Increased fucosylation has a pivotal role in invasive and metastatic properties of head and neck cancer stem cells

// Vincenzo Desiderio 1,3,* , Petros Papagerakis 4,5,* , Virginia Tirino 3,* , Li Zheng 2 , Margarite Matossian 1 , Mark E. Prince 6 , Francesca Paino 3 , Luigi Mele 1,3 , Federica Papaccio 3, Roberta Montella 3 , Gianpaolo Papaccio 3,** and Silvana Papagerakis 1,2,** 1 Department of Otolaryngology, Medical School, University of Michigan, Ann Arbor, MI, USA 2 Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA 3 Department of Experimental Medicine, Section of Biotechnology and Medical Histology and Embryology, Second University of Naples, Italy 4 Department of Orthodontics and Pediatric Dentistry, School of Dentistry, University of Michigan, Ann Arbor, MI, USA 5 Center for Organogenesis, Medical School, University of Michigan, Ann Arbor, MI, USA 6 Department of Otolaryngology, Head and Neck Surgery, Medical School, University of Michigan, Ann Arbor, MI, USA * These authors contributed equally to this work ** Equal senior authors Correspondence: Gianpaolo Papaccio, email: // Silvana Papagerakis, email: // Keywords : cancer stem cells, oral cancer, fucosylation, radiation, cisplatin Received : July 22, 2014 Accepted : November 06, 2014 Published : November 06, 2014 Abstract Oral squamous cell carcinoma (OSCC) is an aggressive malignancy with high mortality rates. Major challenges for OSCC management include development of resistance to therapy and early formation of distant metastases. Cancer stem cells (CSCs) have emerged as important players in both pathologic mechanisms. Increased fucosylation activity and increased expression of fucosylated polysaccharides, such as Sialyl Lewis X (SLe x ), are associated with invasion and metastasis. However, the role of fucosylation in CSCs has not been elucidated yet. We used the spheroid culture technique to obtain a CSC-enriched population and compared orospheres with adherent cells. We found that orospheres expressed markers of CSCs and metastasis at higher levels, were more invasive and tumorigenic, and were more resistant to cisplatin/radiation than adherent counterparts. We found fucosyltransferases FUT3 and FUT6 highly up-regulated, increased SLe x expression and increased adhesion by shear flow assays in orospheres. Inhibition of fucosylation negatively affected orospheres formation and invasion of oral CSCs. These results confirm that orospheres are enriched in CSCs and that fucosylation is of paramount importance for CSC invasion. In addition, SLe x may play a key role in CSC metastasis. Thus, inhibition of fucosylation may be used to block CSCs and metastatic spread.