Tissue hypoxia is frequently observed in macroscopic tumors where it is indicative of poor clinical outcome. However, the hypoxic status of subclinical micrometastases is largely unknown. Li and colleagues determined the distribution of hypoxia in microscopic tumors by immunofluorescent visualization of the hypoxia marker pimonidazole in an animal model of disseminated peritoneal disease. In general, tumors of less than 1 mm in diameter were intensely hypoxic and possessed little vasculature. Larger tumors (1 to 4 mm in diameter) were not significantly hypoxic. The extent of hypoxia in microscopic tumors was reduced by carbogen breathing. If similar patterns of tumor hypoxia occur in human patients, the efficacy of systemic treatments for micrometastatic disease may be compromised by hypoxic resistance. The images on the cover show (top) the distributions of pimonidazole (green), perfusion marker Hoechst 33342 (blue), and the hypoxia-regulated protein carbonic anhydrase 9 (red) in small (<1 mm in diameter) and large peritoneal tumors. CD31 staining (bottom left) indicates that the small hypoxic tumors are avascular while larger tumors have extensive vasculature. The fraction of tumor area staining positive for pimonidazole (PPF) is shown (bottom right) as a function of tumor size. For details, see the article by Li and colleagues on page 7646 of this issue.

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