Effects of reoxygenation on cells from hypoxic regions of solid tumors: anticancer drug sensitivity and metastatic potential.

Tissue hypoxia in regions of solid tumors has been identified as a factor that may affect the behavior of cancer cells. In this study, cells were isolated from hypoxic regions of transplanted murine tumors and tested for sensitivity to anticancer drugs and ability to form experimental metastases. The tumors studied were KHT-C2-LP1 fibrosarcoma and SC-CVII squamous cell carcinoma in C3H mice and B16F10-A1 melanoma in C57BL mice. Our results indicate that the position of tumor cells relative to the vasculature, which determines the degree of tissue oxygenation, does not influence the in vitro sensitivity of cells to either doxorubicin or methotrexate. Conversely, 1-2 days after reoxygenation by introduction into culture, subpopulations of tumor cells demonstrated a transient increase in lung colonization ability. The most hypoxic cells exhibited a metastatic efficiency that was generally twice that of cells from well-oxygenated regions. This behavior is similar to behavior we observed in a previous study when tumor cells were exposed in vitro to conditions of extreme hypoxia. The findings in that study suggested that gene amplification associated with DNA over-replication is responsible for the enhanced metastatic potential, but we found no indication in the present study that gene amplification was involved in the effect observed with the hypoxic tumor subpopulations. These results provide additional evidence that reoxygenated cancer cells have a high colonization ability and that these cells may be important in the formation of distant metastases.