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2. Embryonic Development of the Lymphovascular System and Tumor Lymphangiogenesis

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2. Embryonic Development of the Lymphovascular System and Tumor Lymphangiogenesis 2. EMBRYONIC DEVELOPMENT OF THE LYMPHOVASCULAR SYSTEM AND TUMOR LYMPHANGIOGENESIS JÖRG WILTING, MARIA PAPOUTSI, KERSTIN BUTTLER, AND JÜRGEN BECKER Children’s Hospital, Pediatrics I, University of Goettingen, Robert-Koch-Strasse, Goettingen, Germany INTRODUCTION The embryonic development of the lymphatic vascular system starts considerably later than the blood vascular system. In chick embryos, the first blood vessels can be seen after 1 day of incubation, whereas morphological evidence for lymphatic endothelial cells (LECs) is present around day 5. However, with specific marker molecules, such as the transcription factor Prox1, LEC precursors can be identified in day-3.5 embryos. In the mouse, blood vessel development starts at embryonic day (ED) 7.5, whereas the anlagen of lymph vessels can be seen in the jugular region at ED 10. In human embryos there is a period of 3–4 weeks between the appearance of the first blood vas- cular endothelial cells (BECs) and LECs.There is good evidence that LECs develop from specialized parts of the venous system; however, there is growing evidence that scattered mesenchymal cells integrate into the growing fetal lymphatics. Similarly, lymphatics induced by tumors are derived mainly from local vessels, but, to some extent, pathologic lymphatics seem to develop by integration of circulating cells with lymphendothelial characteristics. In embryos, like in tumors, the most potent inducers of lymphangiogenesis are vascular endothelial growth factor (VEGF)-C and -D,which act mainly via VEGF receptor-3 (flt-4) on LECs.We have shown that blocking of this interaction prevents lymphangiogenesis in experimental A375 melanomas, while blocking of VEGF-A greatly inhibits blood vessel development (hemangiogenesis) in 18 Cancer Metastasis and the Lymphovascular System such tumors. However, local invasive growth of A375 melanoma cells is not significantly inhibited, showing that this tumor cell line induces hemangiogenesis, lymphangiogenesis, and invasiveness by distinct mechanisms. EMBRYONIC LYMPHANGIOGENESIS Development of Embryonic Lymph Sacs The first obvious morphological criteria of the developing lymphatics are the lymph sacs, which are located in close vicinity to deep embryonic veins. Studies on mammalian embryos have shown that there are eight lymph sacs: three paired and two unpaired (30).The first lymph sacs develop in the jugular region, which is the area where the cranial and caudal jugular veins fuse into the common cardinal vein. The LECs of the jugular lymph sacs develop considerably later than the first BECs. In the chick, the first blood vessels can be seen after 1 day of incubation (26), whereas jugular lymph sacs are present around day 5 (5). However, with specific markers, such as the transcription factor Prox1, their precursors can be identified in day-3.5 embryos (40). In the mouse, blood vessel development starts at ED 7.5 (2). The anlagen of the lymph vessels can be seen in the jugular region at ED 10 (34). The consecutive development of BECs and LECs has led to the hypothesis that LECs are derived from BECs, specifically from neighboring veins (29). Recently, Oliver and Harvey (22) have supported this hypothesis on the basis of the expres- sion pattern of the homeobox transcription factor Prox1. Prox1-deficient mice die at ED 14.5.They possess a normal blood vascular system, but the development of the lymphatics is arrested at ED 10.5 (34).The first Prox1-positive endothelial cells (ECs) are located in the jugular segment of the cardinal veins, and it has been pos- tulated that these venous ECs are the precursors for LECs in the embryo (22). In avian embryos, the expression pattern of Prox1 is identical with that of mice.The jugular segment of the cardinal veins is Prox1-positive, and labeling of the early (day 4) blood vessels results in a signal in day 6.5 jugular lymph sacs (40), suggesting a blood vascular origin of lymph sacs. The lymphangiogenic protein vascular endothelial growth factor-C (VEGF-C) is essential for the development of lymph sacs. Mice deficient for VEGF-C, which is the ligand of VEGF receptor-3 (VEGFR-3), do not form lymph sacs. This deficiency can be rescued by the application of VEGF-C (14).The studies are in line with the traditional view of the development of LECs from specific parts of the venous system, also called “cen- trifugal theory.”The main representative of this theory was Sabin (29, 30), who had performed India ink injections into the JLS of pig embryos. At about the same time, an opposing theory, the “centripetal theory,” had been set up by Huntington and McClure (10) and Kampmeier (13), who had studied cat and pig embryos. According