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

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

doi:10.1038/s41389-021-00312-3

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

Oncogenesis. 2021 Mar 5;10(3):23. doi: 10.1038/s41389-021-00312-3.

Authors

Sini Karinen¹, Krista Juurikka^{2

3}, Roosa Hujanen¹, Wafa Wahbi¹, Elin Hadler-Olsen^{4

5}, Gunbjørg Svineng⁴, Kari K Eklund^{6

7}, Tuula Salo^{1

2

3

6

8}, Pirjo Åström^#⁹, Abdelhakim Salem^#^{10

11}

Affiliations

¹ Department of Oral and Maxillofacial Diseases, Clinicum, University of Helsinki, 00014, Helsinki, Finland.
² Cancer and Translational Medicine Research Unit, Faculty of Medicine, University of Oulu, 90014, Oulu, Finland.
³ Medical Research Centre Oulu, Oulu University Hospital and University of Oulu, 90220, Oulu, Finland.
⁴ Department of medical biology, Faculty of Health sciences, Arctic university of Norway, 9037, Tromsø, Norway.
⁵ The Public Dental Health Competence Center of Northern Norway, 9271, Tromsø, Norway.
⁶ Translational Immunology Research Program (TRIMM), Research Program Unit (RPU), University of Helsinki, 00014, Helsinki, Finland.
⁷ Department of Rheumatology, Helsinki University and Helsinki University Hospital, and Orton Orthopedic Hospital and Research Institute, 00014, Helsinki, Finland.
⁸ Helsinki University Hospital (HUS), 00014, Helsinki, Finland.
⁹ The Research Unit of Biomedicine, Faculty of Medicine, University of Oulu, 90014, Oulu, Finland.
¹⁰ Department of Oral and Maxillofacial Diseases, Clinicum, University of Helsinki, 00014, Helsinki, Finland. abdelhakim.salem@helsinki.fi.
¹¹ Translational Immunology Research Program (TRIMM), Research Program Unit (RPU), University of Helsinki, 00014, Helsinki, Finland. abdelhakim.salem@helsinki.fi.

^# Contributed equally.

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.