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 osteosarcoma-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 (APP), 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.

Enhancing anti-tumor potential: low-intensity vibration suppresses osteosarcoma progression and augments MSCs' tumor-suppressive abilities

“…Notably, these levels experienced a further elevation in response to the overexpression of VCL (Figure 8B). It is noteworthy that the tumor-suppressive properties of these proteins have been reported in our earlier studies [15][16][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.…”

“…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.…”

Three unconventional maxims in the natural selection of cancer cells: Generation of induced tumor-suppressing cells (iTSCs)

“…As a potential mechanism for tumor selectivity, we postulate that the levels of target proteins can be elevated in tumor cells rather than non-tumor cells. One such example is the expression of CD47 59 . We have shown previously that a tumor-suppressing protein, CALR, inhibited the progression of osteosarcoma cells via interaction with CD47.…”

Hypoxia inducible factor-1ɑ as a potential therapeutic target for osteosarcoma metastasis

“…Osteosarcoma (OS) is the most common primary bone malignancy, derived from primitive bone-forming mesenchymal cell, for which there are two peak periods of incidence in adolescents and older adults (Shoaib et al, 2022). OS typically develops near the end of the long bone in the lower limbs, with high local invasiveness, rapid infiltration, and early metastasis (Vailas et al, 2019;Li K. et al, 2023a). The pathogenic OPEN ACCESS EDITED BY Duoyi Zhao, Fourth Affiliated Hospital of China Medical University, China characteristic of OS, a spindle stromal cell tumor, is the direct conversion of proliferating tumor cells into bone or tissue that resembles bone from the perspective of pathomorphology (Dong et al, 2022).…”