Expression of Vascular Endothelial Growth Factor in Retinoblastoma

Areán, Carolina; Orellana, María Eugenia; Abourbih, Daniel; Abreu, Carmen; Pifano, Imelda de; Burnier, Miguel N.

doi:10.1001/archophthalmol.2009.386

Cited by 22 publications

(18 citation statements)

References 20 publications

(32 reference statements)

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“…In vitro results further showed that HUVEC proliferation increased when co-cultured with Y-79 cells, an effect that was attenuated by aflibercept treatment. Angiogenesis in retinoblastoma plays an important role in tumor growth and local invasion, and the amount of angiogenesis in the retinoblastoma tumor has been suggested to be a prognostic factor [28, 29]. Therefore, aflibercept treatment could have therapeutic efficacy against retinoblastoma by reducing tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies have demonstrated that retinoblastoma cells express VEGF in hypoxic and normoxic conditions [29, 30, 58]. Moreover, HUVEC proliferation is increased by co-culture with Y-79 cells and reduced by bevacizumab treatment [30].…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, Marback et al reported that tumor angiogenesis in retinoblastoma is a prognostic factor for disease dissemination, and Arean et al reported a positive correlation between the intensity of VEGF staining and mitotic and apoptotic indexes [28, 29]. We previously demonstrated that retinoblastoma cells express VEGF mRNA and secrete VEGF protein, which promotes subsequent proliferation of nearby vascular endothelial cells.…”

Section: Introductionmentioning

confidence: 97%

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Efficacy and safety of aflibercept in in vitro and in vivo models of retinoblastoma

Kim

Choi

Koh

et al. 2016

J Exp Clin Cancer Res

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BackgroundTo evaluate the inhibitory effects of aflibercept on the growth and subretinal invasion of retinoblastoma.MethodsXenotransplantation and orthotopic mouse models were created by injecting Y-79 cells subcutaneously and intravitreally, respectively. After induction of retinoblastoma, animals were intraperitoneally injected with aflibercept (25 mg/kg body weight) or saline twice a week for 3 weeks. Tumor size was measured weekly and compared between the two groups. At 4 weeks, animals were sacrificed and an immunohistochemical examination was conducted to compare the microvascular density and degree of apoptosis between groups. In addition, the degree of choroidal invasion was also analyzed in the orthotopic xenotransplantation model. A co-culture system of Y-79 or WERI-Rb-1 cells and human umbilical vein endothelial cells (HUVECs) was used for in vitro experiments, and the anti-angiogenic effect of aflibercept was evaluated by analyzing cell numbers.ResultsIn the Y-79 xenotransplantation model, aflibercept treatment significantly inhibited tumor growth at 4 weeks versus baseline compared with saline-injected mice (188.53 ± 118.53 mm3 vs. 747.87 ± 118.83 mm3, respectively, P < 0.001). Tumors isolated from aflibercept-treated mice contained fewer blood vessels (8.59 % ± 7.60 % vs. 14.91 % ± 4.53 %, respectively, P < 0.05) and an increased number of apoptotic cells (15.10 ± 9.13 vs. 4.44 ± 2.24, respectively, P < 0.05). In the orthotopic model, the degree of subretinal invasion of tumor cells was significantly reduced after aflibercept treatment (0.07 ± 0.06 vs. 0.15 ± 0.10, P < 0.05). And addition of aflibercept to co-cultures of HUVECs and Y-79, WERI-Rb-1 cells significantly reduced HUVEC proliferation.ConclusionsAflibercept reduced retinoblastoma angiogenesis in association with a significant reduction in tumor growth and invasion. These findings suggest that aflibercept could be used in an adjuvant role together with systemic chemotherapy to reduce tumor size and angiogenesis in retinoblastoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0451-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

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Efficacy and safety of aflibercept in in vitro and in vivo models of retinoblastoma

