title: Lysosomal acid lipase in mesenchymal stem cell stimulation of tumor growth and metastasis.
abstract: 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Cong
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.|IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007165:Immunosuppression Therapy; D008546:Melanoma, Experimental / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D002787:Sterol Esterase / Q000378:metabolism*
chemical_list: D018925:Chemokines; D017077:Culture Media, Conditioned; D016207:Cytokines; C503451:LIPA protein, human; D002787:Sterol Esterase
keywords: lysosomal acid lipase; mesenchymal stem cell; myeloid-derived suppressor cells; tumor growth and metastasis