Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells.

Abstract

Cultured cells subjected to oxygen deprivation have been shown to undergo anomalous DNA synthesis, which can result in DNA overreplication and the generation of cellular variants [Rice, G. C., Hoy, C. & Schimke, R. T. (1986) Proc. Natl. Arad. Sci. USA 83,[5978][5979][5980][5981][5982]. In the present study, murine tumor cells were exposed to severe hypoxia and then tested for their ability to form experimental metastases. Upon reoxygenation, cells transiently, yet dramatically, increased their metastatic potential. Flow cytometric analysis confirmed that hypoxia and reoxygenation induced cell cycle perturbations and DNA overreplication in these tumor cell lines. Fibrosarcoma cells with overreplicated DNA isolated by fluorescence-activated cell sorting proved to be highly metasiatic, although cells with 2-4 times the haploid DNA content in populations treated with hypoxia were also markedly

Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis

“…This interpretation is supported by results from studies of experimental tumours. Thus, exposure of tumour cells to hypoxia in vitro before intravenous inoculation in mice has been shown to increase the frequency of lung colonies in murine tumours (Young et al, 1988) and human melanoma xenografts (Rofstad and Danielsen, 1999). Several mechanisms have been identified that may be involved in hypoxia-induced metastasis of tumours (Rofstad, 2000).…”

Relationship of hypoxia to metastatic ability in rodent tumours

“…Our lab has previously demonstrated in a murine model that metastasis formation by rodent tumour cells can be increased by exposure to hypoxia (Young et al, 1988). When murine fibrosarcoma cells were exposed to hypoxia in vitro they acquired a transient, enhanced ability to form experimental metastases.…”

“…In the previous study by Young et al (1988) metastasis formation was examined with rodent tumour cells after exposure to hypoxia in vitro and intravenous injection of tumour cells back into the animal. The availability of polarographic electrodes allowing direct measurements of tumour oxygenation stimulated us to re-address the question of whether hypoxia affects distant metastasis formation using a spontaneous metastasis model.…”

Hypoxia-associated spontaneous pulmonary metastasis in human melanoma xenografts: involvement of microvascular hot spots induced in hypoxic foci by interleukin 8

“…There is significant evidence that the microenvironment may accelerate the malignant progression of tumours and promote the development of metastatic disease (Rofstad, 2000). Thus, some tumour cells exposed to hypoxia in vitro show increased lung colonization efficiency after intravenous inoculation in mice (Young et al, 1988;Rofstad and Danielsen, 1999). Moreover, clinical studies have demonstrated associations between incidence of metastases and extent of hypoxia in the primary tumour in soft tissue sarcoma (Brizel et al, 1996) and cervical carcinoma (Höckel et al, 1996;.…”