Discoidin Domain Receptor-1 (DDR1) is Involved in Angiolymphatic Invasion in Oral Cancer.

Yu-Lian Chen,Shine-Gwo Shiah,Ting-Yu Lai,Ann-Joy Cheng,Jenn-Ren Hsiao,Su-Fang Lin,Ying-Chieh Ko,Jang-Yang Chang,Wan-Hua Tsai

doi:10.3390/cancers12040841

Abstract

The discoidin domain receptor-1 (DDR1) is a non-integrin collagen receptor recently implicated in the collective cell migration of other cancer types. Previously, we identified an elevated expression of DDR1 in oral squamous cell carcinoma (OSCC) cells. Through the data mining of a microarray dataset composed of matched tumor-normal tissues from forty OSCC patients, we distilled overexpressed genes statistically associated with angiolymphatic invasion, including DDR1, COL4A5, COL4A6 and PDPN. Dual immunohistochemical staining further confirmed the spatial locations of DDR1 and PDPN in OSCC tissues indicative of collective cancer cell invasion. An elevated DDR1 expression at both the transcription and protein level was observed by treating keratinocytes with collagen of fibrillar or basement membrane types. In addition, inhibition of DDR1 kinase activity in OSCC TW2.6 cells disrupted cell cohesiveness in a 2D culture, reduced spheroid invasion in a collagen gel matrix, and suppressed angiolymphatic invasion in xenograft tissues. Taken together, these results suggest that collagen deposition in the affected tissues followed by DDR1 overexpression could be central to OSCC tumor growth and angiolymphatic invasion. Thus, DDR1 inhibitors are potential therapeutic compounds in restraining oral cancer, which has not been previously explored.

Highlights

Head and neck cancer is the sixth most common cancer worldwide; tumors from the oral cavity constitute the most common type of tumor in head and neck cancer [1]
We showed that discoidin domain receptor-1 (DDR1) is one of the top five protein tyrosine kinases overexpressed in betel quid (BQ)-associated oral squamous cell carcinoma (OSCC) cell lines [29]; overexpression of DDR1 in OSCC tissues is statistically associated with three clinical features: angiolymphatic invasion (ALI), perineural invasion (PNI), and lymph node metastasis [30]
The results showed that expression of DDR1 is basement membrane deposition and DDR1 overexpression were concomitant events in BQ-associated positively correlated with COL4A5 and COL4A6, but not other subunits (Figure 2a)

Summary

Introduction

Head and neck cancer is the sixth most common cancer worldwide; tumors from the oral cavity constitute the most common type of tumor in head and neck cancer [1]. In Taiwan, owing to betel quid (BQ) chewing habits, oral cancer incidence and mortality rate has risen rapidly, which prompted many national acts for preventing this disease, including screening patients whose oral lesions are still at premalignant stages. According to the latest report of the Taiwan Cancer Registry Database, the five-year overall survival rate of oral cancer is 55.88% [2]. Similar to other epithelial carcinomas, oral cancer represents the final outcome of a multi-year progression from benign hyperplasia to dysplasia, and from carcinoma in situ to invasive cancer [3]. BQ with or without tobacco is closely associated with various forms of oral premalignant lesions and oral cancer [5]. BQ ingredients are known to provoke tissue inflammation while weakening the local immune surveillance system [6]

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Conclusion