Programmed Cell Death Pathways in Tumor Initiation and Progression

摘要

The effects of cellular apoptotic regulators on tumor initiation and progression are difficult to predict, as oncogenes may have either anti- apoptotic (bcl-2) and pro-apoptotic (c-myc) effects. Anti-apoptotic genes may promote tumor growth by rescuing cells susceptible to apoptosis, due to DNA damage, for example. Pro-apoptotic genes, on the other hand, might increase DNA damage as a substrate for genetic instability. We tested the ability of transgenic bcl-2 to interact with DMBA in the formation of murine mammary tumors. A modest increase in tumor incidence at early time points (7-8 weeks post exposure) was observed in DMBA-treated transgenic vs control female mice. We have examined mammary tumors from transgenic mice for apoptosis using the in situ TUNEL assay. Unexpectedly, apoptotic cells were present at relatively high levels, compared to normal breast tissue (20.5 +/- 12.7/hpf vs 14.2 +/- 4.8/hpf) . Apoptosis is often associated with increased oxidative stress, a potential cause of DNA damage. We have examined Rat-1 cells undergoing c-myc-regulated cell death for early changes in mitochondrial structure and function. Induction of apoptosis led to initial mitochondrial proliferation followed by collapse of mitochondrial transmembrane potential. Increased numbers of mitochondria with a disorganized cristae and ultracondensed morphology were observed in myc-induced apoptosis. Constitutive c-myc expression has been demonstrated to lead to genetic instability. An association between mitochondrial dysfunction, ROS, and genetic instability may explain the apparent retention of apoptotic programs in experimental and human tumors.