to them, the lymphatics develop by confluence of mesenchymal cells, and only the lymph sacs might be of venous origin (13). By means of grafting experiments we have recently shown that LECs of quail embryos are able to integrate into the lymph sacs of chick embryos (38), suggesting an additional, mesenchymal source for lymph sac ECs. 2. Embryonic Development of the Lymphovascular System 19 Transdifferentiation of Venous into Lymphatic Endothelial Cells The lymph vessels of the body wall in the head, neck, and thoracic region are derived from the jugular segment of the cardinal veins.ECs in the cardinal veins obviously have the potency to give rise to two subtypes of ECs: venous and lymphatic.There are two likely mechanisms behind this phenomenon. Either bipotential ECs develop into the two lineages after asymmetric cell division, or venous ECs transdifferentiate into lym- phatic ECs. Both mechanisms could be regulated by the transcription factor Prox1, which was originally cloned in mice due to its homology to the Drosophila homeobox protein prospero (23).Asymmetric distribution of prospero in the cytoplasm of ganglion mother cells of Drosophila regulates asymmetric division into prospero-negative neu- roblasts and prospero-positive neurons or glia cells (11).Alternatively,Prox1 may induce transdifferentiation of venous ECs into lymphatic ECs. Transcriptional profiling of BECs that were transfected with Prox1 cDNA has provided evidence for a shift toward a lymphatic phenotype (9, 28). In the jugular region, a subpopulation of ECs in the cardinal veins start to express Prox1 in ED 10 mouse and ED 4 chick embryos (34, 40). VEGFR-3 expression becomes restricted to the Prox1-positive LECs. Before, VEGFR-3 is expressed in all blood vessels of the embryo and VEGFR-3 knockout (ko) mice die of cardiovascular failure before lymph vessels develop (6).The ECs of the lymph sacs downregulate BEC markers such as type IV collagen and laminin, and upregulate LEC markers such as secondary lymphoid chemokine (SLC/CCL21) and LYVE-1, a sialoglycoprotein receptor for hyaluronan (1, 35). Mesenchymal Lymphangioblasts In the early days of lymphangiogenesis research employing serial sectioning of embryos, it was suggested that lymph vessels develop from “mesenchymal clefts” (10). Using modern terminology, this means the authors assumed that lymph vessels develop from scattered lymphangioblasts in the embryonic mesenchyme.These cells aggregate into tubes and form a communicating vascular system. It is well established that the blood vascular system of higher vertebrates develops in such a way.The pre- cursor cells of BECs are called angioblasts and hemangioblasts, according to their poten- tial to form endothelial cells or both endothelial and blood cells (36). Experimental studies on chick and quail embryos have provided evidence that the paraxial and splanchnic mesoderm contain cells with lymphangiogenic potential. Cells derived from these compartments are capable of integrating into embryonic lymphatics, and lymphangiogenic potential of mesodermal cells is present even before Prox1 is expressed in any of these cells (25, 31, 40). During subsequent development, coex- pression of Prox1 and the endothelial marker QH1 in scattered mesodermal cells of quail embryos seems to be a marker of lymphangioblasts (40). Like in avian embryos, expression of LEC markers can also be observed in scattered mesodermal cells of murine embryos (Fig. 1). These cells are located in various mesodermal compart- ments of the embryo, e.g., in the dermatomes along the body axis (3). Scattered cells in this region are positive for Prox1 and LYVE-1 (Fig. 1a,b).We assume that these cells integrate into the lymph vessels in the dermis of the back. 20 Cancer Metastasis and the Lymphovascular System Figure 1. Staining of ED 11 mouse embryos with antibodies against markers of lymphendothelial cells. (a) Prox1 demarcates scattered cells (arrows) in the dermatomes and lymphatics close to the jugular vein (v). (b) LYVE-1 demarcates scattered cells in the dermatomes close to the neural tube (nt) Evidence for the existence of embryonic lymphangioblasts in other vertebrate species has been provided recently.In Xenopus tadpoles, lymph vessels are obviously derived from both the venous system and from scattered mesenchymal cells (20). Like in other species, Prox1 and VEGF-C are essential for the development of lymph vessels in tadpoles. However, in the zebrafish, the primary source for lymph vessels seems to be the venous system (41). TUMOR LYMPHANGIOGENESIS Growth of tumors is largely dependent on active interactions of tumor cells with the blood vessels of the neighboring healthy tissue (7), and a high density of tumor microvessels is a high risk for hematogenic metastasis (33). However, in human solid cancer, the lymph node status is the most important prognostic indicator
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