumor and host compartments could occur through the exchange of TF containing microvesicles, as recently described for inflammatrory cells and platelets.29 In particular, we suggest that such TF transfer could contribute to procoagulant and proangiogenic reprogramming of endothelial cells in TF expressing tumors9 (Figure 5E). In addition, our study provides an important validation of the widely used ES teratoma model, by documenting the absence of ES-derived blood vessels (vasculogenic mimicry) in these tumors.
Unlike ES cells, many cancer cell types express TF under influence of oncogenic alterations.6 We postulate that in such a context tumor-derived TF may assume a dominant role in tumorigenesis and can be targeted therapeutically, as recently demonstrated by Versteeg32 and others.3,6,33 In these settings host-related TF makes a minimal quantitative contribution to local growth or metastasis, as documented by our experiments with several mouse tumor models (LLC, B16F1).
Interestingly, low levels of host TF led to qualitative repatterning of the tumor microvasculature in B16F1 melanoma. We suggest that lack of similar effects in other tumors tested is attributable to their a priori small caliber vasculature. It is unclear how host TF may impact blood vessel patterning. Although thrombin and PAR-1 were implicated as regulators of vascular development,12,13 our injections of B16F1 cells into PAR-1–/– mice did not recapitulate the vascular patterns observed in low-TF mice (unpublished observation, J. Luyendyk, L. May, and N. Mackman, 2006). Although tumors in low-TF mice were of unchanged size, it is possible that vascular repatterning may influence angiogenic pathways in a qualitative manner, and impact other vascular aspects of tumorigenesis, such as metastasis and therapeutic responses.
We were intrigued by the partial protection of LLC tumor bearing low-TF mice from the toxicity of high doses (MTD) of CTX. This effect was unlikely attributable to a differential drug distribution, pharmacodynamics, or direct toxicity against tumor cells. In this regard, prothrombotic effects of anticancer chemotherapeutics are well established, including in the clinic.2,34 These events may be attributed to endothelial injury,35,36 suppression of the protein C pathway,24 upregulation of TF, and decrease in levels of the tissue factor pathway inhibitor (TFPI).37 Indeed, we observed a lower fibrin deposition in kidneys of CTX-treated tumor bearing low-TF mice (data not shown). These mice demonstrated larger spleens containing greater reserves of lymphocytic cells, relative to their wild-type counterparts. This finding may suggest a hitherto unappreciated role of TF in modulating hematopoietic toxicity of CTX.
Collectively, our findings reveal several novel properties of host TF. We suggest that a complex role of this receptor in tumor growth, angiogenesis, vascular patterning, and drug toxicity has been previously obscured by exclusion of host TF from experimental studies. We observed that the effects of host-related TF are highly context dependent and different in tumors driven by aberrant differentiation (teratoma) or genetic aberrations (mouse melanoma, lung carcinoma). Therefore, defining a universal role for TF in cancer may prove elusive, and targeting this receptor in various tumor settings may require a better understanding of cellular sources of TF and their specific contributions to the malignant process. Still, our study suggests that TF, in its cell-associated and microvesicular forms, may represent an attractive anticancer target, at least in some settings, especially as a regulator of tumor growth or modulator of anticancer drug toxicity.
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Acknowledgments |
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We thank our colleagues, especially to Dr Petr Klement, for their feedback and our families for their inexhaustible support and patience. Danuta Kak assisted in the preparation of figures.
Sources of Funding
This work was supported by operating grants to J.R. from the Canadian Cancer Society (CCS). J.R. is a recipient of the Jack Cole Chair in Pediatric Oncology at McGill University. J.I.W. holds the Canada Research Chair in Thrombosis and the HSFO/JF Mustard Chair in Cardiovascular Research and is PI on the Team Grant from Canadian Institutes of Health Rresearch, which also contributed operating funds to this work.
Disclosures
N.M., NIH grant pending; J.R., CCS grant (M), Nuvelo–honorarium (m), NIH grant consultantship (m); M>$10 000, m<$10 000.
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Footnotes |
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J.Y., L.M., and C.M. contributed equally to this study.
Original received March 28, 2008; final version accepted August 18, 2008.
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F. Schaffner and W. Ruf Tissue Factor and PAR2 Signaling in the Tumor Microenvironment Arterioscler Thromb Vasc Biol, December 1, 2009; 29(12): 1999 - 2004. [Abstract] [Full Text] [PDF]
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L. V. M. Rao and U. R. Pendurthi Sharing Tissue Factor: A Winning Strategy in Tumorigenesis Arterioscler Thromb Vasc Biol, November 1, 2008; 28(11): 1885 - 1886. [Full Text] [PDF]
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