Abstract
Tumors formed by a highly metastatic human lung cancer cell line are characterized by activated signaling via vascular endothelial growth factor (VEGF)-C through its receptor (VEGFR-3) and aggressive lymph node metastasis. In this study, we examined how these highly metastatic cancers acquired aggressive lymph node metastasis. Compared with their lower metastatic counterparts, the highly metastatic tumors formed by this cell line expressed higher amounts of interleukin (IL)-1α, with similarly augmented expression of IL-1α and IL-1β by tumor stromal cells and of VEGF-A and VEGF-C by tumor-associated macrophages. These tumor-associated macrophages were mainly of the M2 type. Administration of a macrophage-targeting drug suppressed the production of these potent angiogenic and lymphangiogenic factors, resulting in decreased tumor growth, angiogenesis, lymphangiogenesis, and lymph node metastasis. In Matrigel plug assays, the highly metastatic cells formed tumors that were extensively infiltrated by M2-type macrophages and exhibited enhanced angiogenesis and lymphangiogenesis. All of these responses were suppressed by the IL-1 receptor (IL-1R) antagonist anakinra. Thus, the IL-1α-driven inflammatory activation of angiogenesis and lymphangiogenesis seems to provide a highly metastatic tumor microenvironment favorable for lymph node metastasis through cross-talk with macrophages. Accordingly, the IL-1R/M2-type macrophage axis may be a good therapeutic target for patients with this form of lung cancer.
Highlights
The treatment of cancer patients is often complicated by tumor angiogenesis and lymphangiogenesis, which are closely associated with tumor metastasis and growth [1,2,3]
The angiopoietin/Tie2 pathway was activated in highly metastatic cells, and an angiopoietin 2-blocking antibody suppressed lung and lymph node metastasis [24]. These findings suggest that the induction of lung and lymph node metastasis, lymphangiogenesis, and tumor growth by highly metastatic lung cancer cells is mediated by enhanced expression of cyclooxygenase 2 (COX2), VEGFR-3-driven signaling, and angiopoietin
Quantitative analyses confirmed that the angiogenesis, lymphangiogenesis, and macrophage and neutrophil infiltration were significantly greater in the LNM35 tumors (Figure 1B)
Summary
The treatment of cancer patients is often complicated by tumor angiogenesis and lymphangiogenesis, which are closely associated with tumor metastasis and growth [1,2,3]. The angiopoietin/Tie pathway was activated in highly metastatic cells, and an angiopoietin 2-blocking antibody suppressed lung and lymph node metastasis [24] Taken together, these findings suggest that the induction of lung and lymph node metastasis, lymphangiogenesis, and tumor growth by highly metastatic lung cancer cells is mediated by enhanced expression of COX2, VEGFR-3-driven signaling, and angiopoietin. Our results show that IL-1-driven inflammatory signaling leads to recruitment of M2-type macrophages through induction of CXC chemokines by cancer cells, thereby promoting tumor growth and lymph node metastasis via tumor lymphangiogenesis and angiogenesis. We discuss whether targeting of IL-1/IL-1 receptor (IL-1R) and/or tumor-supporting M2-type macrophages will offer useful therapeutic strategies for inhibition of tumor growth and lymph node metastasis, through suppression of lymphangiogenesis and angiogenesis by lung cancer cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
