The Biological Role of the Low-Affinity p75 Neurotrophin Receptor in Esophageal Squamous Cell Carcinoma

• Published in: Clinical cancer research 2006-09, Vol.12 (17), p.5096-5103
• Main Authors: OKUMURA, Tomoyuki, TSUNODA, Shigeru, MORI, Yukiko, ITO, Tetsuo, KIKUCHI, Keiji, WANG, Timothy Cragin, YASUMOTO, Shigeru, SHIMADA, Yutaka
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Biological and medical sciences; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; cell line; Cell Line, Tumor; esophageal cancer; Esophageal Neoplasms - genetics; Esophageal Neoplasms - metabolism; Esophageal Neoplasms - pathology; Esophagus; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Male; Medical sciences; Middle Aged; p75NTR; Pharmacology. Drug treatments; Receptor, Nerve Growth Factor - antagonists & inhibitors; Receptor, Nerve Growth Factor - genetics; Receptor, Nerve Growth Factor - metabolism; RNA, Small Interfering - pharmacology; stem cell; Structure-Activity Relationship; Survival Rate; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-2852

In this study, we investigated the clinicopathologic significance of the low-affinity p75 neurotrophin receptor (p75NTR; which is expressed in the stem/progenitor cell fraction of normal esophageal epithelial cells) in 187 resected esophageal squamous cell carcinoma (ESCC) specimens and found that ∼50% of ESCC expressed p75NTR. Our investigation using ESCC cell lines showed that p75NTR was intensely expressed in the cells with high colony-forming capacity but they were sensitive to cell death on inhibition of p75NTR expression with transient transfection of small interfering RNA (siRNA). These findings suggest that p75NTR is necessary for survival and maintenance of ESCC tumors, providing us with a potential target for novel therapies. Purpose: p75NTR is expressed in a stem/progenitor cell fraction of human normal esophageal epithelial cells. In this study, we investigated the expression and biological role of p75NTR in ESCC. Experimental Design: The expression of p75NTR in 187 resected ESCC specimens was immunohistochemically investigated. The expression of p75NTR in 30 ESCC cell lines (KYSEs) was assessed by reverse transcription-PCR, immunocytochemistry, and flow cytometry. The p75NTR-bright and p75NTR-dim/negative cells were isolated from KYSE150 by magnetic beads and colony formation was investigated. The role of p75NTR in KYSEs was assessed by transient transfection of siRNA. Results: p75NTR was expressed in 92 of 187 (49.2%) tumors. In well-differentiated tumors, positive staining was apparent in the first one to two layers from infiltrative margin of the tumors where most of the cells were actively proliferating. In moderately differentiated tumors, p75NTR was expressed in wider range from the margin of the tumors whereas p75NTR was diffusely distributed in poorly differentiated tumors. p75NTR was expressed in all examined KYSEs and the mean proportion of the p75NTR-bright fraction was 30.1%. The size of p75NTR-positive colonies was larger than that of p75NTR-negative colonies derived from KYSE150 ( P < 0.0001). The purified p75NTR-bright cells formed p75NTR-positive large colonies more frequently than the p75NTR-dim/negative cells ( P < 0.0001). Down-regulation of p75NTR expression by siRNA resulted in marked growth inhibition with induction of apoptosis. Conclusions: Our findings suggest that p75NTR is necessary for survival and maintenance of ESCC tumors, providing us with a potential target for novel therapies.