Stem Cell Rev (2008) 4:169–177 DOI 10.1007/s12015-008-9028-y
Endothelial and Hematopoietic Progenitor Cells (EPCs and HPCs): Hand in Hand Fate Determining Partners for Cancer Cells Süleyman Ergün & Hans-Peter Hohn & Nerbil Kilic & Bernhard B. Singer & Derya Tilki
Published online: 8 July 2008 # Humana Press 2008
Abstract Tumor growth and metastasis need new vessel formation by angiogenesis provided by mature endothelial cells and postnatal vasculogenesis provided by endothelial progenitor cells (EPCs). Emerging data suggest a coordinated interaction between EPCs and hematopoietic progenitor cells (HPCs) in these processes. The complexity of the mechanisms governing the new vessel formation by postnatal vasculogenesis has increased by new evidence that not only bone marrow derived EPCs and HPCs seem to be involved in this process but also local progenitors residing within the vascular wall are mobilized and activated to new vessel formation by tumor cells. This review attempts to bring these systemic and local players of postnatal vasculogenesis together and to highlight their role in tumor growth and mestastasis. Keywords Endothelial . Hematopoietic progenitor cells . Cancer cells
S. Ergün (*) : H.-P. Hohn : B. B. Singer Institute of Anatomy, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany e-mail:
[email protected] N. Kilic Department of Hematology and Oncology, University Hospital Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany D. Tilki Department of Urology, University Hospital Groβhadern, Munich, Germany
Introduction Until a decade ago it was generally accepted that new blood vessels for the vascularization of tumor tissue are only generated from pre-existing mature blood vessels, a process called angiogenesis [1–8]. Vasculogenesis, defined as the de novo development of blood vessels from mesenchymal/ mesodermal progenitors, however was believed to be limited to the period of embryonic development [9, 10]. Asahara and co-workers were able to show for the first time that circulating endothelial progenitor cells (EPCs) exist and are recruited for tumor neovascularization [11]. Thus, it was shown that the new formation of blood vessels in adult can also be provided by vasculogenesis, a process which has been called “postnatal vasculogenesis”. Extensive studies during the last 6–7 years led to the identification and characterization of the peripheral blood (C-EPCs) and bone marrow (BM-EPCs) as the sources of EPCs [11–15]. More recently, we were able to demonstrate that CD34(+) EPCs reside in a distinct zone of the human adult vascular wall which form vessel sprouts and can be activated to formation of capillary-like structures by tumor cells using arterial ring assay [16]. Due to their location these progenitor cells were called vascular wall-resident EPCs. Further, recent studies demonstrated that the vascular wall and/or the perivascular zone serve as niches not only for EPCs but apparently also for cancer stem cells [17–19] and probably also for tissue resident HPCs inside as well as outside bone marrow [16, 20, 21]. This review will focus on the interaction between HPCs and EPCs during tumor cell metastasis and vascularization, and particularly highlights the potential role of the vascular wall-resident EPCs in these processes.
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HPCs, EPCs and Tumor Vascularization by Angiogenesis and Postnatal Vasculogenesis It is beyond doubt that a tumor cell cluster cannot grow beyond a microscopic size of a small nodule with a diameter of a few millimetres without new vessels [22]. This dependency on new blood vessels and also on new lymphatics does not only exist for the growth of the primary tumor but even more for metastatic spread [22–25] and for the growth of metastatic lesions at distant sites. New data recently provided by S. Rafii and his co-workers show the formation of a “pre-metastatic niche” by bone marrow derived VEGFR-1(+) cells at the metastatic sites before tumor cells arrive these places [26]. The authors also demonstrate that EPCs are not only involved in tumor blood vessel formation, but that they moreover move to the sites of metastasis nearly concurrently with tumor cells [26]. That means that the EPCs are there even before blood vessel formation has taken place. Leastwise as interesting is the finding by this group that VEGFR-1-positive bone marrow derived HPCs form the pre-metastatic sites in a tumor-specific manner. These emerging findings suggest that different types of progenitors, particularly those of the haematopoietic system and of endothelial cells, hand in hand play an important role in the “guidance” and survival of tumor cells along their way to metastatic sites and for their vascularization at the metastatic sites. This entails a paradigm shift from the conventional view of vascularization of metastatic tumor cells only by angiogenesis to vascularization of metastatic lesions by both angiogenesis and postnatal vasculogenesis provided by EPCs. The strong interdependence between bone marrow derived VEGFR-1(+) HPCs, EPCs and cancer cells suggest that the close interaction between these cells creates a unique microenvironment which is crucial for the survival of tumor cells during their burdensome course to the metastatic site. Thus, determination of the interaction patterns between tumor cells, HPCs and EPCs, and exact identification of sources of EPCs contributing to tumor vascularization would essentially improve our understanding regarding tumor vascularization and anti-angiogenic tumor therapy.
