Incorporating cancer stem cells in radiation therapy treatment response modeling and the implication in glioblastoma multiforme treatment resistance.
OBJECTIVE
To perform a preliminary exploration with a simplistic mathematical cancer stem cell (CSC) interaction model to determine whether the tumor-intrinsic heterogeneity and dynamic equilibrium between CSCs and differentiated cancer cells (DCCs) can better explain radiation therapy treatment response with a dual-compartment linear-quadratic (DLQ) model.


METHODS
The radiosensitivity parameters of CSCs and DCCs for cancer cell lines including glioblastoma multiforme (GBM), non-small cell lung cancer, melanoma, osteosarcoma, and prostate, cervical, and breast cancer were determined by performing robust least-square fitting using the DLQ model on published clonogenic survival data. Fitting performance was compared with the single-compartment LQ (SLQ) and universal survival curve models. The fitting results were then used in an ordinary differential equation describing the kinetics of DCCs and CSCs in response to 2- to 14.3-Gy fractionated treatments. The total dose to achieve tumor control and the fraction size that achieved the least normal biological equivalent dose were calculated.


RESULTS
Smaller cell survival fitting errors were observed using DLQ, with the exception of melanoma, which had a low α/β = 0.16 in SLQ. Ordinary differential equation simulation indicated lower normal tissue biological equivalent dose to achieve the same tumor control with a hypofractionated approach for 4 cell lines for the DLQ model, in contrast to SLQ, which favored 2 Gy per fraction for all cells except melanoma. The DLQ model indicated greater tumor radioresistance than SLQ, but the radioresistance was overcome by hypofractionation, other than the GBM cells, which responded poorly to all fractionations.


CONCLUSIONS
The distinct radiosensitivity and dynamics between CSCs and DCCs in radiation therapy response could perhaps be one possible explanation for the heterogeneous intertumor response to hypofractionation and in some cases superior outcome from stereotactic ablative radiation therapy. The DLQ model also predicted the remarkable GBM radioresistance, a result that is highly consistent with clinical observations. The radioresistance putatively stemmed from accelerated DCC regrowth that rapidly restored compartmental equilibrium between CSCs and DCCs.
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Victoria Y
VY
Yu
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Dan
D
Nguyen
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Frank
F
Pajonk
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Patrick
P
Kupelian
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Tania
T
Kaprealian
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Michael
M
Selch
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California.
Daniel A
DA
Low
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. Electronic address: ksheng@mednet.ucla.edu.
Ke
K
Sheng
D001859:Bone Neoplasms / Q000473:pathology / Q000532:radiotherapy; D001932:Brain Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D001943:Breast Neoplasms / Q000473:pathology / Q000532:radiotherapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D005909:Glioblastoma / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D016014:Linear Models; D008297:Male; D008545:Melanoma / Q000473:pathology / Q000532:radiotherapy; D014411:Neoplastic Stem Cells / Q000528:radiation effects*; D012516:Osteosarcoma / Q000473:pathology / Q000532:radiotherapy; D011471:Prostatic Neoplasms / Q000473:pathology / Q000532:radiotherapy; D011836:Radiation Tolerance; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000532:radiotherapy