Fig. 5
Schematic presentation of VEGFR-2 activation in CC tissue and its association with metastasis. VEGF-D produced by tumor cells in the tumor center and in tumor budding regions has an autocrine affinity for its receptor VEGFR-2. In dissociated tumor cells VEGF-D-mediated receptor activation by autophosphorylation at Tyr1214 seems to be a potential signaling pathway but without effect on the metastatic potential. Tumor cells produce paracrine-acting VEGF-C as well. In inflammatory cells of almost all colon carcinomas there is VEGFR-2 phosphorylation at Tyr 1175 and Tyr 1214 in the tumor center (zone 1) and invasive front (zone 2), without accompanying receptor expression, suggesting receptor activation without cell surface expression. Inflammatory cells are also a possible source of paracrine-acting VEGF-C. Autocrine VEGF-D/VEGFR-2 signaling axis and receptor autophosphorylation at Tyr1214 seem to be main events in CC for capillaries in all three tumor zones and for small vessels in zone 1 and 2. Additionally, the VEGFR-2 receptor of intratumoral microvessels has a close association with its cytoplasmic tyrosine residue Tyr 1175. Independent of the metastatic status an increase of the number of cases can be demonstrated with capillary immunopositivity especially for VEGF-D, VEGFR-2 and pVEGFR-2Tyr1214 in the angiogenically active invasive front. Remarkably, these biomolecules were also often detected in small vessels of marginal tumor areas (zone 2) which are responsible for sufficient tumor vascularization. VEGFR-2 expression in extratumoral capillaries (zone 3) was significantly more common in distant metastatic CC. In addition, paracrine-acting VEGF-C production was independent of the zone and vessel type