Portal de Periódicos da CAPES

Alternative Vascularization Mechanisms in Cancer

2007; Elsevier BV; Volume: 170; Issue: 1 Linguagem: Inglês

10.2353/ajpath.2007.060302

1525-2191

Balázs Döme, Mary J.C. Hendrix, Sándor Paku, József Tóvári, József Tı́már,

Chemotherapy-induced cardiotoxicity and mitigation

Although cancer cells are not generally controlled by normal regulatory mechanisms, tumor growth is highly dependent on the supply of oxygen, nutrients, and host-derived regulators. It is now established that tumor vasculature is not necessarily derived from endothelial cell sprouting; instead, cancer tissue can acquire its vasculature by co-option of pre-existing vessels, intussusceptive microvascular growth, postnatal vasculogenesis, glomeruloid angiogenesis, or vasculogenic mimicry. The best-known molecular pathway driving tumor vascularization is the hypoxia-adaptation mechanism. However, a broad and diverse spectrum of genetic aberrations is associated with the development of the “angiogenic phenotype.” Based on this knowledge, novel forms of antivascular modalities have been developed in the past decade. When applying these targeted therapies, the stage of tumor progression, the type of vascularization of the given cancer tissue, and the molecular machinery behind the vascularization process all need to be considered. A further challenge is finding the most appropriate combinations of antivascular therapies and standard radio- and chemotherapies. This review intends to integrate our recent knowledge in this field into a rational strategy that could be the basis for developing effective clinical modalities using antivascular therapy for cancer. Although cancer cells are not generally controlled by normal regulatory mechanisms, tumor growth is highly dependent on the supply of oxygen, nutrients, and host-derived regulators. It is now established that tumor vasculature is not necessarily derived from endothelial cell sprouting; instead, cancer tissue can acquire its vasculature by co-option of pre-existing vessels, intussusceptive microvascular growth, postnatal vasculogenesis, glomeruloid angiogenesis, or vasculogenic mimicry. The best-known molecular pathway driving tumor vascularization is the hypoxia-adaptation mechanism. However, a broad and diverse spectrum of genetic aberrations is associated with the development of the “angiogenic phenotype.” Based on this knowledge, novel forms of antivascular modalities have been developed in the past decade. When applying these targeted therapies, the stage of tumor progression, the type of vascularization of the given cancer tissue, and the molecular machinery behind the vascularization process all need to be considered. A further challenge is finding the most appropriate combinations of antivascular therapies and standard radio- and chemotherapies. This review intends to integrate our recent knowledge in this field into a rational strategy that could be the basis for developing effective clinical modalities using antivascular therapy for cancer. Until recently, vascularization of malignant tumors was considered the exclusive result of directed capillary ingrowth (endothelial sprouting). However, recent advances have been made in identifying the processes involved in angiogenesis and vascular remodeling. Consequently, the simplistic model of an invading capillary sprout has been deemed insufficient to describe the entire spectrum of morphogenic and molecular events required to form a neovascular network. Before discussing the different ways a tumor is vascularized, we should emphasize that these mechanisms are not mutually exclusive; in fact, in most cases they are interlinked, participating concurrently in physiological as well as in pathological angiogenesis. Although the various types of cancer vascularization share some molecular features and may be controlled in part by similar sets of regulatory factors, a considerable variety of differences also exists. Although the molecular regulation of endothelial sprouting has been extensively studied and reviewed in the literature, the morphogenic and molecular events associated with alternative cancer vascularization mechanisms are less understood. Therefore, this review focuses on the pathogenesis of the different forms of “nonsprouting angiogenesis” and, more specifically, on the possibilities and the potential use of novel antiangiogenic and vascular targeting strategies against alternative tumor vascularization mechanisms. The best-known mechanism by which tumors promote their own vascularization is inducing new capillary buds from pre-existing host tissue capillaries. The first description of this process dates back to the 1970s, when Ausprunk and Folkman1Ausprunk DH Folkman J Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis.Microvasc Res. 1977; 14: 53-65Crossref PubMed Scopus (1088) Google Scholar suggested the following sequence for tumor-induced capillary sprouting (Figure 1, Alt. 1). 