Human Mesenchymal Stem Cells Promote Resistance to Death Signals By Potentiating FGF Signaling in Mantle Cell Lymphoma

Introduction

Mantle cell lymphoma (MCL) represents an aggressive, incurable form of non-Hodgkin’s lymphoma (NHL). The health complications associated with advanced age of MCL patients further restrict treatment with intense chemotherapy. Translocation t(11;14), responsible for overexpression of cyclin-D1 is the hallmark of MCL. An intense analysis of primary MCL had been delayed until development of a tissue culture system, using human mesenchymal stromal cells (hMSC), suitable for propagation of primary MCL cells. We hypothesized that tumor-initiating cells are responsible for MCL relapse and chemoresistance and thus, identification of survival signals responsible for survival and maintenance of MCL-initiating cells (MCL-ICs) is essential for design of successful treatment strategies.

Methods

Isolates of primary MCL cells (n=24) were co-cultured with hMSC and content of MCL-ICs was analyzed by flow-cytometry based on marker expression profile; CD34-CD3-CD45+CD19-. Cytokine array was used to identify the soluble factors enriched in the cocultures and the expression of these factors was confirmed by RT-PCR analysis. The signaling pathways employed by the newly-identified factors were blocked in 3 MCL cell lines (JVM2, Mino, Z138) and cell survival was monitored.

Results

Co-cultures of primary MCL isolates with hMSCs supported the growth of MCL cells for over 4 weeks with continued presence of MCL-ICs (CD34-CD3-CD45+CD19-) representing about 1% of MCL cells. We found IL-6 triggered a FGF/FGFR autocrine loop in primary MCL in cocultures. Patients with MCL showing high FGFR levels in MCL tissues compared to lymphocytes, and the highest FGFR expressing cohort of patients showed a lower overall survival rated compared to those with low FGFR levels. Blockage of FGF/FGFR rendered MCL cells dead and also sensitized the cells to the killing effects of death receptor ligands.

Conclusion

We establish that primary MCL use an FGFR autocrine loop for propagation in cocultures with hMSCs. We defined the factors supporting MCL and MCL-ICs survival; such knowledge is essential for targeting MCL and MCL-ICs.