p53 and p21(waf-1) expression correlates with apoptosis or cell survival in poorly differentiated, but not well-differentiated, retinoblastomas

In human retinoblastomas, rare genetic mutations of the retinoblastoma gene cause massive cell proliferation, altered differentiation, and tumor forma tion; but paradoxically, this is accompanied by extensive apoptotic cell lo ss. We quantified the immunohistochemical distribution of pig, its downstre am effector p21 (WAF-1), and apoptotic cells in 50 human retinoblastomas, w ithin three concentric zones of sleeves of tumor cells surrounding blood ve ssels. In poorly differentiated retinoblastomas, both p53 expression and ap optosis increase toward the outer zone of tumor sleeves, whereas p21 expres sion occurs primarily within the inner zone. This staining pattern of p53 e xpression is reversed in well-differentiated tumors, whereas p21 staining a nd apoptotic cell distributions are unchanged. We detected no p53 mutations in four retinoblastomas and two retinoblastoma cell lines. We postulate th at oxygen and cell "survival/ growth factors" delivered via blood vessels p rotect retinoblastoma cells from apoptosis. In poorly differentiated tumors , apoptosis is spatially associated with increased p53 expression and may b e p53 mediated, but in well-differentiated tumors, apoptosis does not coloc alize with p53 and may be p53 independent. In retinoblastomas, p21 is invol ved not in cell death by apoptosis but in cell survival. Thus, p53 varies i ts expression (and by implication its function) with altered differentiatio n in retinoblastomas.