Blood flow, metabolism, cellular microenvironment, and growth rate of human tumor xenografts.

Better understanding of the micromilieu of human tumors in situ is mandatory for further improvement of diagnostic and therapeutic interventions. Since investigations of untreated tumors of a wide size range are precluded in humans for ethical reasons, size-dependent changes in the pathophysiology of primary and metastatic human tumors were studied using "tissue-isolated" xenografts in nude rats. Tumor types included lung and breast cancers, ovarian and thyroid carcinomas, uterus tumors, and melanomas. A 10-fold variation in weight-adjusted tumor perfusion indicated large variations in angiogenesis which were unrelated to tumor type. Flow values obtained were consistent with data from clinical observations and were comparable to that in isografted rodent tumors. Using actual consumption and supply rates, maximum oxygen and glucose uptake rates were calculated for each tumor type. The capacity to consume oxygen and glucose varied 9-fold and 4-fold, respectively. However, considering actual consumption rates, blood flow was the principal modulator of substrate supply and tumor metabolism in these human tumor xenografts. Consequently, therapeutically relevant parameters of the metabolic micromilieu largely depended on the efficacy of the tumor circulation. Hereby, high metabolic rates concomitant with high flow values coincided with rapid tumor growth. Thus, in order to design the best individualized therapy, flow-related data should supplement histological classification and clinical staging and grading. Further development of relatively noninvasive technologies (magnetic resonance imaging, magnetic resonance spectroscopy, or positron emission tomography) might permit such monitoring.

Pathophysiological approaches to identifying tumor hypoxia in patients.

The present report summarizes observations of the authors on tumor oxygenation and on techniques for characterizing tumor hypoxia in patients. Cryospectrophotometric measurements of HbO2 saturations in tumor microvessels allow for estimates of the proportion of well oxygenated tissue regions. Labeling of tissue areas at oxygen (O2) tensions (pO2) less than 10 mm Hg with misonidazole may be used for a general characterization of the oxygenation status in patient tumors rather than for the determination of the radiobiologically hypoxic cell fraction. Quantitative bioluminescence and single photon imaging make it possible to determine ATP concentrations in absolute terms with a spatial resolution at the cellular level. It is shown that the ATP distribution reflects the efficiency of the O2 supply to tumors. Since all these techniques rely on biopsy material, the measured values can be assessed in relation to the histological structure and vascular pattern of the tumors. Such a direct interrelationship is not obtained when using polarographic microelectrodes in tumor tissue. However, a novel technology, the "computerized pO2 histography" has enabled direct polarographic measurements of pO2 values in patients, in extended and systematic clinical trials. Preliminary results in cervix and breast cancers demonstrate that pO2 values are lower in tumors than in adjacent normal tissues, and that great intra- and intertumoral differences occur even among tumors of the same clinical stages and histological grades, illustrating the necessity of such a pathophysiological approach to an "individualization" of tumor therapy.

Oxygenation of mammary tumors: from isotransplanted rodent tumors to primary malignancies in patients.

As a result of a compromised and anisotropic microcirculation, isotransplanted mammary tumors in mice exhibit hypoxic and anoxic tissue areas which are heterogeneously distributed within the tumor mass. Similarly, in poorly perfused human breast cancer xenografts, hypoxia develops at early growth stages and expands with tumor growth. In contrast, breast cancer xenografts with high perfusion rates exhibit an oxygenation status comparable to that of most normal organs. There is clear experimental evidence that the efficiency of tumor blood flow in isotransplanted tumors and in xenografted human breast cancers is the principal modulator of tissue oxygenation. The pO2 distribution found in primary lesions in patients ranged from the pO2 histograms obtained in "low-flow" isotransplants and xenografts to those measured in "high-flow" breast cancer xenografts or normal tissues. From our extended and systematic clinical studies there is clear indication that the oxygenation status of human breast cancers in situ does not correlate with the clinical stage and/or histological grade of an individual tumor.

Tumor blood flow: the principal modulator of oxidative and glycolytic metabolism, and of the metabolic micromilieu of human tumor xenografts in vivo.

We have investigated therapeutically relevant pathophysiological parameters of human breast and lung cancer xenografts in nude rats. All lung cancers and one breast cancer exhibited rapid growth and high blood flow values paralleled by high metabolic rates. The tissue of these tumors was well oxygenated up to very advanced growth stages. Xenografts from other breast cancer cell lines grew much more slowly, were poorly perfused, and exhibited low metabolic rates. Here, tumor hypoxia and tissue acidosis were evident. These results indicate that significant differences in the metabolic micromilieu can be detected in human tumors; these are due to varying perfusion rates and may be partly responsible for failure to obtain tumor control in individual patients.