Research Papers:

Lysosomal acid lipase in mesenchymal stem cell stimulation of tumor growth and metastasis

Ting Zhao, Cong Yan and Hong Du _

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Oncotarget. 2016; 7:61121-61135. https://doi.org/10.18632/oncotarget.11244

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Ting Zhao1, Cong Yan1,2, Hong Du1,2

1Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

2IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

Correspondence to:

Hong Du, email: [email protected]

Cong Yan, email: [email protected]

Keywords: mesenchymal stem cell, lysosomal acid lipase, myeloid-derived suppressor cells, tumor growth and metastasis

Received: February 24, 2016     Accepted: July 27, 2016     Published: August 12, 2016


Bone marrow mesenchymal stem cells (MSCs) are an important participant in the tumor microenvironment, in which they promote tumor growth and progression. Here we report for the first time that depletion of lysosomal acid lipase (LAL) in MSCs impairs their abilities to stimulate tumor growth and metastasis both in allogeneic and syngeneic mouse models. Reduced cell viability was observed in LAL-deficient (lal−/−) MSCs, which was a result of both increased apoptosis and decreased proliferation due to cell cycle arrest. The synthesis and secretion of cytokines and chemokines that are known to mediate MSCs’ tumor-stimulating and immunosuppressive effects, i.e., IL-6, MCP-1 and IL-10, were down-regulated in lal−/− MSCs. When tumor cells were treated with the conditioned medium from lal−/− MSCs, decreased proliferation was observed, accompanied by reduced activation of oncogenic intracellular signaling molecules in tumor cells. Co-injection of lal−/− MSCs and B16 melanoma cells into wild type mice not only induced CD8+ cytotoxic T cells, but also decreased accumulation of tumor-promoting Ly6G+CD11b+ myeloid-derived suppressor cells (MDSCs), which may synergistically contribute to the impairment of tumor progression. Furthermore, lal−/− MSCs showed impaired differentiation towards tumor-associated fibroblasts. In addition, MDSCs facilitated MSC proliferation, which was mediated by MDSC-secreted cytokines and chemokines. Our results indicate that LAL plays a critical role in regulating MSCs’ ability to stimulate tumor growth and metastasis, which provides a mechanistic basis for targeting LAL in MSCs to reduce the risk of cancer metastasis.

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