1) The basement membrane is locally degraded on the side of the dilated peritumoral postcapillary venule situated closest to the angiogenic stimulus, interendothelial contacts are weakened, and endothelial cells (ECs) emigrate into the connective tissue, toward the angiogenic stimuli. 2) There is formation of a solid cord by ECs succeeding one another in a bipolar fashion. 3) Lumen formation occurs by cell-body curving of a single EC or by participation of more ECs in parallel with the synthesis of the new basement membrane and the recruitment of pericytes/mural cells. The main disadvantages of this model are its inability to identify the nature and origin of the stimulus necessary for lumen formation and the assumption that dedifferentiation and redifferentiation take place during the same process, manifest in the loss and regaining of luminal-basal EC polarity. Furthermore, although it has been well established that the stimulus necessary for lumen formation comes from the developing basement membrane, according to this model, basement membrane deposition occurs after lumen formation. In the early 1990s, a different sprouting model was described2Paku S Paweletz N First steps of tumor-related angiogenesis.Lab Invest. 1991; 65: 334-346PubMed Google Scholar (Figure 1, Alt. 2). This model suggests a three-stage sequence to explain ultrastructural changes during tumor-induced endothelial sprouting. 1) There is structural alteration of the basement membrane characterized by the loss of electron density (gel-sol transition) over the entire circumference of the dilated “mother vessel” (although basement membrane components such as laminin and collagen IV can still be detected by immunohistochemistry). Partial and regulated degradation of the altered basement membrane occur only at places where EC processes (connected by intercellular junctions) are projecting into the connecting tissue. 2) Further migration of ECs, which are arranged in parallel, maintaining their basal-luminal polarity and forming a slit-like lumen, takes place continuously with the lumen of the mother vessel and sealed by intact interendothelial junctions. Basement membrane of low electron density is deposited continuously by the polarized ECs while only the very tip of the growing capillary bud is free of basement membrane material. 3) Proliferating pericytes of the mother vessel migrate along the basement membrane of the capillary bud, resulting in complete pericyte coverage of the new vessel. In parallel, the appearance of electron-dense basement membrane around the maturing capillary buds (sol-gel transition) can be observed. According to the above model, no stimulus is necessary for the induction of lumen formation, because ECs do not lose their polarity during the process. The molecular background of capillary sprouting has been extensively studied and reviewed in the literature.3Carmeliet P Angiogenesis in life, disease and medicine.Nature. 2005; 438: 932-936Crossref PubMed Scopus (2891) Google Scholar During the process, vessels initially dilate and become leaky in response to vascular permeability factor/vascular endothelial growth factor (VPF/VEGF).4Dvorak HF Brown LF Detmar M Dvorak AM Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.Am J Pathol. 1995; 146: 1029-1039PubMed Google Scholar This is mediated by the up-regulation of nitric oxide, the development of fenestrations and vesiculo-vacuolar organelles, and by the redistribution of CD31/PECAM-1 and vascular endothelial (VE)-cadherin. The so-called gel-sol transition of the basement membrane, probably mediated by matrix metalloproteases (MMPs), gelatinases, and the urokinase plasminogen activator system, could be partly responsible for the initiation of EC proliferation and migration. Ang-2 (Angiopoetin-2, a mediator of Tie-2 signaling) is involved in the detachment of pericytes and loosening of the matrix. A vast number of molecules stimulate endothelial proliferation and migration, including transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, members of the chemokine system and the VEGF, fibroblast growth factor, and platelet-derived growth factor (PDGF) families.3Carmeliet P Angiogenesis in life, disease and medicine.Nature. 2005; 438: 932-936Crossref PubMed Scopus (2891) Google Scholar It could be argued that integrins represent the most important adhesion receptors in migrating ECs.5Serini G Valdembri D Bussolino F Integrins and angiogenesis: a sticky business.Exp Cell Res. 2006; 312: 651-658Crossref PubMed Scopus (172) Google Scholar A wide variety of integrins have been shown to be expressed during sprouting, including α1β1, α2β1, α3β1, α5β1, αvβ5, and αvβ3. Perhaps the most important among them is αvβ3, which mediates the migration of ECs in the fibrin-containing cancer stroma and maintains the sol state of the basement membrane because of its ability to bind to MMP-2. During maturation of nascent vessels, PDGF-BB recruits pericytes and smooth muscle cells, whereas TGF-β1 and Ang-1/Tie-2 stabilize the interaction between endothelial and mural cells.3Carmeliet P Angiogenesis in life, disease and medicine.Nature. 