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.
Highlights
Lymph node metastasis is a common clinical finding in many human cancers, and one that is associated both with aggressive disease and poor prognosis
Polyclonal goat anti-human endothelial specific adhesion molecule (ESAM), goat antihuman LYVE-1, and goat anti-mouse vascular endothelial growth factor (VEGF) receptor 3 (VEGFR3) antibodies were from R&D Systems Europe; mouse anti-human Endoglin was from DAKO; polyclonal rabbit anti-human leptin-R antibodies were from Abcam; rat anti-mouse CD31, Endoglin, and MECA-32 monoclonal antibodies were from BD Pharmingen; rabbit anti-Prox1 was from Research Diagnostics Inc.; goat anti-mouse biglycan was from Santa Cruz Biotechnology; and rabbit anti-human CD200 was from Serotec UK
As a model system to study the effects of tumor environment on lymphatic endothelial cells (LEC) phenotype, we used the GFPtransfected T241/VEGF-C tumor line [18] that consistently forms lymph node metastasizing fibrosarcomas when implanted in the dermis of C57BL/6 mice, characterized by formation of extensive intratumoral and peritumoral LYVE-1+ve/Podoplanin+ve/PROX-1+ve lymphatic vessels
Summary
Lymph node metastasis is a common clinical finding in many human cancers, and one that is associated both with aggressive disease and poor prognosis. The target vessels for invasion by lymph-metastasizing tumor cells include preexisting tissue lymphatics abutting the tumor mass either through coincidence or mutual chemoattraction [4], as well as new lymphatic vessels that proliferate either within or around the tumor as a result of lymphangiogenesis [5, 6]. The latter process is regulated primarily by the lymphangiogenic growth factors VEGF-C and VEGF-D generated by tumor cells or by host cells including tissue macrophages [6]. It remains controversial as to whether this metastasis-enhancing effect results from an increase in the number of target vessels due to mitogenesis or if other properties of the newly dividing tumor lymphatics, such as increased permeability, increased lymph flow, or specific changes in lymphatic surface phenotype, predispose them to invasion by tumor [10,11,12,13]
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