Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression

Abstract

Human osteosarcoma is a genetically heterogeneous bone malignancy with poor prognosis despite the employment of aggressive chemotherapy regimens. Because druggable driver mutations have not been established, dissecting the interactions between osteosarcoma cells and supporting stroma may provide insights into novel therapeutic targets. By using a bioluminescent orthotopic xenograft mouse model of osteosarcoma, we evaluated the effect of tumor extracellular vesicle (EV)-educated mesenchymal stem cells (TEMSC) on osteosarcoma progression. Characterization and functional studies were designed to assess the mechanisms underlying MSC education. Independent series of tissue specimens were analyzed to corroborate the preclinical findings, and the composition of patient serum EVs was analyzed after isolation with size-exclusion chromatography. We show that EVs secreted by highly malignant osteosarcoma cells selectively incorporate a membrane-associated form of TGFβ, which induces proinflammatory IL6 production by MSCs. TEMSCs promote tumor growth, accompanied with intratumor STAT3 activation and lung metastasis formation, which was not observed with control MSCs. Importantly, intravenous administration of the anti-IL6 receptor antibody tocilizumab abrogated the tumor-promoting effects of TEMSCs. RNA-seq analysis of human osteosarcoma tissues revealed a distinct TGFβ-induced prometastatic gene signature. Tissue microarray immunostaining indicated active STAT3 signaling in human osteosarcoma, consistent with the observations in TEMSC-treated mice. Finally, we isolated pure populations of EVs from serum and demonstrated that circulating levels of EV-associated TGFβ are increased in osteosarcoma patients. Collectively, our findings suggest that TEMSCs promote osteosarcoma progression and provide the basis for testing IL6- and TGFβ-blocking agents as new therapeutic options for osteosarcoma patients. .

The contribution of immune infiltrates and the local microenvironment in the pathogenesis of osteosarcoma

“…ability to form sarcospheres, expression of stem-associated genes such as Nanog and Oct4) by osteosarcoma cells appeared mediated by the secretion of IL-6 by mesenchymal stem cells [52] [53]. The dialog between osteosarcoma cells and mesenchymal stem cells is bilateral, and mesenchymal stem cells can be educated by tumor-secreted extracellular vesicles [54]. Osteosarcoma extracellular vesicle-educated mesenchymal stem cells contained IL-6 and TGF- and were able to promote the tumor progression in a preclinical model.…”

“…Osteosarcoma extracellular vesicle-educated mesenchymal stem cells contained IL-6 and TGF- and were able to promote the tumor progression in a preclinical model. This tumor growth was blocked by administration of an anti-IL6 receptor antibody [54].…”

Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group

“…Dormancy of disseminated cells within the lung could explain the most common pattern of metastasis: late recurrence. Several groups have identified potential drivers of OS dormancy, [60][61][62] including suggestions that tumor-lung interactions might support the dormancy state, 58,63 though this remains a relatively unexplored field. Additional studies are needed to validate these findings.…”

Modulating the tumor microenvironment with new therapeutic nanoparticles: A promising paradigm for tumor treatment

“…Once recruited, the nontumoral cells are educated to produce a variety of growth factors, chemokines, and matrix‐degrading enzymes to enhance tumor proliferation and invasion. This milieu also provides a support system for tumor cells to fall back on following traditional cytotoxic therapies . Preventing active factors in the tumor environment from promoting tumor cell survival and metastasis is an important consideration in the development of novel therapeutics.…”