Do mesenchymal stromal cells influence microscopic residual or metastatic osteosarcoma in a murine model?
Open accessAbstract
BACKGROUND: Mesenchymal stromal cells (MSCs) have been shown in rodent models to promote primary and pulmonary metastatic sarcoma growth when injected in the presence of gross tumor. In theory, this would limit their use in a clinical setting after limb salvage treatment for osteosarcoma. Although concerning, these models do not translate to the clinical setting wherein MSCs could be used after primary tumor resection to aid in bone healing and incorporation of tumor endoprostheses. If we can determine whether the use of MSCs in this setting is safe, it might improve our ability to augment bone healing in patients undergoing limb salvage. QUESTIONS/PURPOSES: The purpose of this study was to determine (1) whether MSCs promote pulmonary metastatic disease progression in a murine osteosarcoma model; and/or (2) whether they affect local disease recurrence in the presence of microscopic residual osteosarcoma. METHODS: An orthotopic model of luciferase-expressing osteosarcoma was developed. At 10 days, resection of the primary tumor was performed. One hundred fourteen female C3H mice were inoculated with DLM8-luc osteosarcoma in the proximal tibia. Ninety-four mice developed orthotopic osteosarcoma with luciferase expression. Mice with bioluminescent evidence of a primary tumor received either a microscopically "clean" amputation at a time when residual microscopic metastatic disease was present in the lungs (pulmonary metastasis group; n = 65) or a "dirty" amputation (local recurrence group; n = 29). Mice were randomized to receive intravenous MSCs, MSCs at the surgical site, or no MSCs. Mice were monitored for development and progression of pulmonary metastasis and local recurrence by bioluminescence imaging and daily measurements at the surgical site. The number of pulmonary nodules, time to first evidence of metastasis, and size of recurrent tumor were compared using Kruskal-Wallis, analysis of variance, Welch's, t-tests, or Mann-Whitney tests as appropriate for the specific data sets with p < 0.05 considered significant. RESULTS: Mice receiving intravenous MSCs had a faster time to first detection of pulmonary metastasis (2.93 ± 1.90 days) compared with mice with local injection of MSCs (6.94 ± 6.78 days) or no MSCs (5.93 ± 4.55 days) (p = 0.022). MSC treatment did not influence whether mice developed local recurrence (p = 0.749) or size of recurrent tumors (p = 0.221). CONCLUSIONS: MSCs delivered to the surgical site did not promote local recurrence or size of recurrent tumors, but intravenous injection of MSCs did hasten onset of detection of pulmonary metastatic disease. Although local administration of MSCs into a surgical site does not appear to promote either pulmonary metastatic disease or local recurrence, large variation within groups and small numbers diminished statistical power such that a Type II error cannot be ruled out. CLINICAL RELEVANCE: If MSCs are to be used to augment bone healing in the postlimb salvage setting in patients with osteosarcoma, it will be important to understand their influence, if any, on pulmonary micrometastsis or residual microscopic local disease. Although murine models do not completely recapitulate the clinical scenario, these results suggest that intravenous delivery of MSCs may promote micrometastatic pulmonary disease. Local administration into a surgical wound, even in the presence of residual microscopic disease, may be safe, at least in this murine model, but further investigation is warranted before considering the use of MSCs for clinical use in patients with osteosarcoma.
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In a mouse OS model, direct injections of MSCs into the OS tumor site exhibited a significant decrease in local recurrence and a hinderance of OS tumor cell growth compared to intravenous MSCs, MSCs at the surgical area, and no MSCs.
“The mice receiving direct injections of MSCs into the OS tumor site exhibited a significant decrease in local recurrence and a hinderance of OS tumor cell growth compared to the other groups, suggesting that MSCs could be promising for enhancing bone healing in patients with lesions after surgery.”
