The last 20 years of angiogenesis research have been dominated by molecular biology. The detection of the vascular endothelial growth factors (VEGFs) started with the discovery of VEGF in 1989 (61, 62). Since other vascular growth factors were identified and the VEGF family is currently consists mainly of VEGF-A, VEGF-B, VEGF-C, and VEGF-D (36, 63-65). There are three VEGF tyrosine kinase receptors identified so far, VEGFR-1, VEGFR-2, and VEGFR-3. VEGF-A and VEGFR-B are ligands for receptors VEGFR-1 and VEGFR-2, and considered to play an important role in tumour angiogenesis (66). It has been recently revealed that VEGF family members are expressed in a variety of human tumours in different ways and tumour cells have been reported to be able to secrete VEGF-A, VEGF-B, VEGF-C, and VEGF-D (67-69). However, the angiogenic switch is thought to be carefully regulated, and at least some specific genetic events in tumour progression correlate with lymphatic metastasis, suggesting that a "lymphangiogenic switch" mechanism is also a distinct possibility (70). VEGF-C and VEGF-D differ from other VEGF family members by the presence of long N- and C-terminal propeptides flanking the VEGF homology domain (63-65, 71-74). The fully processed or mature forms of VEGF-C and VEGF-D consist of the VHD, which acts as a ligand not only for VEGFR-3, but also for VEGFR-2 (73-75). In mid-gestation embryos, VEGF-C is prominently expressed in regions where the lymphatic vessels undergo sprouting from embryonic veins, such as in the perimetanephric, axillary, and jugular areas, and in the developing mesenterium (5). In adults, VEGF-C is expressed in the heart, small intestine, placenta, ovary, and the thyroid gland. VEGF-C stimulates mitosis and migration of endo-thelial cells and it increases vascular permeability. VEGF-C has been shown to induce lymphangiogenesis in transgenic mouse skin and in mature chick chorioallantoic membrane (76, 77). However, recombinant VEGF-C also promotes angiogenesis when applied to early chorioallantoic membrane of chicks, to mouse cornea or to ischaemic hindlimbs of rabbits (50, 78). Therefore, VEGF-C is likely to play a dual role both as an angiogenic and a lymphangiogenic growth factor. If VEGF-C induces lymphangiogenesis, is it sufficient enough to increase the rate of metastasis to the lymph nodes? It has recently been reported that lymphatics surrounding a VEGF-C overexpressing tumour are enlarged, and it has been suggested that the in crease in lymphatic diameter may be sufficient to increase metastasis (7). Clinical studies correlating the levels of VECF-C in tumours and their metastatic potential have revealed controversial results. However, a significant correlation between VEGF-C expression and lymph node metastasis have been observed in a variety of carcinomas including breast (79), oesophageal (80), gastric (81, 82), colorectal (83), thyroid (84, 85), head and neck (86), prostate (87), and lung (88,89).
VEGF-D is structurally 48% identical to VEGF-C (90, 9l). It contains the eight conserved cysteine residues characteristic of the VEGF family and has a cysteine-rich COOH terminal extension similar to that of VEGF-C. In midgestation mouse embryos, VEGF-D expression is particularly abundant in the developing lung. VEGF-D is expressed in many adult tissues including the vascular endothelium, heart, skeletal muscle, lung, small and large bowel. VEGF-D is mitogenic for endothelial cells. Like VEGF-C, VEGF-D is proteolytically processed after secretion, and it binds to and activates both VEGFR-2 and -3 (65, 73, 90). The fact that VEGF-D binds also VEGFR-2 has made it to be possibly angiogenic. However, the controversy remains as it has been shown that transgenic overexpression of VEGF-D led to lymphatic hyperplasia but not angiogenesis (92).
The secretion of VEGF-C and VEGF-D by some tumours could induce the activation of their receptor, VEGFR-3 on the vascular endothelium and thereby inducing the formation of new lymphatic vessels (Fig. 2). However, little is currently known about the factors that make dome tumours secret these lymphangiogenic factors. Like angiogenesis (formation of new blood vessels), factors such as hypoxia, other growth factors, cytokines and hormones have been studied (93). Regulation by other cytokines and growth factors seems to be promising as it has been recently found that VEGF-C and VEGF-D could indeed be regulated by IL-ip (94) and IL-7 (95) respectively. It is well established that crosstalks and interactions between signalling pathways of these cytokines do exist. Although signalling via VEGFR-3 involves complex molecular pathways, but it mainly involves the MAPK and PI3-K pathways. Recent studies have indicated the presence of cross-talks between the MAPK and the PI3-K pathways as phosphorylation of Raf by Akt resulted in inhibition of the Raf-MEK (MAP kinase) - ERK pathway (96). PI3-Kinase activation is known to mediate signalling transduction of many several cytokines and growth factors. The PI3-K pathway is linked to mitogenesis, but several studies subsequently have shown that this pathway has an important function in regulating cell survival by the activation of the serine-threonine kinase Akt (protein kinase B). The cross talk between MAPK and PI3-K pathways leads to increased cell survival by stimulating the transcription of the pro-survival gene(s) and by post-translational modification and inactivation of components of the cell death machinery. VEGFR-3 can also strongly activates Stat-5 (97), also activated and phosphorylated by IL-7 (98) suggesting that Stat-5 activation is involved in the regulation of lymphatic endothelium.
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