Irresponsiveness of two retinoblastoma cases to conservative therapy correlates with up- regulation of hERG1 channels and of the VEGF-A pathway
Open Access
- 22 September 2010
- journal article
- Published by Springer Science and Business Media LLC in BMC Cancer
- Vol. 10 (1), 504
- https://doi.org/10.1186/1471-2407-10-504
Abstract
Treatment strategies for Retinoblastoma (RB), the most common primary intraocular tumor in children, have evolved over the past few decades and chemoreduction is currently the most popular treatment strategy. Despite success, systemic chemotherapeutic treatment has relevant toxicity, especially in the pediatric population. Antiangiogenic therapy has thus been proposed as a valuable alternative for pediatric malignancies, in particolar RB. Indeed, it has been shown that vessel density correlates with both local invasive growth and presence of metastases in RB, suggesting that angiogenesis could play a pivotal role for both local and systemic invasive growth in RB. We present here two cases of sporadic, bilateral RB that did not benefit from the conservative treatment and we provide evidence that the VEGF-A pathway is significantly up-regulated in both RB cases along with an over expression of hERG1 K+ channels. Two patients showed a sporadic, bilateral RB, classified at Stage II of the Reese-Elsworth Classification. Neither of them got benefits from conservative treatment, and the two eyes were enucleated. In samples from both RB cases we studied the VEGF-A pathway: VEGF-A showed high levels in the vitreous, the vegf-a, flt-1, kdr, and hif1-α transcripts were over-expressed. Moreover, both the transcripts and proteins of the hERG1 K+ channels turned out to be up-regulated in the two RB cases compared to the non cancerous retinal tissue. We provide evidence that the VEGF-A pathway is up-regulated in two particular aggressive cases of bilateral RB, which did not experience any benefit from conservative treatment, showing the overexpression of the vegf-a, flt-1, kdr and hif1-α transcripts and the high secretion of VEGF-A. Moreover we also show for the first time that the herg1 gene transcripts and protein are over expressed in RB, as occurs in several aggressive tumors. These results further stress the relevance of the VEGF-A pathway in RB and the correlation with hERG1, making aggressive and recurrent RB cases good candidates for antiangiogenesis therapies based on the targeting of VEGF-A.Keywords
This publication has 23 references indexed in Scilit:
- Blood Vessel Maturation in Retinoblastoma Tumors: Spatial Distribution of Neovessels and Mature Vessels and Its Impact on Ocular TreatmentInvestigative Ophthalmology & Visual Science, 2009
- Vitreous Levels of Stromal Cell–Derived Factor 1 and Vascular Endothelial Growth Factor in Patients with Retinopathy of PrematurityOphthalmology, 2008
- Tandem high-dose chemotherapy and autologous stem cell rescue in children with bilateral advanced retinoblastomaBone Marrow Transplantation, 2008
- HETEROGENEOUS TUMOR VASCULATURE IN RETINOBLASTOMARetina, 2008
- Retinoblastoma: Review of Current ManagementThe Oncologist, 2007
- VEGFR-1 (FLT-1), β1 integrin, and hERG K+ channel for a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcomeBlood, 2007
- Higher Vessel Densities in Retinoblastoma with Local Invasive Growth and MetastasisThe American Journal of Pathology, 2004
- Tumour angiogenesis as a prognostic factor for disease dissemination in retinoblastomaBritish Journal of Ophthalmology, 2003
- HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic hemopoietic progenitorsLeukemia, 2002
- Choroidal invasion of retinoblastoma: metastatic potential and clinical risk factors.British Journal of Ophthalmology, 1993