Wnt2b and Wnt5a expression is highly associated with M2 TAMs in non‑small cell lung cancer

Abstract

Tumor‑associated macrophages (TAMs), particularly M2 macrophages, promote tumor progression, while Wnt genes encode a family of multi‑functional glycoproteins that serve an important role in tumorigenesis. Immunohistochemical studies were performed to evaluate Wnt2b and Wnt5a expression in tumor and stromal cells in M2 and M1 TAMs and Ki‑67 proliferation index in 160 consecutive patients with resected non‑small cell lung cancer (NSCLC). Overall, 52 tumors (32.5%) were classified as tumoral Wnt2b‑high (Wnt2b‑positive tumor cells >30%) and 95 (59.4%) as stromal Wnt2b‑high (Wnt2b‑positive stromal cells >30%), while 75 (46.9%) were classified as tumoral Wnt5a‑high (Wnt5a‑positive tumor cells >30%) and 63 (39.4%) as stromal Wnt5a‑high (Wnt5a‑positive stromal cells >28%). The density of M2 TAMs was significantly higher in the tumoral (P=0.0024) and stromal Wnt2b‑high groups (P=0.0054). The density of M2 TAMs was also significantly higher in the tumoral (P=0.0005) and stromal Wnt5a‑high groups (P=0.0486). By contrast, no difference in stromal or islet M1 TAM density was observed in relation to tumoral or stromal Wnt2b or Wnt5a status. Furthermore, Ki‑67 proliferation index was significantly higher in the tumoral (P=0.0121) and stromal Wnt2b‑high (P=0.0019) and tumoral Wnt5a‑high (P=0.0088) groups. Overall survival rate was significantly lower in the Wnt2b‑high (P=0.0437), Wnt5a‑high (P=0.0106) and M2 TAM‑high (P=0.0060) groups. Wnt2b and Wnt5a expression in tumor and stromal cells may induce M2 TAMs to produce more aggressive behavior during tumor progression in NSCLC.

Keywords: CD163; Ki‑67; Wnt2b; Wnt5a; lung cancer; macrophage.

Figure 1.

Immunostaining of lung cancer. Carcinoma with (A) positive Wnt2b expression in tumor cells and (B) high density of M2 TAMs. Carcinoma with (C) positive Wnt2b expression in stromal cells and (D) high density of M2 TAMs. Carcinoma with (E) negative Wnt2b expression in tumor and stromal cells and (F) low density of M2 TAMs. Carcinoma with (G) positive Wnt5a expression in tumor and weak Wnt5a expression in stromal cells and (H) high density of M2 TAMs. Carcinoma with (I) high and (J) low density of M1 TAMs. TAM, tumor-associated macrophage.

Figure 2.

M2 TAM density and stromal M1 TAM density in relation to Wnt status. M2 TAM density in relation to (A) tumoral and (B) stromal Wnt2b and (C) tumoral and (D) stromal Wnt5a status. Stromal M1 TAM density in relation to (E) tumoral and (F) stromal Wnt2b and (G) tumoral and (H) stromal Wnt5a status. TAM, tumor-associated macrophage.

Figure 3.

Ki-67 proliferation index in relation to Wnt status. (A) tumoral and (B) stromal Wnt2b and (C) tumoral and (D) stromal Wnt5a status.

Figure 4.

Overall survival of patients with resected NSCLC. (A) in relation to Wnt2b status. (B) in relation to Wnt5a status. (C) in relation to M2 TAM status. TAM, tumor-associated macrophage.