Macrophage infiltration in human non-small-cell lung cancer: the role of CC chemokines

Abstract

Bronchogenic carcinoma is the leading cause of malignancy-related mortality in the United States, with an overall 5-year survival rate of less than 15%. This aggressive behavior reflects, among other traits, the capacity of the tumor to evade normal host immune defenses, and to induce a pro-angiogenic environment. A central feature of any immune response toward tumors is the recruitment of specific immune cell populations. In the present study we investigated the infiltration of monocytes in human specimens of non-small-cell lung cancer (NSCLC). The presence of macrophages in NSCLC tumors was documented by immunohistochemistry. In vitro chemotaxis assays demonstrated higher monocyte chemotactic activity in NSCLC tumor homogenates than in normal lung tissue. We next investigated the expression of CC chemokines within specimens of NSCLC tumors. Levels of the CC chemokines were higher in NSCLC tumor tissue than in normal lung tissue. Immunolocalization showed that the cells associated with antigenic CC chemokines were the malignant tumor cells, as well as occasional stromal cells. Maximal inhibition of monocyte chemotaxis induced by NSCLC in vitro occurred in the presence of neutralizing antibodies to MCP-1 and MIP-1beta. On follow-up of 15 patients in whom we quantified macrophage infiltration, we found that those with recurrence of disease had higher levels of macrophage infiltration in their initial tumors. However, the functional significance of CC-chemokine-mediated macrophage infiltration into NSCLC remains to be determined.

Role of infiltrated leucocytes in tumour growth and spread

“…In breast cancers, this overexpression correlates with a strong leucocytic infiltration in over 95% of cases (Scholl et al, 1994). Similarly, the CC chemokine ligand 2 CCL2/MCP-1 (MCP ¼ monocyte chemoattractant protein 1) has been identified as a major chemokine for macrophages recruitment in several human tumours, including the bladder (Amann et al, 1998), cervix (Riethdorf et al, 1996), ovary (Negus et al, 1995), lung (Arenberg et al, 2000) and breast (Valkovic et al, 1998;Ueno et al, 2000). The level of CCL2/MCP-1 expression is correlated with the increased infiltration of macrophage (Ueno et al, 2000) and the grade of tumour (Amann et al, 1998;Valkovic et al, 1998).…”

Lactoferrin suppresses the Epstein–Barr virus-induced inflammatory response by interfering with pattern recognition of TLR2 and TLR9

“…33 Multiple human tumors have also been showed to express high levels of MCP-1, [34][35][36] and MCP-1 could promote tumor progression and metastasis as well. [37][38][39] The immune cells, such as monocytes/macrophages and dendritic cells, are important constitutes for the microenvironment. 10 These cells rapidly recognize a wide variety of molecules expressed by pathogens, such as EBV.…”

Monocyte chemoattractant protein‐1 expression correlates with macrophage infiltration and tumor vascularity in human esophageal squamous cell carcinomas

“…12,13 MCP-1 is produced by a variety of cells including fibroblasts, endothelial cells, smooth muscle cells and monocytes/macrophages. 14,15 In addition, breast, 16 -18 ovarian 19,20 and lung carcinoma 21 as well as malignant glioma 22 have also been reported to express MCP-1. Moreover, MCP-1 expression is associated with monocyte recruitment in human glioma, 22 breast, 17,18 ovarian 20 and prostate 23 carcinoma.…”