Angiogenic Monocytes
2009; Elsevier BV; Volume: 174; Issue: 5 Linguagem: Inglês
10.2353/ajpath.2009.090198
ISSN1525-2191
Autores Tópico(s)Cell Adhesion Molecules Research
ResumoThis Commentary provides perspective on a related article by Sun-Jin Kim and coworkers (Am J Pathol: 172 AJP08-0819), who assess the contribution of bone marrow-derived cells to tumor angiogenesis in a physiologic, non-myeloablative setting and conclude that the actual angiogenic cell type incorporated in the newly formed vessels is actually monocytes/macrophages. This Commentary provides perspective on a related article by Sun-Jin Kim and coworkers (Am J Pathol: 172 AJP08-0819), who assess the contribution of bone marrow-derived cells to tumor angiogenesis in a physiologic, non-myeloablative setting and conclude that the actual angiogenic cell type incorporated in the newly formed vessels is actually monocytes/macrophages. Ever since the first description of endothelial progenitor cells (EPCs),1Asahara T Murohara T Sullivan A Silver M van der Zee R Li T Witzenbichler B Schatteman G Isner JM Isolation of putative progenitor endothelial cells for angiogenesis.Science. 1997; 275: 964-967Crossref PubMed Scopus (7721) Google Scholar the concept of a circulating pool of distinct bone marrow-derived cells destined to become endothelial cells at sites of angiogenesis has attracted enormous support. This enthusiasm is easily understood, given the far reaching implications of the existence of EPCs for both therapeutic angiogenesis to ischemic tissues, as well as for tumor angiogenesis suppression.2Urbich C Dimmeler S Endothelial progenitor cells: characterization and role in vascular biology.Circ Res. 2004; 95: 343-353Crossref PubMed Scopus (1607) Google Scholar, 3Rafii S Lyden D Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration.Nat Med. 2003; 9: 702-712Crossref PubMed Scopus (1455) Google Scholar In support of this latter concept, a landmark study4Lyden 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 (1693) Google Scholar described blockade of angiogenesis and hence tumor growth by ablating the vascular endothelial growth factor (VEGF)-recruitable bone marrow cells, which were believed to be EPCs. Efforts to challenge the significance of EPCs are often met with disdain,5Kerbel RS Benezra R Lyden DC Hattori K Heissig B Nolan DJ Mittal V Shaked Y Dias S Bertolini F Rafii S Endothelial progenitor cells are cellular hubs essential for neoangiogenesis of certain aggressive adenocarcinomas and metastatic transition but not adenomas.Proc Natl Acad Sci USA. 2008; 105: E54-E55Crossref PubMed Scopus (46) Google Scholar however, even if such studies are based on solid conclusive experimental evidence.6Purhonen S Palm J Rossi D Kaskenpää N Rajantie I Ylä-Herttuala S Alitalo K Weissman IL Salven P Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth.Proc Natl Acad Sci USA. 2008; 105: 6620-6625Crossref PubMed Scopus (339) Google Scholar Still, throughout the past decade many other studies have shown only marginal importance of EPCs in models of ischemic or tumor-induced angiogenesis.2Urbich C Dimmeler S Endothelial progenitor cells: characterization and role in vascular biology.Circ Res. 2004; 95: 343-353Crossref PubMed Scopus (1607) Google Scholar The model systems studied form the core of this controversy: whereas some models using chemical-, radiation-, or genetically-induced myeloablation and bone marrow transfer show high numbers of EPCs incorporated in the newly formed vessels, an equal number of other models show almost complete lack of incorporation of bone marrow-derived cells. In the current issue of The American Journal of Pathology, Sun-Jin Kim and co-workers7Kim SJ, Kim JS, Papadopoulos J, Kim SW, Maya M, Zhang F, He J, Fan D, Langley R, Fidler IJ: Circulating monocytes expressing CD31: implications for acute and chronic angiogenesis. Am J Pathol 174, 5:1972–1980Google Scholar describe an elegant series of experiments to assess the contribution of bone marrow-derived cells to tumor angiogenesis in a physiological, nonmyeloablative setting. They conclude that the actual angiogenic cell type incorporated in the newly formed vessels is monocytes/ macrophages. The model used by Kim and colleagues7Kim SJ, Kim JS, Papadopoulos J, Kim SW, Maya M, Zhang F, He J, Fan D, Langley R, Fidler IJ: Circulating