Non-small cell lung cancer cells induce monocytes to increase expression of angiogenic activity

Tumors are dependent on angiogenesis for survival and propagation. Accumula ted evidence suggests that macrophages are a potentially important source o f angiogenic factors in many disease states. However, the role(s) of macrop hages in non-small cell lung cancer (NSCLC) have not been determined. We hy pothesized that monocyte-derived macrophages are induced by NSCLC to increa se expression of angiogenic factors. To define the role of macrophage-tumor cell interaction with respect to angiogenesis, human peripheral blood mono cytes (PBM) were cocultured with A549 (human bronchoalveolar cell carcinoma ) or Calu 6 (human anaplastic carcinoma) NSCLC cells. The resultant conditi oned medium (CM) was evaluated for angiogenic potential and for expression of angiogenic factors. We found that endothelial cell chemotactic activity (as a measure of angiogenic potential) was significantly increased in respo nse to CM from cocultures of PBM/NSCLC compared with PBM alone, NSCLC alone , or a combination of NSCLC and PBM CM generated separately. Subsequent ana lysis by ELISA reveals markedly increased CXC chemokine expression, with a lesser increase in vascular endothelial growth factor, in CM from PBM/NSCLC coculture. Neutralizing Ab to angiogenic CXC chemokines blocked the increa se in endothelial cell chemotaxis. Furthermore, with separately generated C M as a stimulus, we found that macrophages are the predominant source of in creased CXC chemokine expression. Finally, we found that NSCLC-derived macr ophage migration-inhibitory factor is responsible for the increased express ion of macrophage-derived angiogenic activity. These data suggest that the interaction between host macrophages and NSCLC cells synergistically increa ses angiogenic potential, and that this is due to an increased elaboration of angiogenic CXC chemokines.