Response of the cancer cells to the hypoxic challenge can result in manifestation of malignant features of cancer, including angiogenesis, metabolic change, invasion/metastasis, and chemo- or radio-resistance. Acute hypoxic response of the cultured cancer cell lines has been intensively studied, but what happens in the cancer cells in patient tumors is poorly understood. We previously reported that glycolytic enzymes were not induced in hypoxic region in vivo, while the glycolytic enzymes were remarkably up-regulated when the cells were challenged by acute hypoxia in vitro. Thus, cancer cells might be in metabolically inactive status under chronic hypoxic conditions in vivo.
The energy-consuming process is often activated in cancer cells but the energy consumption of cancer cells in hypoxic region in vivo was not clear. We found that expression of c-Myc and phosphorylation of mTOR, both of which regulate energy consuming process, were suppressed in hypoxic region in vivo. Suppressing energy consuming processes might be a strategy for cancer cells to survive under metabolic stress.
Most of the cancer cell lines in vitro failed to survive under chronic hypoxic conditions (1% oxygen, two weeks). AsPC-1, a pancreatic cancer cell line, was exceptionally able to survive under chronic hypoxic conditions. The ATP turnover was suppressed under chronic but not acute hypoxic conditions. We recently developed a novel culture system for primary cancer cells. The primary cancer cells were able to survive without increase of cell death under chronic hypoxic conditions, suppressing the energy consuming signals, including c-Myc and mTOR. After re-oxygenation, they grew as well as the cells maintained in normoxic conditions. Thus, the primary culture of cancer cells will provide a useful tool for studying the mechanism of cancer dormancy in hypoxia.