Abstract
BackgroundOsteosarcoma 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.MethodsThe 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.ResultsSurgical 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.ConclusionsSurgery-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.
Highlights
Osteosarcoma is a highly metastatic primary bone tumor that predominantly affects adolescents and young adults
While many studies have demonstrated the role of Tumor-associated macrophage (TAM) in tumor progression in the primary tumor, less is known about the macrophages present at the metastatic site, metastasis-associated macrophages (MAMs), which promote later stages of metastasis
Gefitinib reverses the effects of surgical resection of primary tumor on metastasis and macrophage polarization Given that contralateral limb amputation produced the same acute tumor-supportive shift in pulmonary macrophage phenotype as primary tumor resection, we asked whether this change in macrophage polarization persisted 3 weeks after surgery, the time point at which we had seen a significant increase in metastatic nodules following primary tumor resection, but not after contralateral amputation
Summary
Osteosarcoma is a highly metastatic primary bone tumor that predominantly affects adolescents and young adults. The underlying mechanisms that contribute to surgically-accelerated metastasis remain unclear, but it has been repeatedly demonstrated that surgery results in a generalized immunosuppressive state and alters cell-mediated immune function [6,7,8,9]. While a multitude of macrophage subtypes may exist within the tumor microenvironment, macrophages exhibiting tumor supportive functions predominate in most cancers These TAMs secrete pro-angiogenic factors, inhibit NK and T-cell function, and facilitate tumor cell extravasation and invasion by promoting stromal remodeling [14,15,16]. While many studies have demonstrated the role of TAMs in tumor progression in the primary tumor, less is known about the macrophages present at the metastatic site, metastasis-associated macrophages (MAMs), which promote later stages of metastasis. MAMs appear to promote metastatic tumor development in a manner similar to TAMs by initiating angiogenesis, inhibiting anti-tumor immune responses, and promoting matrix remodeling making MAMs potential targets for novel therapeutic intervention to inhibit metastatic development [17]
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