Heterogeneity and Plasticity of Lymphatic Endothelial Cells

Sunju Lee; Inho Choi; Young-Kwon Hong

doi:10.1055/s-0030-1253457

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2010; 36(3): 352-361
DOI: 10.1055/s-0030-1253457

Heterogeneity and Plasticity of Lymphatic Endothelial Cells

Sunju Lee¹ , Inho Choi¹ , Young-Kwon Hong¹

¹Departments of Surgery, and of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California

Abstract

ABSTRACT

Endothelial cells are found in most organs and tissues in our body. Despite their apparent morphological and functional similarities, endothelial cells exhibit remarkable heterogeneity and plasticity. In a strict sense, no two endothelial cells are identical in terms of their biological, immunological, functional, metabolic, morphological, and anatomical aspects. Their heterogeneity and plasticity are now known to be dependent upon and conferred by their microenvironments, arteriovenous-lymphatic cell identity, organ-specific vascular beds, fluid dynamics, vessel sizes, anatomical locations, physiological and pathological states, and more. Although abundant evidence is available to demonstrate endothelial heterogeneity in the blood vascular system, studies of heterogeneity and plasticity of lymphatic endothelial cells are limited because of the short history of lymphatic research. Nonetheless, a growing body of exciting work has begun to discover that lymphatic endothelial cells are as heterogeneous as blood vascular endothelial cells. In this article, we discuss the heterogeneity and plasticity of lymphatic endothelial cells.

