Evaluation of tumor hypoxia and proliferation in canine spontaneous solid tumors

Tumor hypoxia and proliferation have been shown to be related to malignant tumor progression and treatment resistance. Studying tumor hypoxia and proliferation is important to address the biology of tumors and problems which may limit successful therapy. Tumor oxygenation is directly affected by oxygen consumption of tumors. Oxygen consumption is increased in actively proliferating cells. In this study the primary aim was to study the relationship between tumor hypoxia and proliferation in canine spontaneous solid tumors using immunohistochemical methods. Hypoxia was determined by detecting exogenous hypoxia marker, pimonidazole adducts and proliferation was determined by the fraction of cells labeled with proliferating cell nuclear antigen. We hypothesized that hypoxia may be more pronounced in rapidly proliferating tumors due to increased oxygen consumption.; Pimonidazole adduct formation occurred within 20 minutes after intravenous administration and cells with adducts were stable for several days in canine spontaneous tumors. Rapid and stable adduct formation in vivo are the important characteristics of using pimonidazole as a clinically useful hypoxia marker. There was no association between tumor hypoxia and proliferation evaluated by immunohistochemistry. The clinical outcome of the dogs studied in the project is unknown at this time, but these results to date suggest that tumor hypoxia and proliferation measurements are independent and may be potentially complementary predictive factors in canine spontaneous tumors.; Classic diffusion limited hypoxia may be more related to intensive areas of pimonidazole labeling and transient perfusion limited hypoxia may not have been detected with our technique. Perfusion limited hypoxia being related to proliferation might be more complex because the areas of hypoxia are transient and such areas still might be actively proliferating under the transient hypoxic conditions. Methods need to be developed to differentiate acute versus chronic hypoxia to know the true hypoxic fractions and their effects on tumor biology. The type of cells may affect estimates of hypoxia by pimonidazole labeling and it is necessary to evaluate histologic features before designing a study. The hypoxia marker pimonidazole is a powerful tool that can be used in a clinical setting to study tumor biology with minimum invasiveness.