thromboplastin and Retinoblastoma

Retinoblastoma, a well-vascularized tumor that is dependent on a very robust angiogenic response, is the most common intraocular malignancy in children. Tissue factor (TF) is known to regulate tumor progression and in the present study we demonstrated that TF regulates tumor angiogenesis of retinoblastoma. In an orthotopic transplantation model of retinoblastoma, TF was selectively expressed in the proliferative area of retinoblastoma including tumor vessels as well as tumor cells, where TF expression was co-localized with endothelial cells of tumor vessels. TF expression progressively increased with fibroblast growth factor-2 (FGF-2)-induced proliferation of human umbilical vein endothelial cells (HUVECs), which was effectively inhibited by blockade of the TF pathway by TF pathway inhibitor (TFPI). In addition, FGF-2-induced angiogenic processes of migration and tube formation of vascular endothelial cells were also effectively suppressed by TFPI, which would be mediated by inhibition of extracellular signal-regulated kinase activation. Therefore, further to our previous report that TF is involved in tumor cell proliferation of retinoblastoma, our current data suggest that blockade of the TF pathway by TFPI could effectively inhibit tumor growth by suppressing tumor cell proliferation and tumor angiogenesis at the same time.

Topics: Animals; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Female; Fibroblast Growth Factor 2; Human Umbilical Vein Endothelial Cells; Humans; Lipoproteins; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Retinoblastoma; Thromboplastin

Tissue factor (TF) is known to play a role in tumor progression. In retinoblastoma, the expression and role of TF has not been determined yet. Herein, we demonstrated for the first time that TF is closely related to the proliferation of retinoblastoma cells, which could be therefore effectively suppressed by blockade of the TF pathway. TF was selectively expressed on the areas of highly mitogenic activity in an orthotopic transplantation mouse model of retinoblastoma. In addition, the levels of TF expression in retinoblastoma cells were elevated after FGF2 treatment, whereas the proliferative effect of FGF2 on retinoblastoma cells was significantly inhibited by blockade of the TF pathway via TF pathway inhibitor (TFPI). Interestingly, retinoblastoma cells cultured with FGF2 showed increased phosphorylation of both Akt and ERK1/2. Addition of TFPI nearly abolished the FGF2-induced phosphorylation of Akt and ERK1/2 in retinoblastoma cells. Therefore, our data suggest that TF expression in retinoblastoma cells is closely related to tumor cell proliferation and TFPI has the potential to inhibit retinoblastoma cell proliferation via the inhibition of both Akt and ERK1/2 activation.

Topics: Animals; Cell Line, Tumor; Cell Proliferation; Fibroblast Growth Factor 2; Humans; Ki-67 Antigen; Lipoproteins; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neoplasm Transplantation; Proto-Oncogene Proteins c-akt; Retinal Neoplasms; Retinoblastoma; Thromboplastin; Transplantation, Heterologous