Vascular Wall as a Niche for EPCs and HPCs A connection between haematopoietic and endothelial cells is already apparent in embryologic development. The common stem cells, the so-called hemangioblasts, emerge from mesodermal stem cells in the form of small blood islets in the yolk sac. Cells in the circumference of these islets soon differentiate into endothelial cells, mainly by effects of VEGF (vascular endothelial growth factor) and
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FGF-2 (fibroblastic growth factor-2). Further they form vascular tubes as the first step of vascular development. This leads to the formation of the aorta and its main branches in the embryologic development. All other blood vessels, including the vascularization of organs during the fetal period, were believed to develop through angiogenesis [9, 10]. This view served the basis for the hypothesis that tumor vessels can only be generated via angiogenesis. Today we know that the adult organs or tissue components such as bone marrow, peripheral blood and some tissues possess a great potential of vascular progenitor cells, which reside in different niches of the body and can be accessed if required for both physiologic and pathologic processes as tumor growth, wound healing and artherosclerosis [13, 16, 27–38]. The existence of these endothelial progenitor cells is beyond doubt. However, the contribution of these cells to adult vascular development, which has mainly been studied focussing C-EPCs and BM-ECPs, raised doubt because of small number of EPCs integrated into new vessels. Beside experimental tumor models, which showed a tumor-typedependent involvement of EPCs in tumor vascularization [13, 25, 39–42], there were substantiated data showing little or even no contribution of BM-EPCs or C-EPCs to tumor vascularization [43]. In some recent studies it was shown that bone marrow derived EPCs contribute to generation of peri-endothelial cells rather than endothelial cells and new vessel formation [44]. Despite some conflicting results the main body of the literature showing in vitro and in vivo data suggest a clear contribution of the BM-EPC and CEPCs to the new formation of blood vessels and also to tumor vascularization. Particularly, the recently published in vivo data suggest that a few amount of the bone marrow derived EPCs is sufficient to promote the vascularization of metastatic lesions substantially [45]. According to Gao et al., only 12% of the EPCs were involved in the formation of tumor vessels within the metastatic growth of tumor cells but this was obviously enough to induce and to sustain the tumor vascularization and growth as they reversely conformed these findings by suppression of EPC number by 96% via inhibition of Id1, an angiogenesis promoting transcription factor. However, the confusion raised regarding the contribution of EPCs to the formation of new vessels is a) due to the still not exactly standardized methods for phenotypic characterization of these cells via detection of cell surface markers such as CD34, VEGFR-2, Tie-2, VEcadherin and c-Kit which are not expressed exclusively in EPCs, b) due to focusing on the contribution of the EPCs to new vessel formation physically while neglecting their functional interaction with other cell types inducing and accelerating angiogenesis and/or postnatal vasculogenesis, and c) due to neglecting the local sources for EPCs as shown for some organs [27], and particularly for the wall of blood vessels [16, 28, 33, 38, 46, 47].