2005; 438: 932-936Crossref PubMed Scopus (2891) Google Scholar All in all, sprouting is controlled by a tightly regulated balance of proangiogenic factors and inhibitors: an angiogenic cytokine promotes EC proliferation, migration, or lumen formation, whereas an inhibitor interferes with these steps and modulates the proliferation or migration activity of ECs. However, individual tumor types use various combinations of proangiogenic and inhibitory cytokines.3Carmeliet P Angiogenesis in life, disease and medicine.Nature. 2005; 438: 932-936Crossref PubMed Scopus (2891) Google Scholar When tumors arise in or metastasize to a pre-existing, usually well-vascularized, tissue, their growth not only depends on expansion, like a balloon, more typical of slow-growing benign tumors, but also on the invasion of host tissue, allowing the cancer cells close contact with the surface of blood vessels. Therefore, malignant cells may initially associate with and grow preferentially along pre-existing microvessels. Until recently, however, no studies have focused on the role played by the host vasculature in the process of tumor vascularization. Although in 1987 Thompson6Thompson WD Shiach KJ Fraser RA McIntosh LC Simpson JG Tumours acquire their vasculature by vessel incorporation, not vessel ingrowth.J Pathol. 1987; 151: 323-332Crossref PubMed Scopus (79) Google Scholar had already proposed that tumors acquire their vasculature by incorporation of host tissue capillaries, the first study suggesting the existence of vessel co-option was not published until 1999 by Holash et al.7Holash J Maisonpierre PC Compton D Boland P Alexander CR Zagzag D Yancopoulos GD Wiegand SJ Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.Science. 1999; 284: 1994-1998Crossref PubMed Scopus (1941) Google Scholar In their model, Holash and colleagues found that co-option is limited to the initial phases of tumorigenesis.7Holash J Maisonpierre PC Compton D Boland P Alexander CR Zagzag D Yancopoulos GD Wiegand SJ Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.Science. 1999; 284: 1994-1998Crossref PubMed Scopus (1941) Google Scholar However, additional morphological evidence in human malignancies suggests that co-option of pre-existing blood vessels might persist during the entire period of primary or metastatic tumor growth. In cutaneous melanoma, we found that during tumor growth, there are no signs of directed vessel ingrowth; instead, these tumors appear to grow by co-opting the massive vascular plexus present in the peritumoral connective tissue.8Döme B Paku S Somlai B Timar J Vascularization of cutaneous melanoma involves vessel co-option and has clinical significance.J Pathol. 2002; 197: 355-362Crossref PubMed Scopus (115) Google Scholar In non-small cell lung cancer, a putatively nonangiogenic growth pattern was observed.9Pezzella F Pastorino U Tagliabue E Andreola S Sozzi G Gasparini G Menard S Gatter KC Harris AL Fox S Buyse M Pilotti S Pierotti M Rilke F Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis.Am J Pathol. 1997; 151: 1417-1423PubMed Google Scholar In this “alveolar type” of growth, cancer cells filled the alveoli, entrapping but not destroying the co-opted alveolar capillaries. In liver metastases of human colorectal carcinomas, different growth patterns (replacement, pushing, and desmoplastic) were observed, depending on the degree of differentiation. In replacement growth type, the architecture of the liver was preserved, and the ECs of sinusoids showed low mitotic activity. However, pushing and desmoplastic tumor types destroyed the liver architecture.10Vermeulen PB Colpaert C Salgado R Royers R Hellemans H Van Den Heuvel E Goovaerts G Dirix LY Van Marck E Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia.J Pathol. 2001; 195: 336-342Crossref PubMed Scopus (227) Google Scholar According to our previous results in experimental hepatic metastases, during growth of sinusoidal-type metastases, invading cancer cells advance between the basement membrane and the endothelial lining of the sinusoids and evoke proliferation of ECs. This process resulted in the development of large tortuous vessels without basement membrane inside the tumor nodules. Conversely, sprouting-type angiogenesis was observed in portal-type metastases. The replacement growth pattern corresponded to sinusoidal-type metastases of undifferentiated tumors, whereas desmoplastic tumors showed similarities to portal-type metastases.11Paku S Lapis K Morphological aspects of angiogenesis in experimental liver metastases.Am J Pathol. 