Active interaction of human A375 melanoma cells with the lymphatics in vivo.
We have used the avian chorioallantoic membrane (CAM) to study the interaction of tumor cells with the lymphatics in vivo. The vascular endothelial growth factor-C (VEGF-C) has been shown to be lymphangiogenic. We have therefore grown VEGF-C-expressing human A375 melanoma cells on the CAM. These tumors induced numerous lymphatics at the invasive front, and compressed or destroyed VEGF receptor (R)-3-positive lymphatics were observed within the solid tumors. The lymphatics in the CAM and in the A375 melanomas could also be demonstrated with an antibody against Prox 1, a highly specific marker of lymphatic endothelial cells. Proliferation studies revealed a BrdU labeling index of 11.6% of the lymphatic endothelial cells in the tumors and at their margins. A great number of melanoma cells invaded the lymphatics. Such interactions were not observed with VEGF-C-negative Malme 3 M melanoma cells. Lymphangiogenesis was inhibited to some extent when A375 melanoma cells were transfected with cDNA encoding soluble VEGFR-3 (sflt4), and the BrdU labeling index of the lymphatics in these tumors was 3.9%. Invasion of lymphatics and growth of blood vascular capillaries were not inhibited by the transfection. Therefore, tumor-induced lymphangiogenesis seems to be dependent to some extent on VEGF-C/flt4 interactions, but invasion of lymphatics seems to be a distinct mechanism.
Papoutsi
M
M
Anatomisches Institut, Albert-Ludwigs-Universität, Lehrstuhl II, Albertstrasse 17, 79104 Freiburg i. Br., Germany.
Siemeister
G
G
Weindel
K
K
Tomarev
S I
SI
Kurz
H
H
Schächtele
C
C
Martiny-Baron
G
G
Christ
B
B
Marmé
D
D
Wilting
J
J
D000481:Allantoin / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D002455:Cell Division; D002467:Cell Nucleus / Q000648:ultrastructure; D002642:Chick Embryo; D003370:Coturnix; D019084:Fluorescent Antibody Technique, Indirect; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008208:Lymphatic System / Q000473:pathology* / Q000648:ultrastructure; D008546:Melanoma, Experimental / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D051379:Mice; D008819:Mice, Nude; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3; D000098551:Prospero-Related Homeobox 1 Protein
D018398:Homeodomain Proteins; D017978:Receptors, Growth Factor; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; D000481:Allantoin; D020794:Receptor Protein-Tyrosine Kinases; D040321:Vascular Endothelial Growth Factor Receptor-3