Fibroblast growth factor-2 (FGF2) and syndecan-1 (SDC1) are potential biomarkers for putative circulating CD15+/CD30+ cells in poor outcome Hodgkin lymphoma patients

Abstract

BackgroundHigh risk, unfavorable classical Hodgkin lymphoma (cHL) includes those patients with primary refractory or early relapse, and progressive disease. To improve the availability of biomarkers for this group of patients, we investigated both tumor biopsies and peripheral blood leukocytes (PBL) of untreated (chemo-naïve, CN) Nodular Sclerosis Classic Hodgkin Lymphoma (NS-cHL) patients for consistent biomarkers that can predict the outcome prior to frontline treatment.Methods and materialsBioinformatics data mining was used to generate 151 candidate biomarkers, which were screened against a library of 10 HL cell lines. Expression of FGF2 and SDC1 by CD30+ cells from HL patient samples representing good and poor outcomes were analyzed by qRT-PCR, immunohistochemical (IHC), and immunofluorescence analyses.ResultsTo identify predictive HL-specific biomarkers, potential marker genes selected using bioinformatics approaches were screened against HL cell lines and HL patient samples. Fibroblast Growth Factor-2 (FGF2) and Syndecan-1 (SDC1) were overexpressed in all HL cell lines, and the overexpression was HL-specific when compared to 116 non-Hodgkin lymphoma tissues. In the analysis of stratified NS-cHL patient samples, expression of FGF2 and SDC1 were 245 fold and 91 fold higher, respectively, in the poor outcome (PO) group than in the good outcome (GO) group. The PO group exhibited higher expression of the HL marker CD30, the macrophage marker CD68, and metastatic markers TGFβ1 and MMP9 compared to the GO group. This expression signature was confirmed by qualitative immunohistochemical and immunofluorescent data. A Kaplan-Meier analysis indicated that samples in which the CD30+ cells carried an FGF2+/SDC1+ immunophenotype showed shortened survival. Analysis of chemo-naive HL blood samples suggested that in the PO group a subset of CD30+ HL cells had entered the circulation. These cells significantly overexpressed FGF2 and SDC1 compared to the GO group. The PO group showed significant down-regulation of markers for monocytes, T-cells, and B-cells. These expression signatures were eliminated in heavily pretreated patients.ConclusionThe results suggest that small subsets of circulating CD30+/CD15+ cells expressing FGF2 and SDC1 represent biomarkers that identify NS-cHL patients who will experience a poor outcome (primary refractory and early relapsing).

Aberrantly Expressed OTX Homeobox Genes Deregulate B-Cell Differentiation in Hodgkin Lymphoma

“…Moreover, ELISA data demonstrated high FGF2 protein amounts in the supernatants of the cell lines HDLM-2 and KM-H2 ( Fig 5B ), indicating active autocrine FGF2-signalling in KM-H2. Enhanced expression of FGF2, FGFR2 and FGFR3 was detected in HL patient samples in silico ( S3 Fig ), supporting a general activation of this pathway in HL as described recently [ 49 , 50 ]. Treatment of KM-H2 cells with recombinant FGF2 protein yielded no change in OTX2 transcription ( Fig 5C ), consistent with saturated autocrine FGF2 activity in this cell line.…”

Molecular and clinical significance of fibroblast growth factor 2 (FGF2 /bFGF) in malignancies of solid and hematological cancers for personalized therapies

“…In line with this, increased expression of FGF2 and SDC1 was also reported in HL cell lines [68]. Overall, findings suggest that increased expression of FGF2, FGFR, and SCD1 is associated with poor prognosis and chemoresistance [62]. …”

Angiogenesis in Hodgkin’s lymphoma

“…HRS cells not only produce but also have the ability to secrete VEGF [17]. Another study found over-expression of FGF-2 in these cells, and this was confirmed by the study of RT-PCR [23].…”

“…The potential of HRS cells to stimulate angiogenesis was shown in in vitro studies [17,23]. HRS cells not only produce but also have the ability to secrete VEGF [17].…”