Induction of CD44 variant 9-expressing cancer stem cells might attenuate the efficacy of chemoradioselection and Worsens the prognosis of patients with advanced head and neck cancer.
BACKGROUND
At our institute, a chemoradioselection strategy has been used to select patients for organ preservation on the basis of response to an initial 30-40 Gy concurrent chemoradiotherapy (CCRT). Patients with a favorable response (i.e., chemoradioselected; CRS) have demonstrated better outcomes than those with an unfavorable response (i.e., nonchemoradioselected; N-CRS). Successful targeting of molecules that attenuate the efficacy of chmoradioselection may improve results. Thus, the aim of this study was to evaluate the association of a novel cancer stem cell (CSC) marker, CD44 variant 9 (CD44v9), with cellular refractoriness to chemoradioselection in advanced head and neck squamous cell carcinoma (HNSCC).


METHODS
Through a medical chart search, 102 patients with advanced HNSCC treated with chemoradioselection from 1997 to 2008 were enrolled. According to our algorithm, 30 patients were CRC following induction CCRT and 72 patients were N-CRS. Using the conventional immunohistochemical technique, biopsy specimens and surgically removed tumor specimens were immunostained with the anti-CD44v9 specific antibodies.


RESULTS
The intrinsic expression levels of CD44v9 in the biopsy specimens did not correlate with the chemoradioselection and patient survival. However, in N-CRS patients, the CD44v9-positive group demonstrated significantly (P = 0.008) worse prognosis, than the CD44v9-negative group. Multivariate analyses demonstrated that among four candidate factors (T, N, response to CCRT, and CD44v9), CD44v9 positivity (HR: 3.145, 95% CI: 1.235-8.008, P = 0.0163) was significantly correlated with the poor prognosis, along with advanced N stage (HR: 3.525, 95% CI: 1.054-9.060, P = 0.0228). Furthermore, the survival rate of the CD44v9-induced group was significantly (P = 0.04) worse than the CD44v9-non-induced group.


CONCLUSIONS
CCRT-induced CD44v9-expressing CSCs appear to be a major hurdle to chemoradioselection. CD44v9-targeting seems to be a promising strategy to enhance the efficacy of chemoradioselection and consequent organ preservation and survival.
Department of Head and Neck Surgery, National Kyushu Cancer Center, 3-1-1, Notame, Minamiku, Fukuoka 811-1395, Japan.
Takeichiro
T
Aso
Department of Head and Neck Surgery, National Kyushu Cancer Center, 3-1-1, Notame, Minamiku, Fukuoka 811-1395, Japan.
Mioko
M
Matsuo
Department of Head and Neck Surgery, National Kyushu Cancer Center, 3-1-1, Notame, Minamiku, Fukuoka 811-1395, Japan.
Hideyuki
H
Kiyohara
Department of Pathology, National Kyushu Cancer Center, 3-1-1, Notame, Minamiku, Fukuoka 811-1395, Japan.
Kenichi
K
Taguchi
Department of Head and Neck Surgery, National Kyushu Cancer Center, 3-1-1, Notame, Minamiku, Fukuoka 811-1395, Japan.
Fumihide
F
Rikimaru
Department of Cancer Information Research, National Kyushu Cancer Center, 3-1-1, Notame, Minamiku, Fukuoka 811-1395, Japan.
Mototsugu
M
Shimokawa
Department of Otorhinolaryngology and Head and Neck Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashiku, Fukuoka 812-8582, Japan.
Yuichi
Y
Segawa
Department of Head and Neck Surgery, National Kyushu Cancer Center, 3-1-1, Notame, Minamiku, Fukuoka 811-1395, Japan.
Yuichiro
Y
Higaki
Department of Otorhinolaryngology and Head and Neck Surgery, School of Medicine, Kurume University, 67, Asahimachi, Fukuoka, 830-0011, Japan.
Hirohito
H
Umeno
Department of Otorhinolaryngology and Head and Neck Surgery, School of Medicine, Kurume University, 67, Asahimachi, Fukuoka, 830-0011, Japan.
Tadashi
T
Nakashima
Department of Head and Neck Surgery, National Kyushu Cancer Center, 3-1-1, Notame, Minamiku, Fukuoka 811-1395, Japan.
Muneyuki
M
Masuda
D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D059248:Chemoradiotherapy; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D059351:Organ Sparing Treatments; D011379:Prognosis; D016016:Proportional Hazards Models; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D018960:Hyaluronan Receptors