HYPOXIA ARRESTS OVARIAN-CARCINOMA CELL-CYCLE PROGRESSION, BUT INVASION IS UNAFFECTED

Although hypoxic cells are generally resistant to radiation and chemic al therapies designed to halt the spread of neoplastic disease, few in vestigations have been carried out with regard to the molecular mechan isms responsible for this phenomenon, Here, we report of the developme nt of an in vitro model system with which to study the molecular mecha nisms involved in the proliferation and invasion of human ovarian carc inoma cells under hypoxia. Results from [H-3]thymidine incorporation e xperiments indicate that hypoxia triggers cessation of ovarian carcino ma cell DNA synthesis, Flow cytometry analysis of cellular DNA content for hypoxic cultures revealed that cell cycle progression was arreste d, This arrest was found to be reversible upon reoxygenation of the cu ltures, Concomitant with this growth arrest is hypophosphorylation of pRB and a reduction in cyclin A abundance, suggesting that hypoxia ind uces growth arrest by regulating the activities of these crucial cell cycle-regulatory proteins, In vitro invasion assays revealed that hypo xia has no appreciable effect on the invasive ability of these cells, Immunoblotting established that the detected proteolytic activity was due to the matrix metalloproteinase MMP-2, the M(r) 72,000 type IV col lagenase that is most closely associated with the metastatic phenotype in vitro and in vivo. These data support the notion that populations of ovarian carcinoma cells are capable of surviving and invading extra cellular matrix during hypoxic conditions and, after a more suitable o xygen environment is reached, giving rise to new cell colonies.