Tumor angiogenesis is an essential process for supplying rapidly growing malignant tissues with essential nutrients and oxygen. An angiogenic switch allows tumor cells to survive and grow, and provides them access to vasculature resulting in metastatic disease. Monocyte-derived macrophages recruited and reprogrammed by tumor cells serve as a major source of angiogenic factors boosting the angiogenic switch. Tumor endothelium releases angiopoietin-2 and further facilitates recruitment of TIE2 receptor expressing monocytes (TEM) into tumor sites. Tumor-associated macrophages (TAM) sense hypoxia in avascular areas of tumors, and react by production of angiogenic factors such as VEGFA. VEGFA stimulates chemotaxis of endothelial cells (EC) and macrophages. In some tumors, TAM appeared to be a major source of MMP9. Elevated expression of MMP9 by TAM mediates extracellular matrix (ECM) degradation and the release of bioactive VEGFA. Other angiogenic factors released by TAM include basic fibroblast growth factor (bFGF), thymidine phosphorylase (TP), urokinase-type plasminogen activator (uPA), and adrenomedullin (ADM). The same factors used by macrophages for the induction of angiogenesis [like vascular endothelial growth factor A (VEGF-A) and MMP9] support lymphangiogenesis. TAM can express LYVE-1, one of the established markers of lymphatic endothelium. TAM support tumor lymphangiogenesis not only by secretion of pro-lymphangiogenic factors but also by trans-differentiation into lymphatic EC. New pro-angiogenic factor YKL-40 belongs to a family of mammalian chitinase-like proteins (CLP) that act as cytokines or growth factors. Human CLP family comprises YKL-40, YKL-39, and SI-CLP. Production of all three CLP in macrophages is antagonistically regulated by cytokines. It was recently established that YKL-40 induces angiogenesis in vitro and in animal tumor models. YKL-40-neutralizing monoclonal antibody blocks tumor angiogenesis and progression. The role of YKL-39 and SI-CLP in tumor angiogenesis and lymphangiogenesis remains to be investigated.

Implants, transplants, and implantable biomedical devices are mainstream solutions for a wide variety of human pathologies. One of the persistent problems around nondegradable metallic and polymeric implants is failure of macrophages to resolve the inflammation and their tendency to stay in a state, named "frustrated phagocytosis." During the initial phase, proinflammatory macrophages induce acute reactions to trauma and foreign materials, whereas tolerogenic antiinflammatory macrophages control resolution of inflammation and induce the subsequent healing stage. However, implanted materials can induce a mixed pro/ anti-inflammatory phenotype, supporting chronic inflammatory reactions accompanied by microbial contamination and resulting in implant failure. Several materials based on natural polymers for improved interaction with host tissue or surfaces that release antiinflammatory drugs/bioactive agents have been developed for implant coating to reduce implant rejection. However, no definitive, long-term solution to avoid adverse immune responses to the implanted materials is available to date. The prevention of implant-associated infections or chronic inflammation by manipulating the macrophage phenotype is a promising strategy to improve implant acceptance. The immunomodulatory properties of currently available implant coatings need to be improved to develop personalized therapeutic solutions. Human primary macrophages exposed to the implantable materials ex vivo can be used to predict the individual's reactions and allow selection of an optimal coating composition. Our review describes current understanding of the mechanisms of macrophage interactions with implantable materials and outlines the prospects for use of human primary macrophages for diagnostic and therapeutic approaches to personalized implant therapy. J. Leukoc. Biol. 98: 953-962;