Abstract
Previous reports have suggested that the hypoxic microenvironment provides a niche that supports tumor stem cells, and that this might explain clinical observations linking hypoxia to metastasis. To test this, we examined the effects of a hypoxia-activated prodrug, TH-302, on the tumor-initiating cell (TIC) frequency of patient-derived pancreatic xenografts (PDX).The frequencies of TIC, measured by limiting dilution assay, varied widely in 11 PDX models, and were correlated with rapid growth but not with the levels of hypoxia. Treatment with either TH-302 or ionizing radiation (IR), to target hypoxic and well-oxygenated regions, respectively, reduced TIC frequency, and the combination of TH-302 and IR was much more effective in all models tested. The combination was also more effective than TH-302 or IR alone controlling tumor growth, particularly treating the more rapidly-growing/hypoxic models. These findings support the clinical utility of hypoxia targeting in combination with radiotherapy to treat pancreatic cancers, but do not provide strong evidence for a hypoxic stem cell niche.
Highlights
Hypoxia probably occurs to some extent in all solid tumors when oxygen consumption exceeds supply
Rather than being correlated with tumor size, the magnitude of hypoxia appeared to be an innate characteristic of individual Patient-derived xenografts (PDX) models that remained stable in the growing tumor (Supplementary Figure 2C)
We observed a five decade range in tumor-initiating cell (TIC) frequency between models (Table 1), the majority had a TIC frequency of 1:1,000 to 1:16,000 which is similar to previous reports for pancreatic cancer stem cells [14]
Summary
Hypoxia probably occurs to some extent in all solid tumors when oxygen consumption exceeds supply. It has long been recognized that cells become hypoxic as they are pushed away from blood vessels by the proliferation of oxygenated cells. It is recognized that hypoxia has wide-ranging effects, including the increased potential for invasion and metastasis that are not explained by this simple model [5,6,7,8,9,10,11,12]. There is current interest in the effects of acute (or intermittent) hypoxia, due to temporal fluctuations in blood flow, and in adaptive mechanisms that lead to hypoxia tolerance and the accumulation of hypoxic cells. Tumor hypoxia is a dynamic process with major effects on cancer biology, of considerable current interest
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