Hypoxia arrests ovarian carcinoma cell cycle progression, but invasion is unaffected.
Although hypoxic cells are generally resistant to radiation and chemical therapies designed to halt the spread of neoplastic disease, few investigations have been carried out with regard to the molecular mechanisms responsible for this phenomenon. Here, we report of the development of an in vitro model system with which to study the molecular mechanisms involved in the proliferation and invasion of human ovarian carcinoma cells under hypoxia. Results from [(3)]thymidine incorporation experiments indicate that hypoxia triggers cessation of ovarian carcinoma cell DNA synthesis. Flow cytometry analysis of cellular DNA content for hypoxic cultures revealed that cell cycle progression was arrested. This arrest was found to be reversible upon reoxygenation of the cultures. Concomitant with this growth arrest is hypophosphorylation of pRB and a reduction in cyclin A abundance, suggesting that hypoxia induces growth arrest by regulating the activities of these crucial cell cycle-regulatory proteins. In vitro invasion assays revealed that hypoxia 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 collagenase 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 extracellular matrix during hypoxic conditions and, after a more suitable oxygen environment is reached, giving rise to new cell colonies.
Krtolica
A
A
Department of Biochemistry, University of Rochester School of Medicine and Dentistry, New York 14642, USA.
Ludlow
J W
JW
D002277:Carcinoma / Q000201:enzymology / Q000473:pathology*; D002453:Cell Cycle; D015687:Cell Hypoxia; D005260:Female; D018093:Gelatinases / Q000096:biosynthesis; D006801:Humans; D020778:Matrix Metalloproteinase 2; D008666:Metalloendopeptidases / Q000096:biosynthesis; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000473:pathology*; D014407:Tumor Cells, Cultured
D018093:Gelatinases; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2