The tumor microenvironment of metastatic osteosarcoma in the human and canine lung

Abstract

Osteosarcoma is a rare but aggressive bone tumor that develops spontaneously in human and canine patients and most commonly metastasizes to the lung. The presence of lung metastases significantly decreases the survival rate of patients, with minimal benefit seen with available treatments. Canine osteosarcoma is clinically and molecularly similar to human osteosarcoma and develops approximately ten times more frequently than human osteosarcoma making dogs a promising natural model to study disease progression. The development of new therapies for pulmonary metastases requires an understanding of the interplay between tissue resident cells as well as recruited cell types and how those interactions impact seeding and progression within the new metastatic site. This review explores the tumor microenvironment surrounding pulmonary metastases and how current knowledge in canine and human patients can inform better treatments and outcomes for both populations.

Fig. 1. Graphical schematic of the cellular heterogeneity present in the lung microenvironment, showing the tumor surrounding the alveolar space containing type II pneumocytes.

Osteosarcoma tumors secrete tumor-derived exosomes containing components and other factors that influence the normal activity of resident lung cells. The presence of vasculature within the tumor facilitates the dissemination of these factors and may play a role in disease progression. In response, type II pneumocytes secrete surfactant protein B (SP-B) which, in conjunction with tumor-derived exosomes, influences the development of fibrosis. Created in BioRender. Mcgee, L. (2025) https://BioRender.com/i23k019.

Fig. 2. Graphical schematic of the immune cell heterogeneity present in the lung microenvironment.

There is an accumulation of immune cells along the tumor margin, reduced T cell proliferation, prevention of antigen uptake and processing by bone marrow derived cells, and increased neutrophils within the osteosarcoma lung microenvironment. Created in BioRender. Mcgee, L. (2025) https://BioRender.com/a36o974.

Fig. 3. Representative images of immune components surrounding pulmonary osteosarcoma metastases.

Human and canine tumor associated macrophages. Macrophages accumulate around the tumor margin, within alveolar spaces adjacent to a human and b canine osteosarcoma metastases. Scale Bar = 25 µm. Lymphocytes are also known to accumulate along the tumor:non-tumor interface of c human and d canine osteosarcoma metastases. Scale Bar = 100 µm.