Human Bone Marrow Mesenchymal Stem Cells Display Anti-Cancer Activity in SCID Mice Bearing Disseminated Non-Hodgkin's Lymphoma Xenografts

Paola Secchiero,Sonia Zorzet,Raffaella Bosco,Sabrina Ingrao,Barbara Zavan,Elisabetta Melloni,Lorenzo Caruso,Federica Corallini,Giorgio Zauli,Claudio Tripodo

doi:10.1371/journal.pone.0011140

Abstract

BackgroundAlthough multimodality treatment can induce high rate of remission in many subtypes of non-Hodgkin's lymphoma (NHL), significant proportions of patients relapse with incurable disease. The effect of human bone marrow (BM) mesenchymal stem cells (MSC) on tumor cell growth is controversial, and no specific information is available on the effect of BM-MSC on NHL.Methodology/Principal FindingsThe effect of BM-MSC was analyzed in two in vivo models of disseminated non-Hodgkin's lymphomas with an indolent (EBV− Burkitt-type BJAB, median survival = 46 days) and an aggressive (EBV+ B lymphoblastoid SKW6.4, median survival = 27 days) behavior in nude-SCID mice. Intra-peritoneal (i.p.) injection of MSC (4 days after i.p. injection of lymphoma cells) significantly increased the overall survival at an optimal MSC∶lymphoma ratio of 1∶10 in both xenograft models (BJAB+MSC, median survival = 58.5 days; SKW6.4+MSC, median survival = 40 days). Upon MSC injection, i.p. tumor masses developed more slowly and, at the histopathological observation, exhibited a massive stromal infiltration coupled to extensive intra-tumor necrosis. In in vitro experiments, we found that: i) MSC/lymphoma co-cultures modestly affected lymphoma cell survival and were characterized by increased release of pro-angiogenic cytokines with respect to the MSC, or lymphoma, cultures; ii) MSC induce the migration of endothelial cells in transwell assays, but promoted endothelial cell apoptosis in direct MSC/endothelial cell co-cultures.Conclusions/SignificanceOur data demonstrate that BM-MSC exhibit anti-lymphoma activity in two distinct xenograft SCID mouse models of disseminated NHL.

Highlights

Despite the fact that multimodality treatment, including combination chemotherapy, radiation, and target-specific monoclonal antibodies, such as rituximab, can induce high rate of remission in many subtypes of non-Hodgkin’s lymphoma (NHL), significant proportions of patients relapse with incurable disease
Taking into account that the majority of NHL mainly progresses as a systemic malignancy, in this study we have developed and described two animal models that allowed us the investigation of the activity of mesenchymal stem cells (MSC) against NHL in xenografts bearing disseminated tumors
The major finding of the present study is that a single MSC injection, at MSC:tumor cell ratio as low as 1:10, significantly prolonged the survival in animals with indolent (BJAB) and aggressive (SKW6.4) lymphomas

Summary

Introduction

Despite the fact that multimodality treatment, including combination chemotherapy, radiation, and target-specific monoclonal antibodies, such as rituximab, can induce high rate of remission in many subtypes of non-Hodgkin’s lymphoma (NHL), significant proportions of patients relapse with incurable disease. The effect of human bone marrow (BM) mesenchymal stem cells (MSC), which are considered the stromal progenitor stem cells within the BM, on the growth of tumoral cells is controversial. Multimodality treatment can induce high rate of remission in many subtypes of non-Hodgkin’s lymphoma (NHL), significant proportions of patients relapse with incurable disease. The effect of human bone marrow (BM) mesenchymal stem cells (MSC) on tumor cell growth is controversial, and no specific information is available on the effect of BM-MSC on NHL

Methods

Results

Conclusion