KEYWORDS

Lymphatic - endothelial cell - heterogeneity - cell fate

Full Text

References

REFERENCES

1 Asellius G. De lactibus sive lacteis venis. Milan, Italy; Mediolani 1627
2 Harvey W. An Anatomical Study of the Motion of the Heart and Blood in Animals. 1628.
3 Hong Y K, Shin J W, Detmar M. Development of the lymphatic vascular system: a mystery unravels. Dev Dyn. 2004; 231(3) 462-473
4 Sabin F R. On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. Am J Anat. 1902; 1 367-391
5 Sabin F R. On the development of the superficial lymphatics in the skin of the pig. Am J Anat. 1904; 3 183-195
6 Huntington G S, McClure C FW. The anatomy and development of the jugular lymph sac in the domestic cat (Felis domestica). Am J Anat. 1910; 10 177-311
7 Wigle J T, Harvey N, Detmar M et al.. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 2002; 21(7) 1505-1513
8 Wigle J T, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell. 1999; 98(6) 769-778
9 Hong Y K, Lange-Asschenfeldt B, Velasco P et al.. VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB J. 2004; 18(10) 1111-1113
10 Oliver G, Detmar M. The rediscovery of the lymphatic system: old and new insights into the development and biological function of the lymphatic vasculature. Genes Dev. 2002; 16(7) 773-783
11 Srinivasan R S, Dillard M E, Lagutin O V et al.. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev. 2007; 21(19) 2422-2432
12 Wilting J, Schneider M, Papoutski M, Alitalo K, Christ B. An avian model for studies of embryonic lymphangiogenesis. Lymphology. 2000; 33(3) 81-94
13 Wilting J, Papoutsi M, Othman-Hassan K et al.. Development of the avian lymphatic system. Microsc Res Tech. 2001; 55(2) 81-91
14 Wilting J, Aref Y, Huang R et al.. Dual origin of avian lymphatics. Dev Biol. 2006; 292(1) 165-173
15 Oliver G, Sosa-Pineda B, Geisendorf S, Spana E P, Doe C Q, Gruss P. Prox 1, a prospero-related homeobox gene expressed during mouse development. Mech Dev. 1993; 44(1) 3-16
16 Kielman M F, Barradeau S, Smits R, Harteveld C L, Bernini L F. Characterization and localization of the mProx1 gene directly upstream of the mouse alpha-globin gene cluster: identification of a polymorphic direct repeat in the 5'UTR. Mamm Genome. 1996; 7(12) 877-880
17 Tomarev S I, Zinovieva R D, Chang B, Hawes N L. Characterization of the mouse Prox1 gene. Biochem Biophys Res Commun. 1998; 248(3) 684-689
18 Doe C Q, Chu-LaGraff Q, Wright D M, Scott M P. The prospero gene specifies cell fates in the Drosophila central nervous system. Cell. 1991; 65(3) 451-464
19 Hong Y K, Detmar M. Prox1, master regulator of the lymphatic vasculature phenotype. Cell Tissue Res. 2003; 314(1) 85-92
20 Demidenko Z, Badenhorst P, Jones T, Bi X, Mortin M A. Regulated nuclear export of the homeodomain transcription factor Prospero. Development. 2001; 128(8) 1359-1367
21 Hassan B, Li L, Bremer K A, Chang W, Pinsonneault J, Vaessin H. Prospero is a panneural transcription factor that modulates homeodomain protein activity. Proc Natl Acad Sci U S A. 1997; 94(20) 10991-10996
22 Shin J W, Min M, Larrieu-Lahargue F et al.. Prox1 promotes lineage-specific expression of fibroblast growth factor (FGF) receptor-3 in lymphatic endothelium: a role for FGF signaling in lymphangiogenesis. Mol Biol Cell. 2006; 17(2) 576-584
23 Hong Y K, Harvey N, Noh Y H et al.. Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn. 2002; 225(3) 351-357
24 Petrova T V, Mäkinen T, Mäkelä T P et al.. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J. 2002; 21(17) 4593-4599
25 Song K H, Li T, Chiang J YA. A Prospero-related homeodomain protein is a novel co-regulator of hepatocyte nuclear factor 4alpha that regulates the cholesterol 7alpha-hydroxylase gene. J Biol Chem. 2006; 281(15) 10081-10088
26 Steffensen K R, Holter E, Båvner A et al.. Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ-F1 homologue. EMBO Rep. 2004; 5(6) 613-619
27 Qin J, Gao D M, Jiang Q F et al.. Prospero-related homeobox (Prox1) is a corepressor of human liver receptor homolog-1 and suppresses the transcription of the cholesterol 7-alpha-hydroxylase gene. Mol Endocrinol. 2004; 18(10) 2424-2439
28 Liu Y W, Gao W, Teh H L, Tan J H, Chan W K. Prox1 is a novel coregulator of Ff1b and is involved in the embryonic development of the zebra fish interrenal primordium. Mol Cell Biol. 2003; 23(20) 7243-7255
29 Lee S, Kang J, Yoo J et al.. Prox1 physically and functionally interacts with COUP-TFII to specify lymphatic endothelial cell fate. Blood. 2009; 113(8) 1856-1859
