Pharmacological prevention of surgery-accelerated metastasis in an animal model of osteosarcoma

Abstract

Background: Osteosarcoma is a highly metastatic primary bone tumor that predominantly affects adolescents and young adults. A mainstay of treatment in osteosarcoma is removal of the primary tumor. However, surgical excision itself has been implicated in promoting tumor growth and metastasis, an effect known as surgery-accelerated metastasis. The underlying mechanisms contributing to surgery-accelerated metastasis remain poorly understood, but pro-tumorigenic alterations in macrophage function have been implicated. Methods: The K7M2-BALB/c syngeneic murine model of osteosarcoma was used to study the effect of surgery on metastasis, macrophage phenotype, and overall survival. Pharmacological prevention of surgery-accelerated metastasis was examined utilizing gefitinib, a receptor interacting protein kinase 2 inhibitor previously shown to promote anti-tumor macrophage phenotype. Results: Surgical excision of the primary tumor resulted in increases in lung metastatic surface nodules, overall metastatic burden and number of micrometastatic foci. This post-surgical metastatic enhancement was associated with a shift in macrophage phenotype within the lung to a more pro-tumor state. Treatment with gefitinib prevented tumorsupportive alterations in macrophage phenotype and resulted in reduced metastasis. Removal of the primary tumor coupled with gefitinib treatment resulted in enhanced median and overall survival. Conclusions: Surgery-accelerated metastasis is mediated in part through tumor supportive alterations in macrophage phenotype. Targeted pharmacologic therapies that prevent pro-tumor changes in macrophage phenotype could be utilized perioperatively to mitigate surgery-accelerated metastasis and improve the therapeutic benefits of surgery.

Systemic immunity in cancer

“…Although resection substantially reduces the number of systemic MDSCs in the spleen, blood and lung in the 4T1 breast cancer model, functional immunosuppressive PMN-MDSCs can persist in these peripheral tissues for 2 weeks 79 . Persistent immunosuppressive myeloid cells were shown to support pro-tumorigenic niches in the lungs in both breast cancer and osteosarcoma models 79 , 80 . Mechanistically, one study showed that neutrophil extracellular traps increased in the liver following surgical intervention and ensnared tumour cells to promote metastasis 77 .…”

Macrophages in Osteosarcoma Immune Microenvironment: Implications for Immunotherapy

“…Maloney et al demonstrated that macrophage promoted the invasion of osteosarcoma cells and contributed to pulmonary metastasis in the animal model (42). Macrophages within the metastatic lung niche were altered to pro-tumor M2 (MHC-II − /CD206 + ) phenotype and enhanced metastatic progression after the removal of the primary osteosarcoma tumor (83).…”

“…Intriguingly, gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, altered pulmonary macrophage phenotype to block osteosarcoma invasion and reduce metastatic burden via inhibition of macrophage receptor-interacting protein kinase 2 (RIPK2) ( 42 ). Moreover, gefitinib altered macrophage phenotype and relieved surgery-accelerated metastasis and prolonged overall survival in mice model ( 83 ).…”

LINC00319 promotes osteosarcoma progression by regulating the miR‐455‐3p/NFIB axis

“…[ 2 ] Current treatment for OS mainly includes a combination of chemotherapy and limb salvage surgery. [ 3 ] Despite the improvement in numerous treatment methods (chemotherapy and curative resection), the 5‐year overall survival rate of patients with OS is still unsatisfactory. [ 3 ] Therefore, further understanding of the pathogenesis of osteosarcoma (OS) and the transfer mechanism is needed to identify an ideal therapeutic target.…”

“…patients with OS is still unsatisfactory. [3] Therefore, further understanding of the pathogenesis of osteosarcoma (OS) and the transfer mechanism is needed to identify an ideal therapeutic target.…”