Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins
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eLife assessment
There are no known effective treatments available to date for the treatment of osteosarcomas, the earliest identified bone cancer that can spread to other tissues. In this study, the authors have used novel approaches to identify calreticulin and procollagen C-endopeptidase enhancer (PCOLCE) as osteosarcoma tumor suppressor proteins that inhibit osteosarcoma growth both in animal and in vitro cell culture models. These important findings may provide a basis for the future development of more efficient targeted therapies for the treatment of osteosarcomas.
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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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eLife assessment
There are no known effective treatments available to date for the treatment of osteosarcomas, the earliest identified bone cancer that can spread to other tissues. In this study, the authors have used novel approaches to identify calreticulin and procollagen C-endopeptidase enhancer (PCOLCE) as osteosarcoma tumor suppressor proteins that inhibit osteosarcoma growth both in animal and in vitro cell culture models. These important findings may provide a basis for the future development of more efficient targeted therapies for the treatment of osteosarcomas.
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Reviewer #1 (Public Review):
This manuscript demonstrates that the activation of several oncogenic pathways including WNT, PI3K, and PKA in mesenchymal stem cells (MSC) paradoxically induces the expression and secretion of osteosarcoma-suppressing proteins in MSC conditional mediums. The authors provide the in vivo evidence showing that the PKA-induced MSC conditional medium as well as the recombinant calreticulin and procollagen C-endopeptidase enhancer (PCOLCE), the expression of which increases in PKA-induced MSC conditional medium, inhibit osteosarcoma tumor growth and tumor-associated bone destruction in an osteosarcoma xenograft mouse model. The in vitro mechanistic studies further unveil that PKA-induced MSC conditional medium, calreticulin, and PCOLCE suppress cell proliferation, survival, and migration of human osteosarcoma …
Reviewer #1 (Public Review):
This manuscript demonstrates that the activation of several oncogenic pathways including WNT, PI3K, and PKA in mesenchymal stem cells (MSC) paradoxically induces the expression and secretion of osteosarcoma-suppressing proteins in MSC conditional mediums. The authors provide the in vivo evidence showing that the PKA-induced MSC conditional medium as well as the recombinant calreticulin and procollagen C-endopeptidase enhancer (PCOLCE), the expression of which increases in PKA-induced MSC conditional medium, inhibit osteosarcoma tumor growth and tumor-associated bone destruction in an osteosarcoma xenograft mouse model. The in vitro mechanistic studies further unveil that PKA-induced MSC conditional medium, calreticulin, and PCOLCE suppress cell proliferation, survival, and migration of human osteosarcoma cell lines. These inhibitory effects are additive with the canonical Cisplatin chemotherapy in vivo and in vitro. The actions of calreticulin and PCOLCE on osteosarcoma cells are mediated by their interactions with CD47 and APP (amyloid precursor protein), respectively. The strengths of this report are that (a) the data presented are of high quality and convincing. (b) The results largely support the conclusions of this study. (c) The findings are novel and have translational potential to develop more efficient targeted therapies for the treatment of this most malignant primary bone cancer in conjunction with canonical chemotherapies. The weaknesses include (a) the lack of in vivo evidence that the PKA-stimulated MSC conditional medium and calreticulin inhibit osteosarcoma tumor cell proliferation and survival in vivo and (b) the potential effects of these two treatments on osteoblast differentiation and bone formation which may contribute to the higher trabecular and cortical bone mass observed in treated mice have not been examined.
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Reviewer #2 (Public Review):
In this manuscript, Li et al. sought to identify tumor suppressor proteins in mesenchymal stem cell conditioned media in which PKA signaling was up-regulated by treatment with a small molecule, and in osteosarcoma-enriched transcripts, to provide alternative treatment strategies to combat osteosarcoma. They identified several proteins that when forcibly expressed both in vitro and in vivo, can suppress osteosarcoma viability, growth, and motility. This manuscript presents a substantial amount of data, is well organized, and provides a novel approach to addressing osteosarcomas. The data is thorough and convincing and provides an alternative approach to developing cancer therapeutics.
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