title: A novel gene expression profile in lymphatics associated with tumor growth and nodal metastasis.
abstract: Invasion of lymphatic vessels is a key step in the metastasis of primary tumors to draining lymph nodes. Although the process is enhanced by tumor lymphangiogenesis, it is unclear whether this is a consequence of increased lymphatic vessel number, altered lymphatic vessel properties, or both. Here we have addressed the question by comparing the RNA profiles of primary lymphatic endothelial cells (LEC) isolated from the vasculature of normal tissue and from highly metastatic T-241/vascular endothelial growth factor (VEGF)-C fibrosarcomas implanted in C57BL/6 mice. Our findings reveal significant differences in expression of some 792 genes (i.e., >or=2-fold up- or down-regulated, P <or= 0.05) that code for a variety of proteins including components of endothelial junctions, subendothelial matrix, and vessel growth/patterning. The tumor LEC profile, validated by immunohistochemical staining, is distinct from that of normal, inflammatory cytokine, or mitogen-activated LEC, characterized by elevated expression of such functionally significant molecules as the tight junction regulatory protein endothelial specific adhesion molecule (ESAM), the transforming growth factor-beta coreceptor Endoglin (CD105), the angiogenesis-associated leptin receptor, and the immunoinhibitory receptor CD200, and reduced expression of subendothelial matrix proteins including collagens, fibrillin, and biglycan. Moreover, we show similar induction of ESAM, Endoglin, and leptin receptor within tumor lymphatics in a series of human head and neck and colorectal carcinomas, and uncover a dramatic correlation between ESAM expression and nodal metastasis that identifies this marker as a possible prognostic indicator. These findings reveal a remarkable degree of phenotypic plasticity in cancer lymphatics and provide new insight into the processes of lymphatic invasion and lymph node metastasis.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, United Kingdom.
authors.forename: Steven
authors.initials: S
authors.lastname: Clasper
authors.forename: Daniel
authors.initials: D
authors.lastname: Royston
authors.forename: Dilair
authors.initials: D
authors.lastname: Baban
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
authors.forename: Stephan
authors.initials: S
authors.lastname: Ewers
authors.forename: Stefan
authors.initials: S
authors.lastname: Butz
authors.forename: Dietmar
authors.initials: D
authors.lastname: Vestweber
authors.forename: David G
authors.initials: DG
authors.lastname: Jackson
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D000071063:Endoglin; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005354:Fibrosarcoma / Q000098:blood supply / Q000235:genetics / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D062726:Junctional Adhesion Molecules; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D054411:Receptors, Leptin / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000096:biosynthesis / Q000235:genetics
chemical_list: D015815:Cell Adhesion Molecules; D000071063:Endoglin; C502004:Eng protein, mouse; C428190:Esam protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D062726:Junctional Adhesion Molecules; D054411:Receptors, Leptin; D016212:Transforming Growth Factor beta; D042582:Vascular Endothelial Growth Factor C