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.
Highlights
Osteopontin (OPN) can recruit macrophages to the site of inflammation and promote tumorigenesis
The results indicated that M2-Tumor associated macrophage (TAM) infiltration in gastric cancer tissue was correlated with OPN expression as the disease progressed
The results demonstrated that the co-existence of OPN and M2 type tumor associated macrophage (M2-TAM) in gastric cancer was highly associated with the overall survival of gastric cancer patients
Summary
Osteopontin (OPN) can recruit macrophages to the site of inflammation and promote tumorigenesis. M2 tumor-associated macrophages (M2-TAMs) play an important role in cancer progression. This study aimed to clarify the role of OPN and M2-TAMs co-existence in gastric cancer. Surgery remains the only curative therapy for gastric cancer, some studies reported that adjuvant chemotherapy and chemoradiation therapy can improve patient outcomes of resectable gastric cancers [3,4,5]. 50% of gastric cancer patients who underwent radical resection suffered from local recurrence and distant metastasis [6]. Inhibition of chronic inflammation in patients with premalignant disease could reduce cancer risk and cancer recurrence [7], suggesting that chronic inflammation can generate a beneficial microenvironment for tumor progression and metastatic dissemination. Previous studies reported that gastric cancer is often accompanied by the
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