Purpose: To present and evaluate clinical data suggesting that cancer metastasis may be induced by the microenvironment of the primary tumour and to discuss possible mechanisms of microenvironment-induced metastasis, based on a critical review of relevant data from studies of experimental tumours and cells in culture.
Conclusions: Low oxygen tension in the primary tumour is associated with metastasis in soft tissue sarcoma, cervix carcinoma and carcinoma of the head and neck. Multiple mechanisms may be involved in hypoxia-induced metastasis. Thus, hypoxia followed by reoxygenation may induce point mutations and DNA strand breakage leading to deletions, amplifications and genomic instability. Hypoxia may also provide a physiological pressure in tumours selecting for metastatic cell phenotypes. Moreover, hypoxia may induce a temporary increase in the expression of gene products involved in the metastatic cascade, either through gene amplifications or through normal physiological processes by activating oxygen sensors, hypoxia signal transduction pathways and DNA transcription factors. Low glucose concentration, high lactate concentration and low extracellular pH may induce metastasis by similar mechanisms as hypoxia. Tumour reoxygenation during radiation therapy may promote microenvironment-induced metastasis by rescuing hypoxic or nutritionally deprived metastatic cells from dying. Ionizing radiation can elicit a stress response in tumour cells similar to that elicited by hypoxia. Radiation therapy may therefore adversely affect the rate of metastasis in patients who do not achieve control of the primary tumour by enhancing the expression of gene products of importance in metastasis.