Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) Expression Is Increased in Ph⁻Chronic Myeloproliferative Disorders and Correlates with the Microvessel Density and VEGF.

Angiogenesis is a dynamic process regulated by a number of pro- and anti-angiogenic molecules. The most important pro-angiogenic factor is vascular endothelial growth factor (VEGF), which is capable of stimulating mitogenic activity and the proliferation of endothelial cells, increasing vascular permeability, and inducing vasodilation. VEGF carries out many of its functions by means of the VEGF receptor 1 (VEGFR-1) and receptor 2 (VEGFR-2). Increased microvessel density (MVD) has been demonstrated in many haematological malignancies, including Philadelphia chromosome-negative chronic myeloproliferative disorders (Ph⁻CMPDs). Recently, we firstly reported a direct correlation between VEGF immunohistochemical expression and MVD in the bone marrow biopsies (BMBs) of Ph⁻CMPDs patients. Increased protein and RNA expression of VEGFR-1 and VEGFR-2 have been documented in acute myeloid leukemia and myelodysplastic syndrome but, at present, no data have been reported on their expression in Ph⁻CMPDs. In this study we examined MVD and the immunohistochemical expression of VEGF, VEGFR-1 and VEGFR-2 in BMBs of a large series of Ph⁻CMPDs. The study population included 83 consecutive patients (52 males, 31 females, M/F=1.6/1; median age 61 years, range: 18–85), 27 affected by essential thrombocythemia (ET), 21 by polycythemia vera (PV) and 35 by chronic idiopathic myelofibrosis (CIMF), according to the WHO classification. The normal controls (NCs) consisted of 10 BMBs obtained for staging purposes which were free of neoplasias and other abnormalities. MVD was analysed using the “hot-spot” method with the anti-CD34 (QB-END/10) antibody. Immunohistochemical VEGF and VEGFR-1 immunoreactivity was expressed as index, based on the formula [n _(i) = (% of BMB cellularity x % n-positive cells)/10⁴]. VEGFR-1_(i) resulted significantly higher in Ph⁻CMPDs than in NCs (0.25 ± 0.17 vs 0.07± 0.03; p=0.001) and, in particular, in PV (0.30±0.19) and CIMF (0.31±0.17) (Bonferroni’s LSD test; p<0.05). On the contrary, we found significantly reduced VEGFR-2 expression in Ph⁻CMPDs than in NCs (10.43±13.27 vs 58.56±10.11; p<0.001). A direct correlations was demonstrated between the VEGF_(i) and MVD (r:0.71; p<0.001), VEGFR-1_(i) and MVD (r: 0.57; p<0.001) and between VEGFR1_(i) and VEGF_(i) (r:0.58; p<0.001) in Ph⁻CMPDs considered as a whole. We did not find any correlation considering the VEGFR-2. In conclusion, our study demonstrates increased expression of the VEGFR-1 and decreased expression of VEGFR-2 in Ph⁻CMPDs. The increased VEGFR-1 parallels the expression of VEGF and a direct correlations between this pro-angiogenic factor and its receptor has been found. Our data, support the hypothesis of an autocrine VEGF/VEGFR-1 loop in the pathogenesis of Ph⁻CMPDs.