1993; 143: 926-936PubMed Google Scholar In the pushing-type growth pattern, we recently described a mechanism for the development of blood supply and supportive connective tissue12Paku S Kopper L Nagy P Development of the vasculature in “pushing-type” liver metastases of an experimental colorectal cancer.Int J Cancer. 2005; 115: 893-902Crossref PubMed Scopus (35) Google Scholar (Figure 2). This process includes the proliferation of smooth muscle actin-positive stellate, but not endothelial, cells on the surface of the tumor spheroid accompanied by capillarization of the sinusoids in this region. Because of the pressure of the tumor and the proliferating stellate cells, the hepatocytes disappear from the closest vicinity of the tumor, leading to the fusion of the sinusoids and the appearance of vascular lakes at the surface of the tumor. Together with the collagen-producing cells, these vascular lakes are incorporated into the tumor, resulting in the development of vessel-containing connective tissue columns that traverse the tumor. These columns represent the main structural and functional unit, providing blood supply for the inner part of the growing metastasis. Thus, the presence of the above mechanisms further supports earlier observations that vascularization of metastases in the liver is a heterogeneous process, depending on the degree of tumor differentiation or localization of the metastases within the liver.13Paku S Bodoky G Kupcsulik P Timar J Blood supply of metastatic hepatic tumors: suggestions for improved delivery of chemotherapeutic agents.J Natl Cancer Inst. 1998; 90: 936-937Crossref PubMed Scopus (6) Google Scholar Although sprouting capillaries are more vulnerable to apoptosis than their quiescent counterparts,14Brooks PC Montgomery AM Rosenfeld M Reisfeld RA Hu T Klier G Cheresh DA Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels.Cell. 1994; 79: 1157-1164Abstract Full Text PDF PubMed Scopus (2205) Google Scholar maintenance of incorporated mature microvessels depends on the survival of ECs as well. The continued survival of co-opted ECs is intimately tied to their local microenvironment and, in particular, to the presence of pericytes, survival-promoting cytokines, and extracellular matrix proteins. Thus, the molecular repertoire that ECs may use to survive during vessel co-option is diverse and may vary for a given tumor type or host environment. The major players that control this process are angiopoetins and VEGF.7Holash J Maisonpierre PC Compton D Boland P Alexander CR Zagzag D Yancopoulos GD Wiegand SJ Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.Science. 1999; 284: 1994-1998Crossref PubMed Scopus (1941) Google Scholar Based on the model of vessel co-option described by Holash et al7Holash J Maisonpierre PC Compton D Boland P Alexander CR Zagzag D Yancopoulos GD Wiegand SJ Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF.Science. 1999; 284: 1994-1998Crossref PubMed Scopus (1941) Google Scholar and in other recent studies,15Scharpfenecker M Fiedler U Reiss Y Augustin HG The Tie-2 ligand angiopoietin-2 destabilizes quiescent endothelium through an internal autocrine loop mechanism.J Cell Sci. 2005; 118: 771-780Crossref PubMed Scopus (333) Google Scholar Ang-1 activates Tie-2 and induces subsequent signal transduction pathways favoring EC survival, endothelial quiescence, and tumor-vessel maintenance. Conversely, Ang-2 is thought to act as a nonsignaling Tie-2 ligand that binds to endothelial Tie-2 and thereby negatively interferes with agonistic Ang-1/Tie-2 signals. In co-opted blood vessels, the up-regulation of Ang-2 disrupts the interaction between Tie-2 and Ang-1, which in turn causes the destabilization of capillary walls (ie, the detachment of pericytes from the endothelial tube).16Holash J Wiegand SJ Yancopoulos GD New model of tumor angiogenesis: dynamic balance between vessel regression and growth mediated by angiopoietins and VEGF.Oncogene. 1999; 18: 5356-5362Crossref PubMed Scopus (674) Google Scholar Once ECs are separated from pericytes, they become particularly vulnerable. In the presence of VEGF, EC survival and new vessel growth are promoted; however, the lack of stimulatory factors results in the regression of destabilized vessels.17Benjamin LE Golijanin D Itin A Pode D Keshet E Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal.J Clin Invest. 1999; 103: 159-165Crossref PubMed Scopus (1061) Google Scholar VEGF was first described as a survival factor for retinal ECs and has now been shown to promote survival in different EC models. This antiapoptotic and survival function of VEGF seems to depend on an interaction between vascular endothelial growth factor receptor (VEGFR)-2, β-catenin, and VE-cadherin.18Ferrara N Gerber HP LeCouter J The biology of VEGF and its receptors.Nat Med. 2003; 9: 669-676Crossref PubMed Scopus (8094) Google Scholar However, targeting of VEGF has been shown to result in apoptosis only in newly formed tumor vessels and in the developing vasculature of the neonatal mouse but not that of adult mice or of quiescent tumor vascular networks.17Benjamin LE Golijanin D Itin A Pode D Keshet E Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal.J Clin Invest. 