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

Takeichiro Aso, Mioko Matsuo, Hideyuki Kiyohara, Kenichi Taguchi, Fumihide Rikimaru, Mototsugu Shimokawa, Yuichi Segawa, Yuichiro Higaki, Hirohito Umeno, Tadashi Nakashima, Muneyuki Masuda

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Abstract

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). Materials and 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.

Original languageEnglish
Article numbere0116596
JournalPloS one
Volume10
Issue number3
DOIs
Publication statusPublished - Mar 9 2015

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Chemoradiotherapy
Neoplastic Stem Cells
Head and Neck Neoplasms
Stem cells
prognosis
stem cells
Biopsy
Organ Preservation
squamous cell carcinoma
neck
biopsy
Tumors
Tissue Survival
Molecules
neoplasm cells
head and neck neoplasms
Antibodies
Multivariate Analysis
Survival Rate
survival rate

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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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. / Aso, Takeichiro; Matsuo, Mioko; Kiyohara, Hideyuki; Taguchi, Kenichi; Rikimaru, Fumihide; Shimokawa, Mototsugu; Segawa, Yuichi; Higaki, Yuichiro; Umeno, Hirohito; Nakashima, Tadashi; Masuda, Muneyuki.

In: PloS one, Vol. 10, No. 3, e0116596, 09.03.2015.

Research output: Contribution to journalArticle

Aso, Takeichiro ; Matsuo, Mioko ; Kiyohara, Hideyuki ; Taguchi, Kenichi ; Rikimaru, Fumihide ; Shimokawa, Mototsugu ; Segawa, Yuichi ; Higaki, Yuichiro ; Umeno, Hirohito ; Nakashima, Tadashi ; Masuda, Muneyuki. / 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. In: PloS one. 2015 ; Vol. 10, No. 3.
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abstract = "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). Materials and 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.",
author = "Takeichiro Aso and Mioko Matsuo and Hideyuki Kiyohara and Kenichi Taguchi and Fumihide Rikimaru and Mototsugu Shimokawa and Yuichi Segawa and Yuichiro Higaki and Hirohito Umeno and Tadashi Nakashima and Muneyuki Masuda",
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T1 - 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

AU - Aso, Takeichiro

AU - Matsuo, Mioko

AU - Kiyohara, Hideyuki

AU - Taguchi, Kenichi

AU - Rikimaru, Fumihide

AU - Shimokawa, Mototsugu

AU - Segawa, Yuichi

AU - Higaki, Yuichiro

AU - Umeno, Hirohito

AU - Nakashima, Tadashi

AU - Masuda, Muneyuki

PY - 2015/3/9

Y1 - 2015/3/9

N2 - 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). Materials and 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.

AB - 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). Materials and 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.

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