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.