The p75 NTR neurotrophin receptor is a tumor suppressor in human and murine retinoblastoma development.
The transition from the benign retinal tumor retinoma to its malignant counterpart retinoblastoma is accompanied by the loss of expression of the p75(NTR) neurotrophin receptor. This change in expression is mimicked in the TAg-RB murine model of retinoblastoma, where early tumors retain expression of p75(NTR) and advanced tumors lack it. We sought to determine the functional effect on tumor development of absence of p75(NTR) from the onset of TAg-RB tumor initiation. TAg-RB mice were crossed with either p75(NTR) exon 3 (E3KO) or exon 4 knockout (E4KO) mice to produce TAg-RB offspring that lacked one or both normal p75(NTR) alleles. The average tumor area per eye as a percentage of retinal area was measured. TAg-RB/E3KO (TAg-RB(E3KO)) and heterozygous mice showed no significant difference in tumor area compared to the TAg-RB control mice at any time point studied. However, TAg-RB/E4KO (TAg-RB(E4KO)) and heterozygous mice displayed a significantly larger tumor area than the TAg-RB control mice. Furthermore, adenoviral-mediated expression of p75(NTR) in a p75(NTR)-deficient human retinoblastoma cell line resulted in increased apoptosis. Our results confirm that p75(NTR) suppresses progression of both human and TAg-RB murine retinoblastoma, and holds promise as a target for future therapy of the disease.
Dimaras
Helen
H
Department of Molecular and Medical Genetics, University of Toronto, Toronto, Canada.
Gallie
Brenda L
BL
D000256:Adenoviridae; D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D019572:Retinal Neoplasms / Q000378:metabolism*; D012175:Retinoblastoma / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D020800:Receptor, Nerve Growth Factor; D025521:Tumor Suppressor Proteins; D053148:Caspase 3