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 tumor-supportive 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.