30 Yamazaki T, Yoshimatsu Y, Morishita Y, Miyazono K, Watabe T. COUP-TFII regulates the functions of Prox1 in lymphatic endothelial cells through direct interaction. Genes Cells. 2009; 14(3) 425-434
31 François M, Caprini A, Hosking B et al.. Sox18 induces development of the lymphatic vasculature in mice. Nature. 2008; 456(7222) 643-647
32 Hosking B, François M, Wilhelm D et al.. Sox7 and Sox17 are strain-specific modifiers of the lymphangiogenic defects caused by Sox18 dysfunction in mice. Development. 2009; 136(14) 2385-2391
33 Jeltsch M, Kaipainen A, Joukov V et al.. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science. 1997; 276(5317) 1423-1425
34 Joukov V, Pajusola K, Kaipainen A et al.. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J. 1996; 15(2) 290-298
35 Lee J, Gray A, Yuan J, Luoh S M, Avraham H, Wood W I. Vascular endothelial growth factor-related protein: a ligand and specific activator of the tyrosine kinase receptor Flt4. Proc Natl Acad Sci U S A. 1996; 93(5) 1988-1992
36 Kaipainen A, Korhonen J, Mustonen T et al.. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A. 1995; 92(8) 3566-3570
37 Karkkainen M J, Haiko P, Sainio K et al.. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol. 2004; 5(1) 74-80
38 Achen M G, Jeltsch M, Kukk E et al.. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A. 1998; 95(2) 548-553
39 Veikkola T, Jussila L, Makinen T et al.. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J. 2001; 20(6) 1223-1231
40 Baldwin M E, Halford M M, Roufail S et al.. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol. 2005; 25(6) 2441-2449
41 Mäkinen T, Veikkola T, Mustjoki S et al.. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 2001; 20(17) 4762-4773
42 Dumont D J, Jussila L, Taipale J et al.. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science. 1998; 282(5390) 946-949
43 Mäkinen T, Jussila L, Veikkola T et al.. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med. 2001; 7(2) 199-205
44 Hirakawa S, Hong Y K, Harvey N et al.. Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am J Pathol. 2003; 162(2) 575-586
45 Kriehuber E, Breiteneder-Geleff S, Groeger M et al.. Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J Exp Med. 2001; 194(6) 797-808
46 Nagy J A, Vasile E, Feng D et al.. VEGF-A induces angiogenesis, arteriogenesis, lymphangiogenesis, and vascular malformations. Cold Spring Harb Symp Quant Biol. 2002; 67 227-237
47 Kunstfeld R, Hirakawa S, Hong Y K et al.. Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia. Blood. 2004; 104(4) 1048-1057
48 Jackson D G. The lymphatics revisited: new perspectives from the hyaluronan receptor LYVE-1. Trends Cardiovasc Med. 2003; 13(1) 1-7
49 Jackson D G. Biology of the lymphatic marker LYVE-1 and applications in research into lymphatic trafficking and lymphangiogenesis. APMIS. 2004; 112(7–8) 526-538
50 Banerji S, Ni J, Wang S X et al.. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol. 1999; 144(4) 789-801
51 Gale N W, Prevo R, Espinosa J et al.. Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1. Mol Cell Biol. 2007; 27(2) 595-604
52 Wetterwald A, Hoffstetter W, Cecchini M G et al.. Characterization and cloning of the E11 antigen, a marker expressed by rat osteoblasts and osteocytes. Bone. 1996; 18(2) 125-132
53 Schacht V, Ramirez M I, Hong Y K et al.. T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J. 2003; 22(14) 3546-3556
54 Ramirez M I, Millien G, Hinds A, Cao Y, Seldin D C, Williams M C. T1alpha, a lung type I cell differentiation gene, is required for normal lung cell proliferation and alveolus formation at birth. Dev Biol. 2003; 256(1) 61-72
55 Kato Y, Fujita N, Kunita A et al.. Molecular identification of Aggrus/T1alpha as a platelet aggregation-inducing factor expressed in colorectal tumors. J Biol Chem. 2003; 278(51) 51599-51605
56 Zimmer G, Oeffner F, Von Messling V et al.. Cloning and characterization of gp36, a human mucin-type glycoprotein preferentially expressed in vascular endothelium. Biochem J. 1999; 341(Pt 2) 277-284
57 Nose K, Saito H, Kuroki T. Isolation of a gene sequence induced later by tumor-promoting 12-O-tetradecanoylphorbol-13-acetate in mouse osteoblastic cells (MC3T3-E1) and expressed constitutively in ras-transformed cells. Cell Growth Differ. 1990; 1(11) 511-518
58 Rishi A K, Joyce-Brady M, Fisher J et al.. Cloning, characterization, and development expression of a rat lung alveolar type I cell gene in embryonic endodermal and neural derivatives. Dev Biol. 1995; 167(1) 294-306