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Fig. 1 Graphical demonstration of a cross section through middle sized artery. The EPCs are localized within a distinct zone of the vascular wall called “vasculogenic zone” which is localized mainly within the adventitial layer but in close proximity to the smooth muscle cell layer of the vascular wall
vasa vasorum
tunica media with smc v asculogenic ” zone“
tunica intima with mature endothelial cells
Thus, one of the important issues is to exactly know the niche or niches of the EPCs which have to be addressed in order to be able to manipulate them therapeutically. In this regard, the findings of the last few years show a growing impact of the tissue-resident EPCs, potentially present in
adventitia with connective tissue
different organs including the vessel wall. In this review we want to focus the attention of readers on the vascular wallresident EPCs and stem cells. First data indicating the existence of the EPC in the vessel wall were coming from the studies performed on embryologic and/or foetal vascu-
Fig. 2 Higher magnification of the vascular wall as demonstrated in Fig. 1. Detailed studies revealed that not only EPCs but also a few amount of CD45(+) HPCs are present within the vasculogenic zone of the vascular wall. Interestingly, CD34(+) EPCs also cover the wall of the vasa vasorum
vasculogenic zone
CD45(+) HPC
CD34(+) EPCs
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lature [28]. Few years later it was reported that the wall of adult arteries contain EPCs [38]. Shortly after this report it was shown that EPCs reside in a-distinct zone of the vascular wall at the border between smooth muscle cell and adventitial layers, which was called “vasculogenic zone” of the vascular wall [16] (Fig. 1). More recently, the functional impact of the vascular wall-resident EPCs for blood vessel formation and tissue regeneration was underlined by studies on skeletal muscle tissue where it could be shown that only the vessels serve the source for EPC in this tissue [33] and that the EPCs contribute to skeletal muscle tissue regeneration. However, emerging data suggest that the vascular wall does not only harbour EPCs but apparently also CD45 (+) HPCs [16] (Fig. 2) and finally cancer stem cells (CSC) in the peri-vascular niche [17–19, 48–51]. Without going into the detail regarding the CSC [52], this is not the focus of this review, these data suggest a unique microenvironment in the vascular adventitia which brings HPCs and EPC in a close contact and is obviously of benefit for their survival via secreted factors from both cell types. It is conceivable that these factors may act reciprocally on both cell types in a paracrine manner and could keep them not only alive for a long time but maintain their potency of self renewal. Moreover, the vascular adventitia functions as an interface between the inner part of the vascular wall (intima and media layers) and the perivascular space or tissue. In this particular location, these cells can easily be mobilized from the vascular wall into the perivascular space (Fig. 3), as it was shown, by angiogenic stimuli generated by ischemic events or processes of malignancy, but they could also be mobilized through the entire vascular wall towards the vascular lumen, e.g. by atherosclerotic processes. Under ex vivo conditions, it was shown that vascular wall-resident EPCs are mobilized at first towards the peri-vascular space and later also toward the vascular lumen [16], but in in vivo situation, it probably depends on type and location of pathologic processes. Finally, the vascular adventitia contains an own vascular bed, called vasa vasorum, composed Fig. 3 Human arterial ring assay. Vessel sprouting (arrows) from the vascular wall is visible in the surrounding of the arterial ring (a). Local injection of adenoviral vectors containing GFP as reporter gene into the outer layer of the vascular wall and subsequent ring assay show that the sprouting cells are coming from the outer zone of the vascular wall (b) and that they are able to form vascular like structures as demonstrated in the higher magnification [inset in (b)]
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mostly by middle sized arteries and veins as well as micro vessels to supply the outer part of the vascular wall with nutrition and oxygen [53–56]. This is of particular importance with growing diameter of vessel wall. But the location of EPCs and HPCs close to vasa vasorum in the adventitia provides them not only a save access to a conduct for blood supply but also a potential way to be mobilized into the blood circulation. On the other side it is conceivable that circulating bone marrow derived EPC or HPCs reside in the adventitia and/or around the vasa vasorum preferentially after their extravasation. Detailed studies (own unpublished results) on vascular wall of human arteries and veins indeed show that CD34(+) cells are also present within the adventitia of the middle sized vessels of the vasa vasorum of the human internal thoracic artery as depicted graphically (Fig. 4). While these hypothesis needs to be verified by further in vivo analyses, it is sure that vascular wall-resident EPCs can be mobilized by tumor cells implanted in the surrounding of the vessel wall ex vivo [16]. They are also mobilized by skeletal tissue regeneration in vivo [33]. Interestingly, in human arterial ring assays, cells migrated from the vascular wall into the surrounding collagen gel showed a heterogeneity regarding cell surface markers detected by immunostaining or FACS analyses [16]. They do not only express markers specific for EPCs or mature EC such as VEcadherin or von Willebrand-factor but subsets of them were also positive for CD68: a marker for mature macrophages, for αSMA: a marker for smooth muscle cells or pericytes, for CD45: a marker for HPCs and finally CD133 which is recognized as a widely distributed marker for different types of stem cells (Fig. 4) [29, 30, 57–60].
