Abstract
Purpose: :
Development and cancer biology share many properties, as both involve the regulation of cellular differentiation, proliferation, migration and survival. These similarities suggest that many of the same signaling pathways known to regulate development, when dysregulated, lead to tumorigenesis. This is true for the Notch signaling pathway, for which aberrant signaling is found in cancers of many tissues, including the blood, breast, brain, and skin. To further study the oncogenic potential of Notch signaling in the brain and eye, we introduced activated Notch3 into these tissues in mice.
Methods: :
Under ultrasound guidance, we infected embryonic day 9.5 and 10.5 mouse forebrain ventricles with a replication incompetent retrovirus expressing the constitutively active intracellular domain of Notch3 (NICD3) and an alkaline phosphatase reporter.
Results: :
Many animals infected with the NICD3-expressing virus developed grossly observable ocular malformations or tumors within one month of birth. Histological examination of 48 of the 193 animals injected revealed three types of lesions, combinations of which could be found in a single eye. First, focal retinal malformations, which generally showed disruption or disorganization of all layers, were seen in 38 animals (20%). Second, choroidal hyperplasias of varying size, including some large tumors that extended through the sclera and invaded orbital tissues, were identified in 33 animals (17%). These lesions were quite cellular, mitotically active, and contained rare pigmented cells, suggesting a possible relationship to uveal melanoma. Third, hyperplastic lesions and invasive tumors largely composed of fibrillar cells arose in the retina and/or optic nerve of 29 animals (12%). They expressed the glial marker GFAP as well as the progenitor marker nestin and were not densely cellular, but contained numerous mitotic figures. These glioma-like tumors also had the capacity to invade through the sclera and orbital tissues. All three types of lesion expressed alkaline phosphatase, indicating that they arose from virally-infected cells. Interestingly, ocular tumors were not observed in mice infected with a retrovirus expressing the active intracellular domain of Notch1 (NICD1). Further characterization of the focal hyperplasias and invasive tumors is being performed using immunohistochemical and ultrastructural analysis.
Conclusions: :
Activation of Notch3 signaling is sufficient to initiate formation of ocular tumors in mice.
Keywords: melanoma • oncology • signal transduction