1999; 103: 159-165Crossref PubMed Scopus (1061) Google Scholar In summary, although cytokines responsible for EC survival could be the key molecules, their precise role in initiation and maintenance of vessel co-option still requires investigation. IMG refers to vessel network formation by insertion of connective tissue columns, called tissue pillars, into the vessel lumen and to subsequent growth of these pillars, resulting in partitioning of the vessel lumen (Figure 3). This type of angiogenesis, which has been observed in a wide variety of normal and malignant tissues, is faster and more economical than sprouting, occurs within hours or even minutes and does not primarily depend on EC proliferation, basement membrane degradation, and invasion of the connective tissue.19Kurz H Burri PH Djonov VG Angiogenesis and vascular remodeling by intussusception: from form to function.News Physiol Sci. 2003; 18: 65-70PubMed Google Scholar However, in contrast to sprouting, IMG can work only on existing vessel networks. The most important feature of IMG, therefore, seems to be its ability to increase the complexity and density of the tumor microvessel network already built by sprouting, independent of EC proliferation. In addition, IMG can provide more surface area for further sprouting. Its molecular regulation, however, is poorly understood since IMG was first described only a few years ago. Nevertheless, the role of some players is gradually becoming clearer. We know that local stimuli, such as intravascular shear stress, might induce a cascade of physiological or pathological reactions in ECs, and new capillary development by tissue pillar formation could be one of them.20Osawa M Masuda M Kusano K Fujiwara K Evidence for a role of platelet endothelial cell adhesion molecule-1 in endothelial cell mechanosignal transduction: is it a mechanoresponsive molecule?.J Cell Biol. 2002; 158: 773-785Crossref PubMed Scopus (268) Google Scholar Furthermore, intussusception is certainly synchronized by several cytokines. Major candidates are those capable of mediating information between ECs or from ECs to mural cells, such as PDGF-BB, angiopoietins, and their Tie receptors, TGF-β, monocyte chemotactic protein-1, and ephrins and Eph-B receptors.19Kurz H Burri PH Djonov VG Angiogenesis and vascular remodeling by intussusception: from form to function.News Physiol Sci. 2003; 18: 65-70PubMed Google Scholar After the initial stage of immature capillary network formation by sprouting, additional vascular growth and development of complex vascular beds, including their continuous remodeling and adaptation, may occur by intussusception in cancers. The absence of intense EC proliferation in IMG implies that neovascularization by this mechanism would be resistant to angiosuppressive treatment in itself. Glomeruloid bodies (GBs) are best known in high-grade glial malignancies, where they are one of the diagnostic histopathological features of glioblastoma multiforme. However, these complex vascular aggregates have also been described in a wide variety of other malignancies.21Brat DJ Van Meir EG Glomeruloid microvascular proliferation orchestrated by VPF/VEGF: a new world of angiogenesis research.Am J Pathol. 2001; 158: 789-796Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar They are composed of several closely associated microvessels surrounded by a variably thickened basement membrane within which a limited number of pericytes are embedded. In recent studies, the presence of GBs was associated with markers of aggressive tumor behavior and significantly reduced survival in cancer patients.22Straume O Chappuis PO Salvesen HB Halvorsen OJ Haukaas SA Goffin JR Begin LR Foulkes WD Akslen LA Prognostic Importance of Glomeruloid Microvascular Proliferation Indicates an Aggressive Angiogenic Phenotype in Human Cancers.Cancer Res. 2002; 62: 6808-6811PubMed Google Scholar In the first animal model,23Sundberg C Nagy JA Brown LF Feng D Eckelhoefer IA Manseau EJ Dvorak AM Dvorak HF Glomeruloid microvascular proliferation follows adenoviral vascular permeability factor/vascular endothelial growth factor-164 gene delivery.Am J Pathol. 2001; 158: 1145-1160Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar GBs developed in mother vessels from recruitment and proliferation of ECs and pericytes (in the absence of tumor cells), and VEGF was essential for their induction and maintenance. In contrast to this model and based on our previous results in the first experimental tumor model of glomeruloid angiogenesis,24Döme B Timar J Paku S A novel concept of glomeruloid body formation in experimental cerebral metastases.J Neuropathol Exp Neurol. 