59 Tangemann K, Gunn M D, Giblin P, Rosen S D. A high endothelial cell-derived chemokine induces rapid, efficient, and subset-selective arrest of rolling T lymphocytes on a reconstituted endothelial substrate. J Immunol. 1998; 161(11) 6330-6337
60 Gunn M D, Tangemann K, Tam C, Cyster J G, Rosen S D, Williams L T. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci U S A. 1998; 95(1) 258-263
61 Pereira F A, Qiu Y, Tsai M J, Tsai S Y. Chicken ovalbumin upstream promoter transcription factor (COUP-TF): expression during mouse embryogenesis. J Steroid Biochem Mol Biol. 1995; 53 503-508
62 Pereira F A, Qiu Y, Zhou G, Tsai M J, Tsai S Y. The orphan nuclear receptor COUP-TFII is required for angiogenesis and heart development. Genes Dev. 1999; 13(8) 1037-1049
63 Pereira F A, Tsai M J, Tsai S Y. COUP-TF orphan nuclear receptors in development and differentiation. Cell Mol Life Sci. 2000; 57(10) 1388-1398
64 You L R, Lin F J, Lee C T, DeMayo F J, Tsai M J, Tsai S Y. Suppression of Notch signalling by the COUP-TFII transcription factor regulates vein identity. Nature. 2005; 435(7038) 98-104
65 Ribatti D, Nico B, Vacca A, Roncali L, Dammacco F. Endothelial cell heterogeneity and organ specificity. J Hematother Stem Cell Res. 2002; 11(1) 81-90
66 Børsum T, Hagen I, Henriksen T, Carlander B. Alterations in the protein composition and surface structure of human endothelial cells during growth in primary culture. Atherosclerosis. 1982; 44(3) 367-378
67 Milici A J, Furie M B, Carley W W. The formation of fenestrations and channels by capillary endothelium in vitro. Proc Natl Acad Sci U S A. 1985; 82(18) 6181-6185
68 Risau W. Induction of blood-brain barrier endothelial cell differentiation. Ann N Y Acad Sci. 1991; 633 405-419
69 Ager A. Isolation and culture of high endothelial cells from rat lymph nodes. J Cell Sci. 1987; 87(Pt 1) 133-144
70 Aird W C, Edelberg J M, Weiler-Guettler H, Simmons W W, Smith T W, Rosenberg R D. Vascular bed-specific expression of an endothelial cell gene is programmed by the tissue microenvironment. J Cell Biol. 1997; 138(5) 1117-1124
71 Zhu D Z, Cheng C F, Pauli B U. Mediation of lung metastasis of murine melanomas by a lung-specific endothelial cell adhesion molecule. Proc Natl Acad Sci U S A. 1991; 88(21) 9568-9572
72 Lacorre D A, Baekkevold E S, Garrido I et al.. Plasticity of endothelial cells: rapid dedifferentiation of freshly isolated high endothelial venule endothelial cells outside the lymphoid tissue microenvironment. Blood. 2004; 103(11) 4164-4172
73 Podgrabinska S, Braun P, Velasco P, Kloos B, Pepper M S, Skobe M. Molecular characterization of lymphatic endothelial cells. Proc Natl Acad Sci U S A. 2002; 99(25) 16069-16074
74 Nisato R E, Harrison J A, Buser R et al.. Generation and characterization of telomerase-transfected human lymphatic endothelial cells with an extended life span. Am J Pathol. 2004; 165(1) 11-24
75 Nisato R E, Buser R, Pepper M S. Lymphatic endothelial cells: establishment of primaries and characterization of established lines. Methods Mol Biol. 2009; 467 113-126
76 Wick N, Saharinen P, Saharinen J et al.. Transcriptomal comparison of human dermal lymphatic endothelial cells ex vivo and in vitro. Physiol Genomics. 2007; 28(2) 179-192
77 Amatschek S, Kriehuber E, Bauer W et al.. Blood and lymphatic endothelial cell-specific differentiation programs are stringently controlled by the tissue environment. Blood. 2007; 109(11) 4777-4785
78 Breiteneder-Geleff S, Soleiman A, Kowalski H et al.. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol. 1999; 154(2) 385-394
79 Mäkinen T, Adams R H, Bailey J et al.. PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev. 2005; 19(3) 397-410
80 Kawai Y, Hosaka K, Kaidoh M, Minami T, Kodama T, Ohhashi T. Heterogeneity in immunohistochemical, genomic, and biological properties of human lymphatic endothelial cells between initial and collecting lymph vessels. Lymphat Res Biol. 2008; 6(1) 15-27
81 Wick N, Haluza D, Gurnhofer E et al.. Lymphatic precollectors contain a novel, specialized subpopulation of podoplanin low, CCL27-expressing lymphatic endothelial cells. Am J Pathol. 2008; 173(4) 1202-1209
82 Mouta Carreira C, Nasser S M, di Tomaso E et al.. LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res. 2001; 61(22) 8079-8084
83 Arimoto J, Ikura Y, Suekane T et al.. Expression of LYVE-1 in sinusoidal endothelium is reduced in chronically inflamed human livers. J Gastroenterol. 2009; , In press
