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

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.

Potential antitumor therapeutic strategies of human amniotic membrane and amniotic fluid-derived stem cells

“…The results of this study indicated that hAM-MSCs do not have tumorigenic potential. 12 Phermthai et al 35 also demonstrated their chromosomal stability by karyotype analysis. When a clonal hAFS cell line was examined after prolonged in vitro culture, hAFS cells appeared to lack chromosomal mutations associated with tumorigenicity because of their chromosomal stability.…”

“…For instance, previous study reported that bone marrow-derived human multipotent MSCs transplanted resulted in antitumor activity against non-Hodgkin's lymphoma. 12 However, some MSCs have been also shown to increase the in vivo growth of colon cancer, lymphoma and melanoma cells. 13,14 Therefore, it is unclear whether MSCs promote or suppress tumor growth so far.…”

Oncostatin M Modulates the Mesenchymal–Epithelial Transition of Lung Adenocarcinoma Cells by a Mesenchymal Stem Cell-Mediated Paracrine Effect

“…Cell number was quantitated using ImageJ software. For the invasion assay, the membrane was coated with Matrigel (BD Biosciences) diluted with an equal volume of serum-free medium and incubated for at least 1 hour at 37 C before the cells were seeded. Supplementary Fig.…”

GLI2 Transcription Factor Mediates Cytokine Cross-talk in the Tumor Microenvironment

“…One such interaction is that of the malignant B cells and bone marrow stromal cells. Malignant B cells at various stages of development depend on signaling from the surrounding microenvironment to survive and proliferate within the host and promote chemoresistance (3)(4)(5)(6). Bone marrow stromal cells provide malignant B cells with external signals such as soluble growth factors, antigens, cytokines, and cell-cell interactions (7)(8)(9)(10)(11).…”