Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins

Abstract

Osteosarcoma (OS) is the common primary bone cancer that affects mostly children and young adults. To augment the standard-of-care chemotherapy, we examined the possibility of protein-based therapy using mesenchymal stem cells (MSCs)-derived proteomes and OS-elevated proteins. While a conditioned medium (CM), collected from MSCs, did not present tumor-suppressing ability, the activation of PKA converted MSCs into induced tumor-suppressing cells (iTSCs). In a mouse model, the direct and hydrogel-assisted administration of CM inhibited tumor-induced bone destruction, and its effect was additive with cisplatin. CM was enriched with proteins such as calreticulin, which acted as an extracellular tumor suppressor by interacting with CD47. Notably, the level of CALR transcripts was elevated in OS tissues, together with other tumor-suppressing proteins, including histone H4, and PCOLCE. PCOLCE acted as an extracellular tumor-suppressing protein by interacting with amyloid precursor protein, a prognostic OS marker with poor survival. The results supported the possibility of employing a paradoxical strategy of utilizing OS transcriptomes for the treatment of OS.

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“…Notably, these levels experienced a further elevation in response to the overexpression of VCL (Figure 8 B). It is noteworthy that the tumor-suppressive properties of these proteins have been reported in our earlier studies 15 - 17 . In line with these observations, both the administration of MSC CM induced by LIV and the CM overexpressing VCL led to the downregulation of Amyloid precursor protein (APP), phosphorylated Src (p-Src), and Snail in TT2 cells.…”

“…This study revealed heightened ALDOA, PCOLCE, H4, and PPIB levels in MSC CM subjected to LIV treatment. Notably, among these transcripts, PCOLCE and H4 are tumorigenic and substantially expressed in OS, as demonstrated by Kexin et al 17 . PCOLCE, investigated by these researchers, emerged as an extracellular tumor suppressor protein.…”

“…In line with these observations, both the administration of MSC CM induced by LIV and the CM overexpressing VCL led to the downregulation of Amyloid precursor protein (APP), phosphorylated Src (p-Src), and Snail in TT2 cells. Significantly, PCOLCE has been identified as an extracellular tumor-suppressing protein known to bind to APP, thus shedding light on its role in the observed effects 17 . Concurrently, there was an upregulation of cleaved caspase 3 (c-Cas), an established apoptosis marker (Figure 8 C).…”

“…In a paradoxical twist, MSCs were reprogrammed into iTSCs through the overexpression of oncogenes such as β-catenin in the Wnt signaling pathway, Akt in the PI3K signaling pathway, and cMyc 15 , 16 . Additionally, the creation of iTSCs was achieved via the administration of synthetic agents, including BML284 and YS49, serving respectively as activators of the Wnt and PI3K pathways 15 , 17 . Intriguingly, within the CM derived from iTSCs, a collection of tumor-suppressing proteins was identified.…”

“…Intriguingly, within the CM derived from iTSCs, a collection of tumor-suppressing proteins was identified. This ensemble comprised PCOLCE, H4, PPIB, and ALDOA, proteins hitherto unreported for their tumor-inhibitory properties 17 . The present investigation is centered on exploring the capacity of LIV to affect the conversion of MSCs into iTSCs.…”