Date Published: January 28, 2014
Publisher: Public Library of Science
Author(s): Zheng Liang, Arjan Diepstra, Chuanhui Xu, Gustaaf van Imhoff, Wouter Plattel, Anke Van Den Berg, Lydia Visser, Martin Rowe.
The interaction between the tumor cells in classical Hodgkin lymphoma (cHL) and the microenvironment includes aberrant activity of receptor tyrosine kinases. In this study we evaluated the expression, functionality and prognostic significance of Insulin-like growth factor-1 receptor (IGF-1R) in cHL. IGF-1R was overexpressed in 55% (44/80) of cHL patients. Phosphorylated IGF-1R was detectable in a minority of the IGF-1R positive tumor cells. The overall survival (OS, 98%) and 5-year progression-free survival (PFS, 93%) was significantly higher in IGF-1R positive cHL patients compared to IGF-1R negative patients (OS 83%, p = .029 and PFS 77%, p = .047, respectively). Three cHL cell lines showed expression of IGF-1R, with strong staining especially in the mitotic cells and expression of IGF-1. IGF-1 treatment had a prominent effect on the cell growth of L428 and L1236 cells and resulted in an increased phosphorylation of IGF1R, Akt and ERK. Inhibition of IGF-1R with cyclolignan picropodophyllin (PPP) decreased cell growth and induced a G2/M cell cycle arrest in all three cell lines. Moreover, a decrease in pCcd2 and an increase in CyclinB1 levels were observed which is consistent with the G2/M cell cycle arrest. In conclusion, IGF-1R expression in HRS cells predicts a favorable outcome, despite the oncogenic effect of IGF-1R in cHL cell lines.
Classical Hodgkin lymphoma (cHL) is characterized by a minority of malignant Hodgkin and Reed-Sternberg (HRS) cells that usually represent only about 1% of the total number of cells in the tumor tissue. The HRS cells are surrounded by a vast majority of reactive cells including lymphocytes, plasma cells, eosinophils and histiocytes .
The pathogenesis of cHL remains poorly understood. HRS cells are derived from germinal center B cells that have lost their B cell phenotype including immunoglobulin expression . Although normal germinal center B cells that lack functional immunoglobulin undergo apoptosis, HRS cells escape this programmed cell death , . Aberrant activity of multiple RTKs in HRS cells might prevent apoptosis and explain resistance to treatment-induced apoptosis and treatment failure. HRS cells aberrantly express up to 7 different RTKs with extensive heterogeneity regarding the number and combinations in individual cases . In general, a more prominent co-expression has been observed in nodular sclerosis than mixed cellularity cHL . Consistent with these findings we also found that IGF-1R is predominantly expressed in the nodular sclerosis subtype of cHL, although we analyzed a limited number of mixed cellularity HL patients. Overall we demonstrated IGF-1R expression in the vast majority of the HRS cells in 55% of the cHL patients. IGF-1R is not normally expressed by B cells, only some large germinal center B cells show weak expression, but it is expressed by plasma cells . IGF-1R is expressed by mantle cell lymphomas . So, it is possible that expression of IGF-1R by the tumor cells in HL can be an effect of malignant transformation or due to differentiation towards plasma cells. In cHL expression of IRF4/Mum1, expressed in germinal center cells and plasma cells, and Blimp-1, a regulator of plasma cell differentiation, are both detected, although for Blimp-1 only in 23% of patients in a small part of tumor cells .