Differential expression of a gene signature for scavenger/lectin receptors by endothelial cells and macrophages in human lymph node sinuses, the primary sites of regional metastasis.
Sentinel lymph node biopsy for several cancers has shown that metastatic tumour cells are preferentially arrested in the lymph node sinuses. To study the molecular components of this sinusoidal trap, gene profiling of lymph node (sinuses) versus tonsil (no sinuses) was performed. Among other groups of molecules, an intriguing gene signature of scavenger and lectin-like receptors was identified. Nine of the 13 genes were preferentially expressed in sinusoidal cells by immunohistochemistry. Using stabilin-2 and monoclonal antibody 3A5 as exclusive endothelial cell (EC) and macrophage (Mvarphi) markers, respectively, lymph node sinusoidal ECs (stabilin-2+, LYVE-1+, DC-SIGNR+, MARCO+, stabilin-1+, MMR+) and sinusoidal Mvarphi (MMR+, DC-SIGN+, sialoadhesin+, CD163+, stabilin-1+ ) showed distinct, but overlapping expression patterns of the signature molecules by double labelling immunofluorescence. The number of stabilin-1+ sinusoidal Mvarphi, however, varied considerably between samples, indicating turnover/differentiation dynamics in this sinusoidal cell population. In the hepatic sinuses, LYVE-1 and CD36 were strongly up-regulated on both sinusoidal ECs and Mvarphi, while DC-SIGNR and DC-SIGN were strongly down-regulated; in contrast to lymph node sinusoidal ECs, MARCO was confined to Mvarphi (Kupffer cells) in the liver sinuses. As Mvarphi are not present in the wall and lumen of splenic sinuses, splenic sinuses expressed a considerably reduced repertoire of scavenger/lectin receptors lacking sialoadhesin, CD36, CD163, and MARCO; in addition, DC-SIGNR was absent from splenic sinusoidal ECs, while DC-SIGN and thrombomodulin were strongly expressed. Interestingly, most of the signature molecules are known to mediate tumour cell adhesion in addition to their functions as scavenger or pattern recognition receptors. This study establishes a gene and tissue database platform to test the hypothesis that additive expression of the lymph node sinus signature genes in sinusoidal ECs and Mvarphi may contribute to selective tumour cell metastasis in lymph nodes and liver including organ-specific mechanisms, such as intraluminal retention or transmigration, while sparing the spleen.
Martens
J-H
JH
Department of Dermatology, University Medical Centre Mannheim, Ruprecht-Karls University Heidelberg, Mannheim, Germany.
Kzhyshkowska
J
J
Falkowski-Hansen
M
M
Schledzewski
K
K
Gratchev
A
A
Mansmann
U
U
Schmuttermaier
C
C
Dippel
E
E
Koenen
W
W
Riedel
F
F
Sankala
M
M
Tryggvason
K
K
Kobzik
L
L
Moldenhauer
G
G
Arnold
B
B
Goerdt
S
S
D015415:Biomarkers / Q000032:analysis; D015815:Cell Adhesion Molecules / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D037102:Lectins / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism* / Q000473:pathology; D008207:Lymphatic Metastasis; D008264:Macrophages / Q000378:metabolism*; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D014066:Palatine Tonsil / Q000378:metabolism; D051116:Receptors, Scavenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000378:metabolism
D015415:Biomarkers; D015815:Cell Adhesion Molecules; D037102:Lectins; D051116:Receptors, Scavenger