SPP1 Derived from Macrophages Is Associated with a Worse Clinical Course and Chemo-Resistance in Lung Adenocarcinoma

SIMPLE SUMMARY: Osteopontin, also called secreted phosphoprotein 1 (SPP1), is expressed by cancer cells and is known as a poor prognostic factor. Although the production of SPP1 by tumor-associated macrophages (TAMs) has been attracting much attention recently, there have been no studies distinguishing the SPP1 expression of cancer cells and TAMs. In the present study, we demonstrated the following points. (1) Increased SPP1 expression on TAMs is associated with a worse clinical course in EGFR-wild-type adenocarcinoma. (2) SPP1 expression on macrophages is dependent on GM-CSF-mediated macrophage differentiation. (3) Macrophage-derived SPP1 potentially contributed to chemoresistance in lung cancer. ABSTRACT: Osteopontin, also called secreted phosphoprotein 1 (SPP1), is a multifunctional secreted phosphorylated glycoprotein. SPP1 is also expressed in tumor cells, and many studies demonstrated that a high level of circulating SPP1 is correlated with a poor prognosis in various cancers. SPP1 is expressed not only by tumor cells but also by stromal cells, such as macrophages. However, there have been no studies distinguishing the SPP1 expression of cancer cells and tumor-associated macrophages (TAMs). Thus, in this study, we tried to accurately evaluate the SPP1 expression status on cancer cells and TAMs separately in patients with non-small cell lung cancer by using double immunohistochemistry. We demonstrated that high SPP1 expression on TAMs predicted a poor prognosis in lung adenocarcinoma patients. Additionally, we investigated the expression mechanisms related to SPP1 using human-monocyte-derived macrophages and revealed that the SPP1 expression level increased in macrophage differentiation mediated by granulocyte-macrophage colony-stimulating factor. Furthermore, SPP1 contributed to anti-cancer drug resistance in lung cancer cell lines. In conclusion, SPP1 production on TAMs predicted a poor prognosis in lung adenocarcinoma patients, and TAM-derived SPP1′s involvement in the chemo-resistance of cancer cells was suggested.