The rise and fall of apoptosis during multistage tumorigenesis: down-modulation contributes to tumor progression from angiogenic progenitors.
In a mouse model of multistage tumorigenesis of islet beta-cells, apoptosis was activated concomitant with T-antigen oncogene-induced cell proliferation, further increased in the angiogenic stage, and markedly reduced in solid tumors. Crosses to p53-null mice confirmed this stage-specific variation as a p53-independent apoptotic process. Several apoptosis regulators were expressed, of which bcl-xL was up-regulated in tumors. When overexpressed throughout the pathway, bcl-xL protected most oncogene-expressing cells from apoptosis, enhancing progression from angiogenic progenitor to tumor without affecting earlier transitions. Further, two classes of solid tumor are described, distinguished by size and apoptotic incidence, implicating apoptosis regulation in expansive tumor growth. Thus, down-modulation of apoptosis selectively contributes to late steps in a tumorigenesis pathway.
Naik
P
P
Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0534, USA.
Karrim
J
J
Hanahan
D
D
D000818:Animals; D000957:Antigens, Viral, Tumor / Q000235:genetics*; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D018273:Carcinoma, Islet Cell / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53 / Q000502:physiology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein
D000957:Antigens, Viral, Tumor; C494812:Bcl2l1 protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein