Exploring the Role of Osteosarcoma-Derived Extracellular Vesicles in Pre-Metastatic Niche Formation and Metastasis in the 143-B Xenograft Mouse Osteosarcoma Model

Abstract

The pre-metastatic niche (PMN) is a tumor-driven microenvironment in distant organs that can foster and support the survival and growth of disseminated tumor cells. This facilitates the establishment of secondary lesions that eventually form overt metastasis, the main cause of cancer-related death. In recent years, tumor-derived extracellular-vesicles (EVs) have emerged as potentially key drivers of the PMN. The role of the PMN in osteosarcoma metastasis is poorly understood and the potential contribution of osteosarcoma cell-derived EVs to PMN formation has not been investigated so far. Here, we characterize pulmonary PMN development using the spontaneously metastasizing 143-B xenograft osteosarcoma mouse model. We demonstrate the accumulation of CD11b+ myeloid cells in the pre-metastatic lungs of tumor-bearing mice. We also establish that highly metastatic 143-B and poorly metastatic SAOS-2 osteosarcoma cell-derived EV education in naïve mice can recapitulate the recruitment of myeloid cells to the lungs. Surprisingly, despite EV-induced myeloid cell infiltration in the pre-metastatic lungs, 143-B and SAOS-2 EVs do not contribute towards the 143-B metastatic burden in the context of both spontaneous as well as experimental metastasis in severe-combined immunodeficient (SCID) mice. Taken together, OS-derived EVs alone may not be able to form a functional PMN, and may perhaps require a combination of tumor-secreted factors along with EVs to do so. Additionally, our study gives a valuable insight into the PMN complexity by providing the transcriptomic signature of the premetastatic lungs in an osteosarcoma xenograft model for the first time. In conclusion, identification of regulators of cellular and molecular changes in the pre-metastatic lungs might lead to the development of a combination therapies in the future that interrupt PMN formation and combat osteosarcoma metastasis.

Tumor extracellular vesicles drive metastasis (it's a long way from home)

“…Additionally, exogenous EVs, such as bovine milk‐derived EVs, could directly impact metastasis 165 . Finally, tumor‐secreted EVs are not always sufficient to induce PMN formation and require the additional contribution of tumor‐secreted factors 128 . Therefore, the relative contribution of tumor released soluble factors and EVs and their potential cooperation will have to be studied in detail (see Table 1, outstanding questions).…”

“…In brief, macrophage migration inhibitory factor (MIF) contained in tumor EVs induces the secretion of TGF‐β by Kupffer cells, which in turn promotes the production of fibronectin by hepatic stellate cells and ultimately the recruitment of bone marrow‐derived macrophages to the liver 38 . Moreover, osteosarcoma EVs‐associated TGFβ1, upon internalization by lung fibroblasts‐induced pulmonary fibroblast differentiation and upregulated variety of ECM components that promoted invasive competence of these cells and tumor progression in distant PMN 128 . Interestingly, depending on the tumor subtype they come from, breast cancer EVs can induce different compositions of ECM in lung PMNs 30 .…”

Pre-metastatic Niche Formation in Different Organs Induced by Tumor Extracellular Vesicles

“…Exosomes from highly metastatic melanomas reprogram BMDCs toward a pro-vasculogenic phenotype by transferring EV-associated MET, and thus, increasing the metastatic behavior of primary tumors ( Peinado et al, 2012 ). Osteosarcoma-derived EVs can increase CD11b + myeloid cell infiltration in the lungs ( Mazumdar et al, 2020a ). In pancreatic cancer, highly metastatic pancreatic cancer cell-derived exosomes recruit CD11b + and CD45 + hematopoietic progenitor cells at the PMN ( Yu et al, 2017 ).…”

The basic characteristics of extracellular vesicles and their potential application in bone sarcomas

“…Macrophages and cancer cells negative for the fusion gene absorb the protein, while the exosomal fusion protein Rab22a-NeoF1 could promote its receptor-negative cancer cells metastasize in mouse lungs through the activation of RhoA activation by the binding partner PYK2 of their donor cells [60]. OS-derived EVs could recapitulate the infiltration of myeloid cells into the lungs of naive mice, but it is not enough to promote OS metastasis [61]. Mazumdar et al also proved that EVs derived from OS cells could cause cancer-related fibroblast/fibroblast differentiation [62].…”