Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins

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.