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

Abstract

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.

Regulation of cancer stem cell properties, angiogenesis, and vasculogenic mimicry by miR-450a-5p/SOX2 axis in colorectal cancer

“…*P < 0.05, **P < 0.01. transcription factor KLF4 not only promotes cancer stem cell-like characteristics in osteosarcoma 30 but also mediated sprouting angiogenesis via Notch 20 . In retinoblastoma tumor, stemness-related SOX2 was associated with eyes with higher VEGF-A expression and tumor invasiveness 31 . Whether SOX2 is capable of modulating angiogenesis and VM in CRC needs to be explored further.…”

Tigecycline as a dual inhibitor of retinoblastoma and angiogenesis via inducing mitochondrial dysfunctions and oxidative damage

“…Histopathologically, retinoblastoma tumor shows perivascular sleeves consisting of neoplastic cells, demonstrating a close association of tumor cells with blood vessels 24 . High vascularization in retinoblastoma has been shown to be linked with chemoresistance, dissemination and poor prognosis 16 , 25 . In contrast, angiogenesis inhibition alone by bevacizumab or pigment epithelium-derived factor suppresses retinoblastoma growth without producing significant systemic toxicity 26 , 27 .…”

Leucine-Rich α-2-Glycoprotein-1 (LRG-1) Expression in Retinoblastoma

“…11 VEGF-A expression in the present study did not show a statistically significant correlation with HRF (P ¼ 0.06). However, Garcia et al 19 demonstrated that HRF retinoblastoma tumors elicited more angiogenesis than non-HRF tumors as they expressed more VEGF, especially in the tumor and iris. Similarly, Areán et al 10 reported on a positive correlation between VEGF staining intensity and time of progression and mitotic and apoptotic indexes.…”

“…LRG-1 binds directly to the TGF-b accessory receptor endoglin (CD105), which in the presence of TGF-b1 results in promotion of the proangiogenic Smad1/5/8 signaling pathway. 11 Endoglin expression in retinoblastoma was studied by Garcia et al 19 It was found to be expressed in low levels in the HRF and non-HRF tumors and in the nonneoplastic retina. Its significant expression, however, was observed in the iris neovascular membranes of HRF retinoblastomas.…”