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.