Acute (cyclic) hypoxia enhances spontaneous metastasis of KHT murine tumors.

Hypoxia exists in most human and rodent solid tumors and has been shown to correlate with poor survival in carcinoma of the cervix, carcinoma of the head and neck, and soft tissue sarcoma. It exists both chronically, due to the poorly organized vasculature of solid tumors, and acutely, due to fluctuations in blood flow. It has been found that tumors that are more hypoxic are more likely to metastasize in humans and in rodent models, and it has been demonstrated that exposure of tumor cells to hypoxia in vitro can transiently enhance their metastatic potential when they are reinjected i.v. into mice. The purpose of the present study was to determine whether experimentally imposed hypoxic stress in vivo, either chronic or acute, affects the process of spontaneous metastasis in tumor-bearing mice. We exposed mice bearing KHT tumors to low oxygen conditions (5-7% O(2) breathing) daily during tumor growth in an attempt to induce additional chronic (2 h/day) and acute (12 x 10 min/day) hypoxia in their tumors. By monitoring tumor pO(2) levels over the course of treatment, we demonstrated that these treatments produce acute and chronic hypoxia within the tumor tissue. The acute but not the chronic hypoxia treatment significantly increased the number of spontaneous microscopic lung metastases in the mice by a factor of about 2, and the results suggest that this effect was due to the changes induced in the primary tumor. This study describes a novel method for studying the effects of hypoxia in solid tumors and demonstrates that acute and chronic hypoxia can have different effects on tumor cell behavior in vivo.

Effects of tumour acidification with glucose+MIBG on the spontaneous metastatic potential of two murine cell lines.

In addition to hypoxia, acidic extracellular pH (pH(e)) is recognised as one of the microenvironmental characteristics of solid tumours. A number of studies have examined ways to increase tumour acidity in order to improve tumour-specific targeting of certain drugs and the effectiveness of hyperthermia. However, previous data have shown that exposure of murine tumour cells to acid conditions in culture can enhance their metastatic potential when injected subsequently into mice, raising the concern that deliberate tumour acidification might increase the probability of metastasis. In this study, we examined the effects of in vivo tumour acidification and hypoxia on the spontaneous metastatic potential of the murine KHT-C fibrosarcoma and B16F1 melanoma cell lines. A tumour-specific increase in extracellular acidity, demonstrated by measurements with pH electrodes, was achieved by daily intraperitoneal injections of meta-iodo-benzylguanidine (MIBG) and/or glucose. This method of tumour acidification during tumour growth did not significantly enhance the spontaneous metastatic potential of the two murine cell lines.