Tumor cells use several mechanisms to invade extracellular matrix and metastasize to distant organs and the interaction between tumor cells and stromal cells in the tumor microenvironment plays an important role in tumor growth and metastasis [86-88]. Tumor-associated macrophages (TAMs) are prominent stromal cells in this interaction [89,90].

Based on molecules expression, cytokines/chemokines and biogenic products, macrophages can be categorised as Ml which produce effector molecules (reactive oxygen intermediates, reactive nitrogen intermediates, TNFa) limiting tumor growth or M2 subtype. M2 macrophages promote tumor growth and metastasis by secretion of matrix-degrading enzymes, angiogenesis factors and immunosuppressive cytokines/chemokines [91-93]. The balance in macrophage subtypes will be determined by tumor microenvironment including other immune system-infiltrating cells and their products. In older humans, cancer and inflammatory chronic diseases have bring the majority of information about function and preferential polarisation to Ml or M2 in macrophages.

NSCLC patients without pre-operative chemotherapy/radiotherapy and short (average 1 year) or long survival (average 5.4 years) after resection (aged 58.0 ± 1.4 and 60.5 ± 1.3 respectively) had their lung tissue evaluated for the presence of macrophage subtypes M1 (CD68/HLA-DR) and M2 (CD68/CD163) in tumor islets, tumor stroma, or a combination of tumor islets and stroma [94]. M1 macrophage density in the tumor islets and stroma of patients with long survival time was significantly higher than the M1 macrophage density in the tumor islets and stroma of patients with short survival time. M2 macrophage density was not different when the lung tissue of short and long survival patients were compared. The authors also showed that M1 macrophage density in the tumor islets, stroma, or islets and stroma was positively associated with patient survival time whereas M2 density showed no association [94].

Patients with gastric cancer (>70 years old) and peritoneal dissemination had a higher number of peritoneal macrophages with M2 phenotype (CD68/CD163 or CD68/CD204) than those without peritoneal dissemination. The authors concluded that the predominance of M2 phenotype could contribute to tumor proliferation/ progression and is thus a promising target in the treatment of peritoneal dissemination in gastric cancer [95]. Gastric cancer patients (61.7 ± 1.2 years old) submitted to resection had their tissue specimens analysed for the presence of M1 and M2 macrophages. It was observed that patients with M1 density higher than 7.0 (n = 27) had a significantly superior survival rate (1-year survival rate = 81 %, 2-year survival rate = 55 %, 3-year survival rate = 26 %, 4-year survival rate = 22 % and 5-year survival rate = 18 %) compared to patients with lower M1 density. In the multivariate analysis M1/M2 ratio was a positive independent predictor of survival. M1 and M2 expression are potential markers to discriminate patients that could be more benefited from radically resection of gastric cancer [96]. Kurahara et al. evaluated 76 cases of pancreatic head cancer submitted to curative resection. Tumor infiltrating M2-polarized macrophages were associated with high incidence of lymph node metastasis and thus poor prognosis [97].

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