Pharmacological prevention of surgery-accelerated metastasis in an animal model of osteosarcoma. J Transl Med 2020 Apr 30;18(1):183
Date
05/02/2020Pubmed ID
32354335Pubmed Central ID
PMC7193344DOI
10.1186/s12967-020-02348-2Scopus ID
2-s2.0-85084362205 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
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.
Author List
Kallis MP, Maloney C, Blank B, Soffer SZ, Symons M, Steinberg BMAuthor
Caroline Maloney MD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBone Neoplasms
Cell Line, Tumor
Disease Models, Animal
Lung Neoplasms
Mice
Neoplasm Metastasis
Osteosarcoma
