Metastasis blood test by flow cytometry: In vivo cancer spheroids and the role of hypoxia

Cancer hypoxia correlates with therapeutic resistance and metastasis, suggesting that hypoxic adaptation is a critical survival advantage for cancer stem cells (CSCs). Hypoxic metabolism, however, may be a disadvantage in aerobic circulation as the extremely low incidence of metastasis—compared to t...

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Veröffentlicht in:International journal of cancer 2015-04, Vol.136 (7), p.1528-1536
Hauptverfasser: Denes, Viktoria, Lakk, Monika, Makarovskiy, Andrew, Jakso, Pal, Szappanos, Szabolcs, Graf, Laszlo, Mandel, Laszlo, Karadi, Istvan, Geck, Peter
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Sprache:eng
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Zusammenfassung:Cancer hypoxia correlates with therapeutic resistance and metastasis, suggesting that hypoxic adaptation is a critical survival advantage for cancer stem cells (CSCs). Hypoxic metabolism, however, may be a disadvantage in aerobic circulation as the extremely low incidence of metastasis—compared to the high circulating tumor‐cell numbers (CTCs)—appears to suggest. As rare metastatic CSCs still survive, we searched for a mechanism that protects them from oxygen in circulation. CSCs form multicellular spheroids in vitro from virtually all cancers tested. We asked, therefore, whether cancers also form spheroids in vivo and whether circulating spheroids play a role in metastasis. We used metabolic, apoptotic and hypoxia assays, we measured aerobic barriers and calculated hypoxia vs. spheroid‐size correlations. We detected metabolic/oxidative stress in spheroids, we found correlation between stem cell presence and hypoxia and we showed that the size of hypoxic spheroids is compatible with circulation. To detect spheroids in patients, we worked out a new light‐scatter flow cytometry blood test and assayed 67 metastatic and control cases. We found in vivo spheroids with positive stem cell markers in cancer blood and they showed exclusive correlation with metastasis. In conclusion, our data suggest that metastatic success depends on CSC‐association with in vivo spheroids. We propose that the mechanism involves a portable “micro‐niche” in spheroids that may support CSC‐survival/adaptation in circulation. The new assay may establish a potential early marker of metastatic progression. What's new? Even when malignant cells enter the bloodstream, they don't always cause metastasis, so testing for them doesn't indicate the disease will spread. Only cancer stem cells can start a new tumor, but no test can distinguish these from other circulating tumor cells. In this paper, the authors show that cancer stem cells, which normally thrive in hypoxic conditions, form spheroid bodies to protect themselves from oxygen in the bloodstream. They developed an assay to detect these spheroids, and they demonstrated that circulating spheroids always indicate metastatic disease. Thus, testing for spheroids in the bloodstream could help predict imminent metastasis.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.29155