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Effect of c-Met and CD44v6 Expression in Resistance to Chemotherapy in Esophageal Squamous Cell Carcinoma

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Abstract

Background

c-Met relies on CD44v6 for its activation and signaling in several cancer cell lines. However, the correlation of c-Met and CD44v6 expression and its biological significance in esophageal squamous cell carcinoma (ESCC) remains unknown.

Methods

Expression of c-Met and CD44v6 was examined by immunohistochemistry (IHC) in 147 ESCC specimens. We analyzed the impact of c-Met and CD44v6 expression on clinicopathological parameters, including chemoresistance or prognosis in ESCC.

Results

High expression of c-Met and CD44v6 in cancerous lesions was identified in 49.7% and 50.3% of all patients, respectively. The c-Met-high group comprised more advanced pT and pM stages than the c-Met-low group. In addition, more patients in the c-Met-high group received neoadjuvant chemotherapy (NACT) than the c-Met-low group (64.4% vs. 43.2%, P = 0.010). On the other hand, the CD44v6-high group was associated with more advanced pT/pN stages and a poorer clinical response to NACT (response rate 53.5% vs. 77.8%, P = 0.025) than the CD44v6-low group. Double-positive immunostaining of c-Met and CD44v6 was identified in 28.6% of all cases, and multivariate analysis of overall survival (OS) identified them (hazard ratio 1.79, 95% confidence interval 1.03–3.04, P = 0.038) as independent prognostic factors in addition to pN and pM stage.

Conclusions

c-Met/CD44v6 were associated with tumor progression or chemoresistance. Double-positive expression of c-Met and CD44v6 negatively impacted patient prognosis in ESCC, implying that c-Met and CD44v6 are candidates for targeted therapy in ESCC.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Osaka University, Graduate School of Medicine, Suita City, Osaka, Japan

    Takeo Hara MD, Tomoki Makino MD, PhD, Makoto Yamasaki MD, PhD, Koji Tanaka MD, PhD, Yasuhiro Miyazaki MD, PhD, Tsuyoshi Takahashi MD, PhD, Yukinori Kurokawa MD, PhD, Kiyokazu Nakajima MD, PhD, Masaki Mori MD, PhD & Yuichiro Doki MD, PhD

  2. Osaka International Cancer Institute, Osaka, Osaka, Japan

    Nariaki Matsuura MD, PhD

  3. Department of Molecular Pathology, Osaka University Graduate School of Medicine, Division of Health Sciences, Suita City, Osaka, Japan

    Nariaki Matsuura MD, PhD

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Contributions

TH, TM, MY, MM, and YD: conception, design of the study; TH, TM, MY, KT, and YD: surgery and acquisition of clinical data; TH: immunohistochemical staining; TH, TM, and NM: evaluation of immunohistochemical staining; TH, TM, YM, TT, YK, and KN: analysis of data; TH: drafting the article; TM: critical revision of the article; MM and YD: final approval of the article.

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Correspondence to Tomoki Makino MD, PhD.

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Supplemental Fig. S1

Kaplan-Meier survival analysis of overall survival among patients who (a) did not receive preoperative therapy classified by c-Met expression, (b) did not receive preoperative therapy classified by CD44v6 expression, (c) did not receive preoperative therapy classified by c-Met and CD44v6 expression, (d) received preoperative chemotherapy classified by c-Met expression, (e) received preoperative chemotherapy classified by CD44v6 expression, and (f) received preoperative chemotherapy classified by c-Met and CD44v6 expression (TIFF 193 kb)

Supplemental Fig. S2

Kaplan-Meier survival analysis of overall survival according to c-Met/CD44v6 expression in (a) pT1-2 group, (b) pN0 group, (c) pT3-4 group, (d) pN1-3 group (TIFF 154 kb)

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Hara, T., Makino, T., Yamasaki, M. et al. Effect of c-Met and CD44v6 Expression in Resistance to Chemotherapy in Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 26, 899–906 (2019). https://doi.org/10.1245/s10434-018-07126-5

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  • DOI: https://doi.org/10.1245/s10434-018-07126-5

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