Neurotrophin Receptors TrkA and TrkB in Retinoblastoma Are Differentially Expressed Depending on Cellular Differentiation

Abstract

Retinoblastoma is the most common primary intraocular malignancy in children. With the progression of retinoblastoma, retinoblastoma cells lose their ability to differentiate. Regardless of many attempts to identify prognostic factors in retinoblastoma, further investigation for prognostic factors of retinoblastoma progression is still required because of the lack of sensitivity and specificity of these prognostic factors in predicting disease progression. We demonstrated that the differential expression of the neurotrophin receptors TrkA and TrkB is closely related to the differentiation of retinoblastoma cells. While retinoblastoma cells expressed TrkA as well as TrkB, their growth rates were not influenced by the addition of nerve growth factor to the culture medium. In experimental animal models of retinoblastoma, TrkA expression was primarily detected in more differentiated areas with high nm23 immunoreactivity whereas TrkB expression was apparent in more proliferative areas with high Ki67 immunoreactivity. With retinoic-acid-induced differentiation of retinoblastoma cells, TrkA expression significantly increased whereas TrkB significantly decreased. The differential expression of TrkA and TrkB with differentiation of retinoblastoma cells was mediated by extracellular-signal-regulated kinase 1/2 activation, which was confirmed by immunocytochemistry of TrkA. Therefore, our results suggest that the differential expression of TrkA and TrkB could be valuable as a therapeutic target, for instance using specific inhibitors.

Inhibitory Activity of Bevacizumab to Differentiation of Retinoblastoma Cells

“…As demonstrated in figure 1B, TrkA as well as VEGFR-2 were expressed in high level in both retinoblastoma cell lines. As depicted in our recent report [20], neurotrophin receptors including TrkA and TrkB are differentially expressed in retinoblastoma cells depending on cellular differentiation status. In particular, TrkA expression is related to differentiation of retinoblastoma cells.…”

“…Considering our recent report that TrkA is involved in differentiation of retinoblastoma cells [20], This VEGF-induced activation of TrkA strongly encourage to investigate the effect of VEGF blockade on differentiation of retinoblastoma cells. Expectedly, VEGF neutralization using bevacizumab could lead to inhibition of differentiation of retinoblastoma cells without any affection to cellular viability.…”

“…The retinoblastoma cells expressed VEGFR-2 as well as TrkA which is a neurotrophin receptor associated with differentiation of retinoblastoma cells [20]. TrkA in retinoblastoma cells was activated with VEGF treatment.…”

L1 increases adhesion-mediated proliferation and chemoresistance of retinoblastoma

“…In the progression of retinoblastoma, retinoblastoma tumors lose their characteristics of differentiated retinal cells [8, 9]. Retinoblastoma tumors from patients who underwent enucleation at older age demonstrate fewer Flexner-Wintersteiner rosettes which represent differentiated retinoblastoma tumors [6].…”

“…Retinoblastoma cells which constitute Flexner-Wintersteiner rosettes retain features of primordial photoreceptor cells [4–7]. However, as in other cancers, with the progression of retinoblastoma, retinoblastoma cells lose their ability to differentiate [8, 9] and there was a significant inverse relationship between age at enucleation and the degree of tumor differentiation, demonstrated by the presence of rosettes [6]. …”