Insulin-Like Growth Factor 1 Receptor Is a Prognostic Factor in Classical Hodgkin Lymphoma

Abstract

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.

Insulin-like growth factor I is expressed in classical and nodular lymphocyte-predominant Hodgkin’s lymphoma tumour and microenvironmental cells

“…Furthermore, using specific markers (CD3, CD15, CD20, CD68), we identify IGF-I in specific cells of the microenvironment in cHL. Additionally, we confirm the presence of the IGF-1R in cHL cells as recently described (Liang et al 2014) by immunohistochemistry on a histopathological tissue array.…”

“…So far, IGF-I mRNA and peptide have been found to be produced by human peripheral lymphocytes only in low amounts (Arkins et al 1993;Kelley and Arkins 1994) or after mitogen stimulation (Nyman and Pekonen 1993). Nevertheless, most recently, IGF-I has been shown to stimulate the in vitro tumour growth of Hodgkin cell lines via the IGF-1R, which has been localised in cHL tumour cells, whereas the ligand has been detected in the cell culture supernatant (Liang et al 2014) but remains to be localised. Thus, in the present study, we aimed at localising the ligand IGF-I in HRS cells of cHL, in the LP cells of NLPHL and in the microenvironment, which, as described above, is essential for the pathogenesis and maintenance of tumour cells and which in HL only constitute a minority of the tumour mass (Steidl et al 2011).…”

“…Interestingly, IGF-I has been reported to be "unexpectedly" stimulated by IL-24, a mediator of apoptosis in human B cells and activated B cells express the IGF-1R and undergo apoptosis (Hadife et al 2013); this could be of particular significance in light of the recent finding that patients expressing the IGF-1R on cHL tumour cells demonstrate a better clinical outcome (Liang et al 2014). Nevertheless, in the same study, IGF-I has been shown to stimulate tumour cell growth in vitro (Liang et al 2014), whereas IGF-I and its receptor are upregulated by B cells undergoing apoptosis (Hadife et al 2013).…”

“…IGF-I protects human lymphocytes against apoptosis (AvilaGomez et al 2009) indicating the potential role of IGF-I in the transition of apoptosis-evading B lymphocytes to HL cells. Most recently, IGF-I has been shown to specifically stimulate tumour cell growth in Hodgkin cell lines via the IGF-1R in vitro but HL patients expressing IGF-1R on cHL tumour cells demonstrate a better clinical outcome which supports a role of the IGF-I system in HL; however, the data are still contradictory (Liang et al 2014). IGF-I has not as yet been localised within HL tissue.…”

Insulin-like growth factor-1 receptor expression in pediatric tumors: a comparative immunohistochemical study

“…In our study, about 56% (22 of 39) of the specimens were found to be expressing IGF-1R, in line with the 55% expression rate reported by Liang et al However, in the case of HL, the expression of IGF-1R with regard to inhibitory options is somewhat arguable. Liang et al reported that IGF-1R is strongly expressed in mitotic cHL cells and inhibition of IGF-1R decreases proliferation and induces cell-cycle arrest in cell lines, but in clinical correlation analysis the expression of IGF-1R was found to be related with better prognosis (17). Koh et al recently reported a much lower expression of IGF-1R (about 14%) in HRS cells and found a similar prognostic value as reported by Liang et al (18).…”