Tumour cells express functional lymphatic endothelium-specific hyaluronan receptor in vitro and in vivo: Lymphatic mimicry promotes oral oncogenesis?

Sini Karinen,Gunbjørg Svineng,Elin Hadler-Olsen,Tuula Salo,Abdelhakim Salem,Wafa Wahbi,Kari K. Eklund,Krista Juurikka,Pirjo Åström,Roosa Hujanen

doi:10.1038/s41389-021-00312-3

Abstract

Lymphatic metastasis represents the main route of tumour cell dissemination in oral squamous cell carcinoma (OSCC). Yet, there are no FDA-approved therapeutics targeting cancer-related lymphangiogenesis to date. The lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1), a specific lymphatic marker, is associated with poor survival in OSCC patients. In this study, we present a potential novel mechanism of lymphatic metastasis in OSCC—lymphatic mimicry (LM), a process whereby tumour cells form cytokeratin+/LYVE-1+, but podoplanin-negative, mosaic endothelial-like vessels. LM was detected in one-third (20/57; 35.08%) of randomly selected OSCC patients. The LM-positive patients had shorter overall survival (OS) compared to LM-negative group albeit not statistically significant. Highly-metastatic tumour cells formed distinct LM structures in vitro and in vivo. Importantly, the siRNA-mediated knockdown of LYVE-1 not only impaired tumour cell migration but also blunted their capacity to form LM-vessels in vitro and reduced tumour metastasis in vivo. Together, our findings uncovered, to our knowledge, a previously unknown expression and function of LYVE-1 in OSCC, whereby tumour cells could induce LM formation and promote lymphatic metastasis. Finally, more detailed studies on LM are warranted to better define this phenomenon in the future. These studies could benefit the development of targeted therapeutics for blocking tumour-related lymphangiogenesis.

Highlights

Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the head and neck region arising anywhere in the oral cavity
The following criteria were set to identify the lymphatic mimicry (LM) phenomenon in tumour tissues: (1) intratumoural vessel- or capillary-like structures; (2) LM lining is positive for oral squamous cell carcinoma (OSCC) tumour marker (CK+) staining; and (3) positive for lymphatic endothelial cells (LEC) marker (LYVE-1+) staining
Some CK+/lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1)+ cells were seen as a few “hot spots” in nests of densely packed tumour cells, where LYVE-1 immunoreactivity was observed in the tumour cell membrane and cytoplasm (Fig. 1b)

Summary

Introduction

Oral squamous cell carcinoma (OSCC) is one of the most common cancers in the head and neck region arising anywhere in the oral cavity. We examined the presence of lymphatic vessel-like structures (i.e. LM) in primary OSCC tumours (n = 57) using specific tumour and LEC markers (CK and LYVE-1, respectively). The OSCC tissues contained vessel-like structures lined by CK+/LYVE-1+ cells as depicted in (Fig. 1a).

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Results

Conclusion