Cellular Sources for Vascularization of Tumors Even though the mechanisms of tumor vascularization are not yet completely clarified and the findings have not been
Stem Cell Rev (2008) 4:169–177 Fig. 4 Phenotypic heterogeneity of the cells sprouting from the vascular wall. Immunostaining and FACS analyses on cells isolated from the collagen gel after performing ring assays show that there are cells with markers characteristic for different cell types such as macrophages, smooth muscle cells or hematopoietic cells in addition to the CD34(+) cells involved in the vascular like sprouts
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CD34(+) EPCs
vasculogenic zone
cell types generated from the vasculogenic zone after ring assay • VE-cadherin (+) mature EC forming vessel sprouts • CD68(+) macrophages • a-SMA (+) cells associated to EC • CD133 (+) cells CD45(+) HPC
completely translated into clinical use, it is established that tumor cells can activate existing blood vessels to sprouting of new blood vessels, thus inducing angiogenesis. A commonly observed and known finding studying tumor vessels is the fact that despite a high level of vascularization of tumors, the mitotic activity detected in endothelial cells of pre-existing blood vessels closely around the tumor is in the majority of tumors at a low level. These data suggest the existance of additional sources for generation of endothelial cells which form new vessels. Given the findings regarding the tissue-resident EPCs in general and vascular wall-resident EPC in particular we can hypothesize that the difference between the relatively little mitotic activity of the mature endothelium and high vascular density in tumors is closed by involvement of EPCs mobilized from BM, peripheral blood or even the local reservoirs such as the vascular wall. Presumably a considerable part of the tumor blood vessels are formed by endothelial precursor cells. This complex process of blood vessel formation acquiring endothelial cells from different sources might be responsible for the heterogeneity of tumor vascular bed as described by numerous publications [61–63]. Furthermore, the generation and mobilization of αSMA (+) cells from the vascular wall into the surrounding of the vessel rings by tumor cells suggest that not only EPC/EC but also mural cells contributing to the stabilization of new blood vessels can locally be provided from the wall of existing mature vessels. Finally, the existence of HPCs, the generation of inflammatory cells such as macrophages within the vascular wall [16, 64] and
the accumulation of mast cells in the vascular adventitia [65] promote the new vessel formation since macrophages and mast cells knowingly produce and secrete potent proangiogenic factors such as VEGF at high level. Data obtained from ex vivo experiments with human vessel rings from the human internal thoracic artery which were co-incubated with prostate cancer cell line DU-145 in collagen gel show a significantly accelerated mobilization of CD34-positive EPCs from the vessel wall and formation of vascular sprouts [16]. The co-existence of EPCs and HPCs in the vascular adventitia indicates a still existing symbiosis of these two types of stem cells in the adult similar to that shown for embryologic development [9, 10]. This might be of relevance regarding survival of the EPCs within the vascular wall and also regarding their activation by tumor cells. In summary it can be concluded that vascular wall-resident EPCs might be, (a) an additional local cellular source for the formation of tumor vessels, (b) mobilized from the vessel wall for the formation of new tumor blood vessels earlier than the mature existing endothelial cells, and (c) contributing to the heterogeneity of tumor blood vessels.
Guidepost for Tumor Cells to their Metastatic Niche? The metastasis of tumor cells is a multistep and complex process composed by release of single tumor cells from the primary tumor, which enter blood or lymphatic vessels, transport in blood circulation, adhesive interaction with
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vascular endothelial cells, extravasation with the passage through the vascular wall, arriving metastatic site, colonization and growth with inducing of neovascularization at the metastatic site [66]. Without going into detail of this highly complex process it is obvious that tumor cells need support and guidance to overcome the metastasis course equipped with severe hurdles. So far it is too early to declare an assured guidepost position of circulating VEGFR-1(+) HPCs and/or EPCs. The exciting findings of S. Rafii and his colleagues [26] approve that the VEGFR-1-positive HPCs from the bone marrow act as a form of mobile guidance for the circulating tumor cells to their future metastatic station in the lung, liver or other organs. In in vivo experimental tumor models using different tumor cell types this group could show that the VEGFR-1(+) HPCs of the bone marrow arrived much earlier at future metastatic sites than tumor cells themselves. EPCs coincided with the arrival of tumor cells, before vascularization of tumor cell clusters has occurred. Removal of VEGFR-1(+) HPCs from the bone marrow prevents tumor metastasis in experimental tumor models. As it is generally known, different tumor types, e.g. prostate carcinoma or malignant melanoma, metastasize to predetermined locations. Rafii and colleagues [26] were able to show that VEGFR-1(+) HPCs, e.g. in the case of implantation of melanoma tumor cells into mice, invaded the lung, liver, testis, spleen and kidney, which are all
TC
common metastatic sites for this tumor, and formed the premetastatic niche. Up to now, it has not been studied yet, which role vascular wall resident HPCs possibly do play in this setting. Nevertheless, there are convincing data indicating that EPCs are mobilized and activated to form new blood vessels in the metastatic sites. To which extent tissue-resident, especially the vascular wall-resident EPCs do accompany tumor cells on their way to metastatic sites needs further studies. It is conceivable to hypothesize that BM derived VEGFR-1(+) HPCs and/or tumor cells might activate the vascular wall-resident EPCs and HPCs by their passage through the vascular wall migrating from the vessel lumen to the perivascular space as depicted graphically (Fig. 5). Since we could find (unpublished results) CD34(+) cells not only in the wall of large and middle sized vessels but also covering the wall of vasa vasorum as well as of arterioles and venuls in different organs such as testis, prostate and kidney we postulate that the vascular wallresident EPCs are involved in the metastatic processes escorting the tumor cells outside the blood vessels to the pre-metastatic niche formed by VEGFR-1(+) HPCs [26]. Two possible ways of interdependence between BM derived VEGFR-1(+) HPCs and vascular wall-resident EPCs can be imagined: a) VEGFR-1(+) HPCs activate the vascular-resident EPCs by secreting the pro-angiogenc factors and cytokines like VEGF or FGF-2 which act on EPC during the passage of HPCs through the vascular wall.