monocytes expressing CD31: implications for acute and chronic angiogenesis. Am J Pathol 174, 5:1972–1980Google Scholar is based on parabiosis: surgically joining the circulation of two mice, one wild-type and one GFP-transgenic, to establish a common circulation. The contribution of the GFP-positive cells to angiogenesis in the wild-type mouse is studied via three established techniques: wound healing, implanted gel foam fragments drenched in angiogenic growth factors, and, finally, in subcutaneous tumors. Using a panel of markers and multicolor confocal microscopy, Kim and colleagues7Kim SJ, Kim JS, Papadopoulos J, Kim SW, Maya M, Zhang F, He J, Fan D, Langley R, Fidler IJ: Circulating monocytes expressing CD31: implications for acute and chronic angiogenesis. Am J Pathol 174, 5:1972–1980Google Scholar show that the majority of GFP-positive cells in newly formed vessels in the wild-type mouse actually stain positive for the widely-used and well-established macrophage marker F4/80. These F4/80- and CD31-positive cells do not express EPC markers, and no GFP-positive cells that would qualify as EPCs were found. In contrast, GFP-positive circulating monocytes stained positive for both CD14 (monocyte marker) and VEGFR2 (endothelial cell marker). Interestingly, CD31-negative GFP-positive cells were also found, surrounding the newly formed vessels. Given the currently unquestioned reputation of F4/80 as genuine macrophage marker, Kim and colleagues7Kim SJ, Kim JS, Papadopoulos J, Kim SW, Maya M, Zhang F, He J, Fan D, Langley R, Fidler IJ: Circulating monocytes expressing CD31: implications for acute and chronic angiogenesis. Am J Pathol 174, 5:1972–1980Google Scholar conclude that it is circulating, bone marrow-derived monocytes that actually home to tumors to engage in angiogenesis. In itself, the concept of monocytes being able to contribute to angiogenesis is not novel. As early as 2003, Urbich and colleagues8Urbich C Heeschen C Aicher A Dernbach E Zeiher AM Dimmeler S Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells.Circulation. 2003; 108: 2511-2516Crossref PubMed Scopus (520) Google Scholar showed that EPCs have distinct monocytic features, and EPCs can be cultured from CD14-positive cells. In addition, monocytes were shown in vivo to be able to contribute to angiogenesis as EPCs.9Rehman J Li J Orschell CM March KL Peripheral blood "endothelial progenitor cells" are derived from monocyte/macrophages and secrete angiogenic growth factors.Circulation. 2003; 107: 1164-1169Crossref PubMed Scopus (1509) Google Scholar Later, in the stem cell era, these monocytes were even classified as multipotent monocytic cells acting as endothelial stem cells.10Kuwana M Okazaki Y Kodama H Satoh T Kawakami Y Ikeda Y Endothelial differentiation potential of human monocyte-derived multipotential cells.Stem Cells. 2006; 24: 2733-2743Crossref PubMed Scopus (116) Google Scholar Still, although it has become quite established in recent years that myeloid cells play a pivotal role in tumor angiogenesis, their exact nature remains elusive. Myeloid cells expressing Tie-211Venneri MA De Palma M Ponzoni M Pucci F Scielzo C Zonari E Mazzieri R Doglioni C Naldini L Identification of proangiogenic TIE2-expressing monocytes (TEMs) in human peripheral blood and cancer.Blood. 2007; 109: 5276-5285Crossref PubMed Scopus (389) Google Scholar and VEGFR2, formerly established endothelial markers, have been described.12McLean K Buckanovich RJ Myeloid cells functioning in tumor vascularization as a novel therapeutic target.Transl Res. 2008; 151: 59-67Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar This means that there might be specific subclasses of monocytes destined to home to sites of ischemia or tumor development, using Tie-2 and/or VEGFR2 to home to gradients of angiopoietin or VEGF, respectively.13Ahn GO Brown JM Role of endothelial progenitors and other bone marrow-derived cells in the development of the tumor vasculature.Angiogenesis. 