2003; 62: 655-661PubMed Google Scholar we believe that GB formation starts immediately after tumor cell extravasation, much earlier than necrosis appears within the metastases. We found that the proliferating and migrating tumor cells are able to pull the capillaries and the adjacent capillary branching points into the tumor cell nests. This process leads to the appearance of simple coiled vascular structures that later develop into GBs with multiple narrowed afferent and efferent capillaries (Figure 4). Despite the absence of sprouting angiogenesis, necrosis was scarce in these lesions, suggesting that the blood supply from the pre-existent vascular bed is sufficient to provide the tumor cells with oxygen and nutrients. This type of GB formation cannot be termed as true angiogenesis; it rather represents a remodeling of the existing vasculature of the host tissue. Whether GBs represent an accelerated form of angiogenesis or a dysfunctional, possibly abortive, form remains an open question. However, it cannot be excluded that “active” and “passive” types of glomeruloid angiogenesis can operate concurrently in various cancer types. Vasculogenesis (defined as the in situ differentiation of vascular ECs from primitive precursor cells) has long been thought to occur only in the early phases of vascular development. Recent studies, however, have demonstrated that circulating bone marrow-derived endothelial progenitor cells (EPCs) home to sites of physiological and pathological neovascularization and differentiate into ECs (Figure 5). EPCs may be mobilized by tumor tissue-derived cytokines from the bone marrow by a mechanism recently described by Asahara et al.25Asahara T Kawamoto A Endothelial progenitor cells for postnatal vasculogenesis.Am J Physiol. 2004; 287: C572-C579Crossref Scopus (462) Google Scholar Best characterized among these cytokines is VEGF. During tumor progression, the level of circulating VEGF has been shown to rise, and this level was found to correlate with the number of EPCs in the circulation. Furthermore, PDGF-CC promoted vascularization in part by stimulating outgrowth of EPCs. In contrast, Ang-1 was shown to reduce EPC mobilization from bone marrow (reviewed in 26Garmy-Susini B Varner JA Circulating endothelial progenitor cells.Br J Cancer. 2005; 93: 855-858Crossref PubMed Scopus (67) Google Scholar). After homing, ie, after adhesion and insertion of EPCs into the monolayer of surrounding mature vascular ECs, additional local stimuli may promote the activation of local endothelium to express adhesion molecules to recruit EPCs. This process may be completed by mechanisms not yet elucidated. In addition to the physical contribution of EPCs to newly formed microvessels, the angiogenic cytokine release of EPCs may be a supportive mechanism to improve neovascularization as well.27Urbich C Aicher A Heeschen C Dernbach E Hofmann WK Zeiher AM Dimmeler S Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells.J Mol Cell Cardiol. 2005; 39: 733-742Abstract Full Text Full Text PDF PubMed Scopus (660) Google Scholar It is also important to note that Lyden et al recently identified VEGFR-1+ hematopoietic progenitor cells that multiply in the bone marrow, mobilize to the peripheral blood along with VEGFR-2+ EPCs, and incorporate into pericapillary connective tissue, thus stabilizing tumor vasculature.28Lyden D Hattori K Dias S Costa C Blaikie P Butros L Chadburn A Heissig B Marks W Witte L Wu Y Hicklin D Zhu Z Hackett NR Crystal RG Moore MA Hajjar KA Manova K Benezra R Rafii S Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth.Nat Med. 2001; 7: 1194-1201Crossref PubMed Scopus (1709) Google Scholar More interestingly, these cells seem to home in before the tumor cells arrive, promoting metastatic growth by forming niches where cancer cells can locate and proliferate.29Kaplan RN Riba RD Zacharoulis S Bramley AH Vincent L Costa C MacDonald DD Jin DK Shido K Kerns SA Zhu Z Hicklin D Wu Y Port JL Altorki N Port ER Ruggero D Shmelkov SV Jensen KK Rafii S Lyden D VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.Nature. 2005; 438: 820-827Crossref PubMed Scopus (2602) Google Scholar Although EPCs obviously participate in the vascularization process of malignant tumors, it is still unclear whether they are essential for these processes or what the relative contribution of EPCs is compared with that of in situ proliferating ECs. Moreover, it has yet to be determined whether EPCs can be targeted to treat certain types of malignancies, or alternatively—as they are endowed with the capacity to home to the tumor vasculature—can be used to deliver toxins or vascular-targeting agents. “Vasculogenic mimicry” is defined by the unique ability of aggressive melanoma cells to express an EC phenotype and to form vessel-like networks in three-dimensional culture, “mimicking” the pattern of embryonic vascular networks