Kim

Choi

Koh

et al. 2016

J Exp Clin Cancer Res

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“…Hence VEGF-A represents one of the most powerful targets in antiangiogenesis therapy. Indeed in a retrospective study on several RB cases [14] was reported a positive correlation between VEGF-A staining intensity and different clinico-pathological markers of malignancy (mitotic and apoptotic indexes).…”

Section: Introductionmentioning

confidence: 99%

Irresponsiveness of two retinoblastoma cases to conservative therapy correlates with up- regulation of hERG1 channels and of the VEGF-A pathway

et al. 2010

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BackgroundTreatment 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.Case presentationTwo 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.ConclusionsWe 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.

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“…[23][24][25] Some studies have addressed the importance of VEGF in the development of retinal vasculature 26 and in survival of the newly formed retinal vessels. 27 Other studies 28 have found correlations between VEGF staining intensity and time to retinoblastoma progression and its mitotic and apoptotic indexes. Although these studies described VEGF expression in the tumor, they did not elaborate on its spatiotemporal expression or coexpression with other important angiogenic markers.…”

mentioning

confidence: 96%

Expression of Angiogenic Factors in Invasive Retinoblastoma Tumors Is Associated With Increase in Tumor Cells Expressing Stem Cell Marker Sox2

Garcia

Gombos²,

Prospero³

et al. 2015

Archives of Pathology &Amp; Laboratory Medicine

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Context Progression of retinoblastoma is associated with increased tumor angiogenesis. However, a clear relationship between the expression of angiogenic markers in specific regions of the tumor and tumor progression has not been established. This study investigates the association between angiogenic factors in retinoblastomas with choroidal and/or optic nerve invasion (high-risk/invasive retinoblastoma) and expression of Sox2, a stem cell marker. Objective To investigate the association between the expression of angiogenic factors and markers of tumor invasiveness, such as the stem cell marker Sox2, in retinoblastoma tissues. Design Immunohistochemistry was used to evaluate coexpression of the angiogenic growth factors vascular endothelial growth factor A (VEGF-A), VEGF receptor 2 (VEGFR-2), and endoglin (CD105); markers of glial differentiation (vimentin and glial fibrillary acidic protein); and a neural stem cell marker (Sox2). Expression was assessed in nonneoplastic and neoplastic ocular tissues collected from enucleated eyes of patients with retinoblastoma. During qualitative data interpretation, evaluating pathologists were masked to patient grouping. Results Expression of VEGF-A and VEGFR-2 in noninvasive (non–high-risk feature) retinoblastoma tumors was lower than in the invasive, or high-risk feature tumors. Moreover, our data indicate that the tumor cells, and not the surrounding stroma, secrete VEGF-A and that angiogenesis is mostly localized to the iris. Finally, our data showed that the expression of the neural stem cell marker Sox2 is associated with eyes with increased VEGF-A expression and tumor invasiveness. Conclusions Increased expression of angiogenic factors, with a concomitant increase in expression of the stem cell marker Sox2 observed in retinoblastoma tissues, may partially explain the aggressiveness of these tumors. The complex interaction of angiogenic and stem cell–related pathways in these tumors, especially in high-risk feature retinoblastoma, suggests that targeting tumor cells capable of secreting vasculogenic factors, as well as proangiogenic genes and signaling pathways, may be necessary for development of effective antimetastatic retinoblastoma drugs.

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Expression of Vascular Endothelial Growth Factor in Retinoblastoma

Cited by 22 publications

References 20 publications

Efficacy and safety of aflibercept in in vitro and in vivo models of retinoblastoma

Efficacy and safety of aflibercept in in vitro and in vivo models of retinoblastoma

Irresponsiveness of two retinoblastoma cases to conservative therapy correlates with up- regulation of hERG1 channels and of the VEGF-A pathway

Expression of Angiogenic Factors in Invasive Retinoblastoma Tumors Is Associated With Increase in Tumor Cells Expressing Stem Cell Marker Sox2

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