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  • The tumor microenvironment is enriched with EMVs that

    2019-06-12

    The tumor microenvironment is enriched with EMVs that are derived not only by proliferating tumor cells, but also from infiltrating macrophages and neutrophils, and support tumor cell survival, growth, invasion and metastasis. Tumor derived EMVs also have the potential to modulate surrounding stromal cells, and facilitate rapid phenotype adjustments for maintaining cellular homeostasis during physiological and pathological states. In particular, a recent study has demonstrated that exosomes sodium channel or EMVs derived from mesothelioma cancer cells can stimulate differentiation of fibroblasts to α-smooth muscle sodium channel expressing myofibroblasts [56]. Acquisition of myofibroblast phenotype in the stromal microenvironment is associated with increased tumor growth, angiogenesis and metastasis [56,57]. In our study, we report the presence of both EMVs and myofibroblasts in OS tissue, isolated from the primary tumors of the BOOM model. A preclinical BOOM model like the one described in this paper and others [11,12,58] will continue to shed light on OS pathobiology and tumor microenvironment in primary and metastatic sites. These models are also invaluable in conducting chemopreventive, chemotherapeutic and genetic (gene silencing or RNA interference or gene therapy) studies especially when clinical trials are challenging because of limited number of samples and the patient category (pediatric). Our goal is to expand the use of the preclinical BOOM model and obtain mechanistic information underlying tumorigenesis; matrix remodeling, dynamic cross-talk between tumor–stroma; and metastasis, and screen potential antineoplastic or tumor modulating agents. Multi-modality application of the preclinical BOOM model will help to identify new therapeutically relevant targets for drug development against OS. We anticipate this strategy will provide a powerful first step before further evaluation using naturally occurring in canine OS models (comparative oncology approach) and then testing in pediatric patients. Our model has provided a powerful tool for following the progression of cancer cells in real time. Also, for future studies the BOOM model provides a platform for collecting information on threshold-dose of luciferase-tagged OS cell lines to generate tumors orthotopically, cellular, molecular, histological and μ-CT changes dynamically. One of the limitations of the BOOM model is that it does not allow a “complete” evaluation of host immune responses to OS. The lymphocyte mediated immune response especially the T-cell response is lost in the immunocompromised mouse model [59]. Despite the above discussed limitations, there are clear scientific benefits that can be derived from the BOOM model. For example, as stated previously, the frequency of ras mutations in clinical OS is unknown, but successful metastasis of 143B cells to lungs and kidneys from tibia i.e. the primary site demonstrates the reliability of this model to investigate the mechanism(s) underlying tumor progression and metastasis. In conclusion, we have successfully developed and characterized a bioluminescent orthotopic model that can be used to study OS pathobiology, and to evaluate potential therapeutic agents. Key novel findings of this study include: (a) multimodality approach for extensive characterization of the BOOM model using 143B human OS cell line; (b) evidence of in vivo Ki-67 staining of 143B cells; (c) evidence of renal metastasis in OS orthotopic model using 143B cells, (d) evidence of Runx2 expression in the metastatic lung tissue, (e) evidence of osteoblastic and osteolytic lesions with destruction of cortical bone due to increasing tumor burden; and (f) evidence of the presence of extracellular membrane vesicles and myofibroblasts in the tumor tissue from the BOOM model, suggesting a possible role of tumor-stroma intercellular communication in osteosarcoma progression.
    Acknowledgment
    Introduction Lung cancer is the most common cause of cancer-related deaths worldwide [1]. With modern cancer therapies, the 5 year survival rate for all lung cancer stages is around 16% [1], with a median overall survival of 9–13 months for advanced non-operable disease [2]. Bone is a common site of metastatic cancer spread in NSCLC patients (20–40%), comparable in frequency to liver (25–30%) and the contralateral lung (40–50%) [2–5]. The reported variability in sites of metastatic spread clearly differs between studies and is associated with whether data was obtained from imaging or autopsy series [6].