The significance of the co-existence of osteopontin and tumor-associated macrophages in gastric cancer progression

Abstract

BackgroundOsteopontin (OPN) can recruit macrophages to the site of inflammation and promote tumorigenesis. M2 tumor-associated macrophages (M2-TAMs) also play an important role in cancer progression. This study aimed to clarify the role of OPN and M2-TAMs co-existence in gastric cancer.MethodsThe levels of OPN and M2-TAMs were evaluated by immunohistochemical staining in 170 resected gastric cancer specimens that were collected from 1998 to 2012. M2-TAMs were identified by staining for an M2 marker, CD204. The prognostic significance and correlation between OPN and CD204 expression were analyzed. A co-culture system of OPN+-AGS and U937 cells was designed to study the effect of OPN on the skewing of macrophages toward M2-TAMs for gastric cancer progression in vitro and in vivo.ResultsPatients with high expression (>50%) of OPN or CD204 exhibited poor 5-year overall survival rates (48.61%, p = 0.0055, and 52.14%, p = 0.0498, respectively). A positive correlation was observed between OPN and CD204 expression and high co-expression of OPN and CD204 demonstrated poor 5-year overall survival rates (48.90%, p = 0.0131). In the co-culture study, OPN was able to attract U937 cells and skew them toward M2-TAMs through paracrine action. The M2-TAMs could increase the invasiveness of OPN+-AGS cells and the growth rate of xenograft of a mixture of co-cultured OPN+-AGS and U937 cells.ConclusionOPN can skew macrophages toward M2-TAMs during gastric cancer progression. The co-existence of OPN and infiltrating M2-TAMs correlates with disease progression and poor survival and thus can serve as a prognostic marker in gastric cancer.

New Mechanisms of Tumor-Associated Macrophages on Promoting Tumor Progression: Recent Research Advances and Potential Targets for Tumor Immunotherapy

“…Dimethyl sulfoxide can suppress mouse 4T1 breast cancer growth by modulating TAM differentiation [133]. It was found that PA-MSHA can reeducate CD163 + TAMs into M1 macrophages through the TLR4-mediated pathway in MPE [27]. M-CSFR signaling was found to govern the phenotype of M2-like MHC-II lo TAMs, and its blockade results in preferential differentiation of monocytes into M1-like MHC-II hi TAMs [134].…”

Trametinib Drives T-cell–Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis

“…We confirmed the trametinib-driven decrease in osteopontin secretion in separate ELISA experiments (Figure 7B). We focused on osteopontin because it has been reported to induce MDSCs expansion (25) and tumor recruitment of macrophages (24). Supporting the relevance of our proteomic analysis, the tumor-driven increase of osteopontin in plasma was abrogated by short-term (3 day) treatment with trametinib in Brpkp110-bearing mice (Figure 7C).…”

“…Among these, osteopontin has been implicated in the recruitment of macrophages into tumors (23) and its expression is positively correlated with CD204 + M2-like macrophages (24). Osteopontin secreted by tumor cells has also been reported to drive the expansion of MDSCs in the spleens of tumor-bearing mice through activation of the ERK1/2-MAPK pathway in myeloid progenitors (25).…”

Tumor-Associated Macrophages Promote Epigenetic Silencing of Gelsolin through DNA Methyltransferase 1 in Gastric Cancer Cells

“…In gastric cancer, TAM infiltration is associated with phenotypes such as angiogenesis, depth of invasion, and nodal status that characterize aggressive malignancies. High infiltration of TAMs conferred a poor prognosis in gastric cancer after resection (7,8). The invasiveness of gastric cancer cells could be enhanced by coculture with TAMs (8).…”

“…High infiltration of TAMs conferred a poor prognosis in gastric cancer after resection (7,8). The invasiveness of gastric cancer cells could be enhanced by coculture with TAMs (8). However, the way in which TAMs promote gastric tumorigenesis remains unclear.…”