Microenvironment and Immunology Myeloid Cell Receptor LRP1/CD91 Regulates Monocyte Recruitment and Angiogenesis in Tumors

Recruitment of monocytes into sites of inflammation is essential in the immune response. In cancer, recruited monocytes promote invasion, metastasis, and possibly angiogenesis. LDL receptor-related protein (LRP1) is an endocytic and cell-signaling receptor that regulates cell migration. In this study, we isografted PanO2 pancreatic carcinoma cells into mice in which LRP1 was deleted in myeloid lineage cells. Recruitment of monocytes into orthotopic and subcutaneous tumors was significantly increased in these mice, compared with control mice. LRP1-deficient bone marrow–derived macrophages (BMDM) expressed higher levels of multiple chemokines, including, most prominently, macrophage inflammatory protein-1a/CCL3, which is known to amplify inflammation. Increased levels of CCL3were detected in LRP1-deficient tumor-associatedmacrophages (TAM), isolated fromPanO2 tumors, and in RAW264.7macrophage-like cells inwhich LRP1was silenced. LRP1-deficient BMDMs migrated more rapidly than LRP1-expressing cells in vitro. The difference in migration was reversed by CCL3neutralizing antibody, by CCR5-neutralizing antibody, and by inhibiting NF-kB with JSH-23. Inhibiting NF-kB reversed the increase in CCL3 expression associated with LRP1 gene silencing in RAW 264.7 cells. Tumors formed in mice with LRP1-deficient myeloid cells showed increased angiogenesis. Although VEGF mRNA expression was not increased in LRP1-deficient TAMs, at the single-cell level, the increase in TAM density in tumors with LRP1-deficient myeloid cells may have allowed these TAMs to contribute an increased amount of VEGF to the tumor microenvironment. Our results show that macrophage density in tumors is correlated with cancer angiogenesis in a novel model system. Myeloid cell LRP1 may be an important regulator of cancer progression. Cancer Res; 73(13); 1–11. 2013 AACR.