From Mesenchymal Stem/Stromal Cells: Immunomodulatory and Bone Regeneration Potential after Tumor Excision in Osteosarcoma Patients (2023) · cites this paper as [103]
The Local Recurrence Study reports no significant difference in recurrent-tumor dimension or volume between MSC-treated and untreated mice (p = 0.221 and p = 0.524), and says all mice developed local recurrence. The Discussion likewise reports no observed effect of surgical-site or intravenous MSC injection on local recurrence; it does not report a separate direct-into-tumor injection group or hindered tumor growth. (LLM, conf=0.92)
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Experimental — accuracy not yet measuredLow concentrations of injected ASCs into a tumor xenograft led to inhibition of OS tumor growth, while higher concentrations led to stimulation of tumor growth.
“They found that low concentrations of injected ASCs into a tumor xenograft led to the inhibition of OS tumor growth, while higher concentrations of injected ASCs led to the stimulation of tumor growth [102,103,104,105].”
From Mesenchymal Stem/Stromal Cells: Immunomodulatory and Bone Regeneration Potential after Tumor Excision in Osteosarcoma Patients (2023) · cites this paper as [103]
The Discussion (page unavailable) reports that previous studies found MSCs can promote osteosarcoma tumor growth. But the Mesenchymal Stromal Cell Treatment section describes only one ASC dose, and neither it nor the reported results establishes inhibition at low concentrations or stimulation at higher concentrations. (LLM, conf=0.78)
Experimental — accuracy not yet measuredData from animal models indicates that mesenchymal stromal cells could accelerate pulmonary metastases.
“Data from animal models indicates that mesenchymal stromal cells could accelerate pulmonary metastases, promote proliferation of sarcoma cells and increase chemoresistance.”
From Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice (2019) · cites this paper as [94]
The recurrence rate and the size of the recurrent tumours were not affected significantly by delivery of the mesenchymal stromal cells at the surgical site or intravenously.
“The recurrence rate and the size of the recurrent tumours, however, were not affected significantly by delivery of the MSCs at the surgical site or intravenously [94].”
From Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice (2019) · cites this paper as [94]
Mice that received mesenchymal stromal cells intravenously developed the first detectable metastases significantly earlier (2.93 ± 1.90 days) than those that received local injection of mesenchymal stromal cells (6.94 ± 6.78 days) and those that received no mesenchymal stromal cells (5.93 ± 4.55 days).
“Mice that received MSCs intravenously developed the first detectable metastases significantly earlier (2.93 ± 1.90 days) than those that received local injection of MSCs (6.94 ± 6.78 days) and those that received no MSCs (5.93 ± 4.55 days).”
From Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice (2019) · cites this paper as [94]
MSCs could be promising for enhancing bone healing in patients with lesions after surgery.
“The mice receiving direct injections of MSCs into the OS tumor site exhibited a significant decrease in local recurrence and a hinderance of OS tumor cell growth compared to the other groups, suggesting that MSCs could be promising for enhancing bone healing in patients with lesions after surgery.”
From Mesenchymal Stem/Stromal Cells: Immunomodulatory and Bone Regeneration Potential after Tumor Excision in Osteosarcoma Patients (2023) · cites this paper as [103]
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- Authors
- Aanstoos, M. E., Regan, D. P., Rose, R. J., Chubb, L. S., & Ehrhart, N. P.
- Affiliations
- Colorado State University (US)
- Venue
- Clinical Orthopaedics & Related Research
- Published
- 2016-03
- Volume
- 474
- Issue
- 3
- Pages
- 707-715
- ISSN
- 0009-921X (ISSN-L)
- PMC
- PMC4746149
- OpenAlex
- W350983018
- Cited by
- 28
- References
- 30
- Citations by year
- 2025: 2 · 2024: 1 · 2023: 5 · 2022: 4 · 2021: 5 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 1 · 2015: 2
- FWCI
- 1.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Orthopaedics and Related Research (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Colorado State University
- National Institutes of Health (T32OD010437)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Sarcoma Diagnosis and Treatment
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- mesenchymal stem cells, osteosarcoma, lung metastasis, local recurrence, microscopic residual disease, limb salvage, bone regeneration, orthotopic tumor model, bioluminescence imaging, cell therapy safety, tumor resection
- MeSH terms
- Animals, Bone Neoplasms, Disease Models, Animal, Female, Luminescent Measurements, Lung Neoplasms, Neoplasm Recurrence, Local, Random Allocation, Osteosarcoma, Tibia, Mice, Mesenchymal Stem Cells
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