2009; 8: 970-976Google Scholar Thus, these cells might function as novel targets for anti-tumor therapy. In fact, a landmark study by De Palma and colleagues14De Palma M Mazzieri R Politi LS Pucci F Zonari E Sitia G Mazzoleni S Moi D Venneri MA Indraccolo S Falini A Guidotti LG Galli R Naldini L Tumor-targeted interferon-alpha delivery by Tie2-expressing monocytes inhibits tumor growth and metastasis.Cancer Cell. 2008; 14: 299-311Abstract Full Text Full Text PDF PubMed Scopus (224) Google Scholar used Tie2-expressing monocytes to inhibit tumor growth and metastasis by targeted interferon-α delivery. Is this the final knockout for the EPCs role in tumor angiogenesis? Much of the evidence for the existence of EPCs is based on in vitro culture experiments. The concept of an EPC as a circulating angioblast or endothelial stem cell was fuelled by a number of studies that showed the presence of a circulating cell in both adult15Lin Y Weisdorf DJ Solovey A Hebbel RP Origins of circulating endothelial cells and endothelial outgrowth from blood.J Clin Invest. 2000; 105: 71-77Crossref PubMed Scopus (1338) Google Scholar and umbilical cord blood16Ingram DA Mead LE Tanaka H Meade V Fenoglio A Mortell K Pollok K Ferkowicz MJ Gilley D Yoder MC Identification of a novel hierarchy of endothelial progenitor cells using human peripheral and umbilical cord blood.Blood. 2004; 104: 2752-2760Crossref PubMed Scopus (1321) Google Scholar that was capable of almost unlimited growth in culture. Characterization during culturing identified these cells as being endothelial, based not only on surface markers, but also on function, ie, formation of capillary-like tubes. Unfortunately, culturing prohibits fate- mapping, preventing the characterization of the original cell from which the culture was derived. Was it a genuine angioblast/EPC, or was it a CD14-positive myeloid cell capable of transdifferentiating into endothelium? Progenitor cells positive for both endothelial markers (KDR/VEGFR2) and the stem cell marker CD133 have been identified. But, as mentioned previously and again established in the current study by Kim and colleagues,7Kim SJ, Kim JS, Papadopoulos J, Kim SW, Maya M, Zhang F, He J, Fan D, Langley R, Fidler IJ: Circulating monocytes expressing CD31: implications for acute and chronic angiogenesis. Am J Pathol 174, 5:1972–1980Google Scholar CD14-positive myeloid cells can be positive for VEGFR2, and they can be cultured to resemble endothelium given the appropriate conditions of matrix support, endothelium medium, and growth factors.8Urbich C Heeschen C Aicher A Dernbach E Zeiher AM Dimmeler S Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells.Circulation. 2003; 108: 2511-2516Crossref PubMed Scopus (520) Google Scholar The paucity of angioblast-like cells in blood makes their potential contribution to postnatal angiogenesis questionable, and indeed no such cell type was shown to be relevant in the parabiosis model described by Kim,7Kim SJ, Kim JS, Papadopoulos J, Kim SW, Maya M, Zhang F, He J, Fan D, Langley R, Fidler IJ: Circulating monocytes expressing CD31: implications for acute and chronic angiogenesis. Am J Pathol 174, 5:1972–1980Google Scholar consistent with recent reports.6Purhonen S Palm J Rossi D Kaskenpää N Rajantie I Ylä-Herttuala S Alitalo K Weissman IL Salven P Bone marrow-derived circulating endothelial precursors do not contribute to vascular endothelium and are not needed for tumor growth.Proc Natl Acad Sci USA. 2008; 105: 6620-6625Crossref PubMed Scopus (339) Google Scholar Instead, cells positive for F4/80 and VEGFR2 were the predominant type contributing in these in vivo tumor angiogenesis models. It will be quite important to establish, however, whether these cells constitute a specific subclass of monocytes destined to become angiogenic, based on specific surface markers. Specific subclasses of monocytes have been recently established to home to atherosclerotic lesions.17Tacke F Alvarez D Kaplan TJ Jakubzick C Spanbroek R Llodra J Garin A Liu J Mack M van Rooijen N Lira SA Habenicht AJ Randolph GJ Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques.J Clin Invest. 2007; 117: 185-194Crossref PubMed Scopus (1013) Google Scholar, 18Swirski FK Libby P Aikawa E Alcaide P Luscinskas FW Weissleder R Pittet MJ Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata.J Clin Invest. 