Increased Expression of Delta-like Ligand 4 in Mycosis Fungoides
Hikari Boki, Tomomitsu Miyagaki, Yuki Shono, Hiroaki Kamijo, Tomonori Oka, Hiraku Suga, Yoshihide Asano, Makoto Sugaya, Shinichi Sato
In many malignancies, dysregulation of the Notch pathways, composed of 4 Notch receptors (Notch1–4) and 5 Notch ligands (Jagged1–2, Delta-like ligand-1, 3–4), is associated with their development. In mycosis fungoides, interaction between Notch1 and Jagged1 is known to activate the Notch pathways and promote the proliferation of tumour cells. However, the involvement of other Notch ligands has not been reported. This study investigated the roles of Delta-like ligand 4 in mycosis fungoides. Delta-like ligand 4 mRNA levels in lesional skin of patients with mycosis fungoides were significantly elevated compared with those of normal controls, and correlated with disease-specific mortality. Immunohistochemical staining demonstrated prominent expression of Delta-like ligand 4 on vascular endothelial cells and tumour cells in mycosis fungoides lesional skin. In addition, Delta-like ligand 4 augmented the proliferation of cutaneous T-cell lymphoma cell lines. These results suggest that enhanced Delta-like ligand 4 expression may contribute directly to the progression of mycosis fungoides through proliferating tumour cells.
In many malignancies, including mycosis fungoides, dysregulation of the Notch pathways has been reported to be associated with their development. Thus, Notch-specific monoclonal antibodies against Notch1, Notch2 or Notch3 have been developed for the treatment of malignancies. This study found that expression levels of Delta-like ligand 4, one of the Notch ligands, was increased in lesional skin of patients with mycosis fungoides, and that Delta-like ligand 4 had the capacity to induce proliferation of cutaneous T-cell lymphoma cell lines. These results suggest that not only monoclonal antibodies against Notch receptors, but also anti-Delta-like ligand 4 antibodies, may be a useful therapeutic tool for mycosis fungoides.