84 Schmid-Schönbein G W. The second valve system in lymphatics. Lymphat Res Biol. 2003; 1(1) 25-29 discussion 29-31
85 Leak L V, Burke J F. Ultrastructural studies on the lymphatic anchoring filaments. J Cell Biol. 1968; 36(1) 129-149
86 Skobe M, Detmar M. Structure, function, and molecular control of the skin lymphatic system. J Investig Dermatol Symp Proc. 2000; 5(1) 14-19
87 Baluk P, Fuxe J, Hashizume H et al.. Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med. 2007; 204(10) 2349-2362
88 Chi J T, Chang H Y, Haraldsen G et al.. Endothelial cell diversity revealed by global expression profiling. Proc Natl Acad Sci U S A. 2003; 100(19) 10623-10628
89 Garrafa E, Alessandri G, Benetti A et al.. Isolation and characterization of lymphatic microvascular endothelial cells from human tonsils. J Cell Physiol. 2006; 207(1) 107-113
90 Garrafa E, Trainini L, Benetti A et al.. Isolation, purification, and heterogeneity of human lymphatic endothelial cells from different tissues. Lymphology. 2005; 38(4) 159-166
91 Mouta-Bellum C, Kirov A, Miceli-Libby L et al.. Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene-targeting of the PI3K regulatory isoforms p85alpha, p55alpha, and p50alpha. Dev Dyn. 2009; 238(10) 2670-2679
92 Norrmen C, Vandevelde W, Ny A et al.. Liprin {beta}1 is highly expressed in lymphatic vasculature and is important for lymphatic vessel integrity. Blood. 2010; 115(4) 906-909
93 Torres-Vázquez J, Kamei M, Weinstein B M. Molecular distinction between arteries and veins. Cell Tissue Res. 2003; 314(1) 43-59
94 Weinstein B M, Lawson N D. Arteries, veins, Notch, and VEGF. Cold Spring Harb Symp Quant Biol. 2002; 67 155-162
95 Johnson N C, Dillard M E, Baluk P et al.. Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity. Genes Dev. 2008; 22(23) 3282-3291
96 Shawber C J, Funahashi Y, Francisco E et al.. Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. J Clin Invest. 2007; 117(11) 3369-3382
97 Kang J, Yoo J, Lee S. An exquisite cross-control mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells. Blood. 2010; , In press
98 Partanen T A, Alitalo K, Miettinen M. Lack of lymphatic vascular specificity of vascular endothelial growth factor receptor 3 in 185 vascular tumors. Cancer. 1999; 86(11) 2406-2412
99 Valtola R, Salven P, Heikkilä P et al.. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol. 1999; 154(5) 1381-1390
100 Witmer A N, van Blijswijk B C, Dai J et al.. VEGFR-3 in adult angiogenesis. J Pathol. 2001; 195(4) 490-497
101 Nakamura Y, Yasuoka H, Tsujimoto M et al.. Flt-4-positive vessel density correlates with vascular endothelial growth factor-d expression, nodal status, and prognosis in breast cancer. Clin Cancer Res. 2003; 9(14) 5313-5317
102 Clarijs R, Schalkwijk L, Hofmann U B, Ruiter D J, de Waal R MW. Induction of vascular endothelial growth factor receptor-3 expression on tumor microvasculature as a new progression marker in human cutaneous melanoma. Cancer Res. 2002; 62(23) 7059-7065
103 Clasper S, Royston D, Baban D et al.. A novel gene expression profile in lymphatics associated with tumor growth and nodal metastasis. Cancer Res. 2008; 68(18) 7293-7303
104 Royston D, Jackson D G. Mechanisms of lymphatic metastasis in human colorectal adenocarcinoma. J Pathol. 2009; 217(5) 608-619
105 Fiedler U, Christian S, Koidl S et al.. The sialomucin CD34 is a marker of lymphatic endothelial cells in human tumors. Am J Pathol. 2006; 168(3) 1045-1053
106 Aguilar B, Hong Y K. The Origin of Kaposi Sarcoma Tumor Cells. Kerala, India; Research Signpost 2009: 123-138
107 Kaposi M. Idiopathisches multiples pigmentsarcom der haut. Arch Dermatol und Syphillis. 1872; 4 265-273
108 Chang Y, Cesarman E, Pessin M S et al.. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science. 1994; 266(5192) 1865-1869
109 Dayan A D, Lewis P D. Origin of Kaposi's sarcoma from the reticulo-endothelial system. Nature. 1967; 213(5079) 889-890
110 Carroll P A, Brazeau E, Lagunoff M. Kaposi's sarcoma-associated herpesvirus infection of blood endothelial cells induces lymphatic differentiation. Virology. 2004; 328(1) 7-18
111 Hong Y K, Foreman K, Shin J W et al.. Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet. 2004; 36(7) 683-685
112 Wang H W, Trotter M W, Lagos D et al.. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet. 2004; 36(7) 687-693

Young-Kwon HongPh.D.

Assistant Professor, Departments of Surgery and of Biochemistry & Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California

1450 Biggy St. NRT6501, M/C9601, Los Angeles, CA 90033

Email: young.hong@usc.edu