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.
Highlights
Tumor progression and metastasis are greatly influenced by non-malignant cells in the microenvironment
Our study demonstrates that lysosomal acid lipase (LAL) deficiency in mesenchymal stem cells (MSCs) impairs their stimulation of tumor growth and metastasis by restricting MSC proliferation, reducing synthesis and secretion of tumor-promoting cytokines/chemokines, inducing CD8+ T lymphocytes and decreasing accumulation of myeloid-derived suppressor cells (MDSCs), and impairing differentiation towards tumor-associated fibroblasts (TAFs)
We used B16 melanoma cells as a model to compare the tumorpromoting ability between lal+/+ and lal−/− MSCs, and to investigate the underlying mechanisms involved in the process
Summary
Tumor progression and metastasis are greatly influenced by non-malignant cells in the microenvironment. Many of these cells are derived from the bone marrow, and recruited by cancer cells to enhance their survival, growth, invasion and dissemination [1]. Numerous studies have shown that bone marrow-derived MSCs participate in tumor progression by establishing a favorable tumor microenvironment [3,4,5,6]. MSCs support the tumor vasculature by differentiating into pericytes and perhaps endothelial cells, and secreting vasculogenic growth factors [6], and differentiate into tumor-associated fibroblasts (TAFs), which establish cytokine networks that promote progression and migration [7]. MSCs display immunomodulatory properties by inhibiting proliferation and function of several major immune cells [8], which might be an important mechanism through which MSCs promote tumor growth or increase incidence of tumor formation
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