deriving mechanisms responsible for the lack of correlation between hypoxia and acidity in solid tumors推导机制负责在实体肿瘤缺氧和酸度之间缺乏相关性.pdfVIP

Deriving Mechanisms Responsible for the Lack of Correlation between Hypoxia and Acidity in Solid Tumors 1 1,2 3 1,2 Hamid R. Molavian , Mohammad Kohandel *, Michael Milosevic , Sivabal Sivaloganathan 1 Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada, 2 Center for Mathematical Medicine, Fields Institute for Research in Mathematical Sciences, Toronto, Ontario, Canada, 3 Radiation Medicine Program, Princess Margaret Hospital, and Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada Abstract Hypoxia and acidity are two main microenvironmental factors intimately associated with solid tumors and play critical roles in tumor growth and metastasis. The experimental results of Helmlinger and colleagues (Nature Medicine 3, 177, 1997) provide evidence of a lack of correlation between these factors on the micrometer scale in vivo and further show that the distribution of pH and pO2 are heterogeneous. Here, using computational simulations, grounded in these experimental results, we show that the lack of correlation between pH and pO2 and the heterogeneity in their shapes are related to the heterogeneous concentration of buffers and oxygen in the blood vessels, further amplified by the network of blood vessels and the cell metabolism. We also demonstrate that, although the judicious administration of anti-angiogenesis agents (normalization process) in tumors may lead to recovery of the correlation between hypoxia and acidity, it may not normalize the pH throughout the whole tumor. However, an increase in the buffering capacity inside the blood vessels does appear to increase the extracellular pH throughout the w