2007; 117: 195-205Crossref PubMed Scopus (974) Google Scholar Such angiogenic monocytes might be functionally interchangeable with the term EPC (of myeloid origin), although they cannot be named angioblasts. The concept of cross talk between hematopoietic and endothelial lineage cells is not entirely hypothetical; during embryogenesis both endothelial cells and hematopoietic cells derive from a common ancestor: the hemangioblast. The difference between EPCs and angiogenic monocytes is not semantics, but exclusion of cellular mimicry.19Rizzino A A challenge for regenerative medicine: proper genetic programming, not cellular mimicry.Dev Dyn. 2007; 236: 3199-3207Crossref PubMed Scopus (34) Google Scholar Single surface markers do not type a cell (except in fluorescence-activated cell sorting); genetic programming determines the function of a cell in vivo. This genetic programming is, however, subject to change, as exemplified by recent progress in stem cell technology.20Park IH Zhao R West JA Yabuuchi A Huo H Ince TA Lerou PH Lensch MW Daley GQ Reprogramming of human somatic cells to pluripotency with defined factors.Nature. 2008; 451: 141-146Crossref PubMed Scopus (2384) Google Scholar Therefore, appropriate culturing might expand cells of whatever origin to serve as therapeutic progenitor cells.21Urbich C Dimmeler S Endothelial progenitor cells functional characterization.Trends Cardiovasc Med. 2004; 14: 318-322Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar, 22Obi S Yamamoto K Shimizu N Kumagaya S Masumura T Sokabe T Asahara T Ando J Fluid shear stress induces arterial differentiation of endothelial progenitor cells.J Appl Physiol. 2009; 106: 203-211Crossref PubMed Scopus (147) Google Scholar Whether these cells will actually incorporate in newly formed vessels as genuine endothelium, or supply the necessary growth factors and conditions for adult endothelium to expand, is not an issue of practical importance.23Urbich 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 (653) Google Scholar After all, by now it is well established that many different bone marrow-derived cells are essential for VEGF-induced angiogenesis, many of which are recruited to sites of ischemia and retained by SDF1 until perfusion is restored.24Grunewald M Avraham I Dor Y Bachar-Lustig E Itin A Jung S Chimenti S Landsman L Abramovitch R Keshet E VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells.Cell. 2006; 124: 175-189Abstract Full Text Full Text PDF PubMed Scopus (1013) Google Scholar In this light, the presence of bone marrow-derived GFP-positive, but CD31/F4/80-negative cells in the tumors as described by Kim and colleagues,7Kim SJ, Kim JS, Papadopoulos J, Kim SW, Maya M, Zhang F, He J, Fan D, Langley R, Fidler IJ: Circulating monocytes expressing CD31: implications for acute and chronic angiogenesis. Am J Pathol 174, 5:1972–1980Google Scholar is highly interesting and their future typing would give essential clues as to what types of bone marrow-derived cells are actually involved in maintaining tumor angiogenesis.4Lyden 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 (1693) Google Scholar In conclusion, the study by Kim and colleagues7Kim SJ, Kim JS, Papadopoulos J, Kim SW, Maya M, Zhang F, He J, Fan D, Langley R, Fidler IJ: Circulating monocytes expressing CD31: implications for acute and chronic angiogenesis. Am J Pathol 174, 5:1972–1980Google Scholar in the current issue of the AJP again fuels the controversy regarding the in vivo role of genuine EPCs (angioblast), but also establishes a pivotal role of F4/80-positive myeloid cells (angiogenic monocytes) in tumor angiogenesis in a nonmyeloablative, physiological setting. In its purest essence, it adds the already established marker molecule F4/80 to the list of things to type in vascular progenitor cell typing. As such it will not only fuel controversy, but also adds another piece to the puzzle of defining the true circulating pro-angiogenic progenitor cell. Circulating Monocytes Expressing CD31: Implications for Acute and Chronic AngiogenesisThe American Journal of PathologyVol. 174Issue 5PreviewTo identify the roles of various circulating cells (eg, endothelial and/or stem and progenitor cells) in angiogenesis, we parabiosed a wild-type syngeneic mouse with a transgenic syngeneic green fluorescent protein mouse. Following the establishment of a common circulation between these parabionts, we investigated acute (7 to 10 days), subacute (2 to 3 weeks), and chronic (4 to 6 weeks) phases of angiogenesis in wild-type mice using wound healing, implanted gel foam fragments, and subcutaneous tumor assays, respectively. Full-Text PDF
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