TC with EPCs
VEGFR-1(+)
pre-metastatic niche“ ” formed by VEGFR-1(+) BM-derived cells Fig. 5 Potential role of vascular wall-resident EPCs in the metastasis of tumor cells in interaction with HPCs. BM-derived VEGFR-1(+) HPCs form the “pre-metastatic niche” as demonstrated by Kaplan et al. [26]. Putting this model together with the vascular wall-resident EPCs it can be hypothesized that vascular wall-resident EPC may be mobilized by either a the local interaction between EPCs and HPCs within the vascular wall, or b the interaction of the vascular wall-resident EPCs
with tumor cells (TC). Outside the vessel wall EPCs coming from the blood circulation and/or EPCs mobilized from the vascular wall probably escort the TC to the metastatic niche. This process might be fate determining for the TC because of a microenvironment important for the survival of TC and induction of angiogenesis for vascularisation of TC at the metastatic site
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By this mechanism VEGFR-1(+) HPCs also can induce the mobilization of the EPCs from the vascular wall and determine their migration route via chemotactic stimuli and potential modulation of extra cellular matrix, and, b) the VEGFR-1(+) HPCs first stimulate the passage of the tumor cells through the vascular wall via yet unknown mechanisms and subsequently, the tumor cells themselves secrete chemotactic stimuli like VEGF and/or placental growth factor (PIGF) and induce the mobilization of the vascular wall-resident EPCs which then escort the tumor cells to the metastatic sites (Fig. 5). The coincidence of tumor cells and EPCs at the pre-metastatic niche, as demonstrated by Kaplan et al. [26], supports this assumption. During this process EPCs probably differentiate to mature endothelial cells which subsequently can provide new vessel formation at the metastatic site. While these potential mechanisms still need to be verified emerging data strongly suggest that we should not only consider the systemic factors such as bone marrow derived EPCs and HPC or HSC but also, and probably much stronger than yet, the local cellular and molecular sources on EPCs and HPCs contributing to the survival and vascularization of tumor cells outside the blood stream or lymphatic channels.
Conclusions and Perspectives These findings let assume that it is still a long way to go until tumors can be starved out as the pioneer of tumor angiogenesis and anti-angiogenic tumor therapy, Judah Folkman, has prophesied about 37 years ago. The idea is still fascinating, but its realization seems to be more complex than believed. It comprises of molecular, cellular and morphologic processes which are highly intricate with each other. Their decipherment will need a lot of research and endurance. The crucial finding in the area of tumor vascularization research in the last 6–7 years was the realization that it does not only take place through existing endothelial cells as it was believed in the beginning of tumor angiogenesis research in the seventies and until a decade ago, but that also EPCs derived from bone marrow or mobilized locally from the vascular wall, and possibly HPCs are relevantly involved in this process. The partial success achieved by the entrance of anti-angiogenic drugs in the clinical therapy of some tumor types during the last few years such as VEGF- or small tyrosine kinase-receptor antagonists is encouraging for identification of additional mechanisms of tumor vascularization. In summary, we can conclude that circulating or tissue bound HPCs and EPCs hand in hand control survival, vascularization and metastasis of tumor cells. The potential interaction between bone derived VEGFR-1(+) HPCs, local HPCs within the vascular wall, EPCs mobilized from bone
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marrow and EPCs mobilized from the vascular wall locally with each other on the one side and with spreading tumor cells on the other side seems to play a crucial role in the guidepost of tumor cells to and their vascularization at the metastatic niche. The deciphering of the intricate molecular and cellular mechanisms behind these processes is challenging and would essentially open new perspectives in the antiangiogenic therapy of tumors. Acknowledgment The authors thank F. Chalajour, E. Zengin and U. Gehling for their advice and scientific support in preparing of this review.
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