While several studies link the cell-surface marker CD44 to cancer progression, conflicting results show both positive and negative correlations with increased CD44 levels. Here, we demonstrate that the survival outcomes of genetically induced glioma-bearing mice and of high-grade human glioma patients are biphasically correlated with CD44 level, with the poorest outcomes occurring at intermediate levels. Furthermore, the high-CD44-expressing mesenchymal subtype exhibited a positive trend of survival with increased CD44 level. Mouse cell migration rates in ex vivo brain slice cultures were also biphasically associated with CD44 level, with maximal migration corresponding to minimal survival. Cell simulations suggest that cell-substrate adhesiveness is sufficient to explain this biphasic migration. More generally, these results highlight the potential importance of non-monotonic relationships between survival and biomarkers associated with cancer progression.
Bibliographical noteFunding Information:
The study was supported by U.S. NIH grants RC1-CA145044 and R01-CA172986 to D.J.O. and S.R.R.; a University of Minnesota Institute for Engineering in Medicine Group grant to D.J.O.; U.S. NIH grant R01-CA138437; American Cancer Society grant RSG-09-189-01-LIB; the State of Minnesota, Minnesota Partnership for Biotechnology and Medical Genomics, and Children's Cancer Research Fund to J.R.O.; U.S. NIH grants T32-GM008471, T32-DA022616, and F31-NS67937 to S.A.D.; National Science Foundation Graduate Research Fellowship 00006595 to B.L.B.; and the Minnesota Supercomputing Institute.
© 2017 The Authors
- biphasic migration
- biphasic survival