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The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.

Tumor-associated macrophages have protumoral functions Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the primary and metastatic tumor microenvironments (TMEs). In most cases in human cancers, their [...], Tumor-associated macrophages (TAMs) promote metastasis and tumor cell extravasation, survival, and growth. In hepatocellular carcinoma (HCC), the presence of TAM subpopulations correlates with poor outcome. In this issue of the JCI, Ning et al. report on their use of cell culture, mouse models, and human data sets to investigate the interactions between aerobic glycolysis and carbonic anhydrase XII (CA12) expression in HCC. Aerobic glycolysis promoted CA12 upregulation in TAMs, which induced a protumoral phenotype to promote tumor growth and metastasis. Tumor cell factors derived from HCC samples induced CA12 upregulation in tumor-infiltrating TAMs via the HIF1[alpha] pathway. In preclinical models of HCC, CA12 inhibition reduced tumor growth and lung metastasis and reduced TAM infiltrate. Notably, dual treatment with anti-PD1 and CA12 inhibitors synergistically attenuated tumor growth and metastasis and enhanced survival compared with either treatment alone. These findings suggest that targeting CA12 in combination with immune-checkpoint blockade may provide treatment options for HCC.

Author(s): Alice Plein [sup.1] , Alessandro Fantin [sup.1] , Laura Denti [sup.1] , Jeffrey W. Pollard [sup.2] , Christiana Ruhrberg [sup.1] Author Affiliations:(1) UCL Institute of Ophthalmology, University College London, [...], The earliest blood vessels in mammalian embryos are formed when endothelial cells differentiate from angioblasts and coalesce into tubular networks. Thereafter, the endothelium is thought to expand solely by proliferation of pre-existing endothelial cells. Here we show that a complementary source of endothelial cells is recruited into pre-existing vasculature after differentiation from the earliest precursors of erythrocytes, megakaryocytes and macrophages, the erythro-myeloid progenitors (EMPs) that are born in the yolk sac. A first wave of EMPs contributes endothelial cells to the yolk sac endothelium, and a second wave of EMPs colonizes the embryo and contributes endothelial cells to intraembryonic endothelium in multiple organs, where they persist into adulthood. By demonstrating that EMPs constitute a hitherto unrecognized source of endothelial cells, we reveal that embryonic blood vascular endothelium expands in a dual mechanism that involves both the proliferation of pre-existing endothelial cells and the incorporation of endothelial cells derived from haematopoietic precursors.New blood vessel endothelial cells arise from differentiation of erythro-myeloid progenitor cells to complement the proliferation of pre-existing endothelial cells.

When treatment also promotes disease A century after Virchow hypothesized the association between inflammation and cancer, it is becoming evident that inflammatory mediators lead to cancer progression and metastasis (1). [...], In this issue of the JCI, Panigrahy et al. demonstrate that preoperative administration of the antiinflammatory drug ketorolac or specialized proresolving mediators (SPM) called resolvins increases disease-free survival rates and prevents metastasis after surgery and chemotherapy in mouse models of cancer. The antitumor response was partially mediated by tumor- specific T cell immunity and immunological memory.

Macrophages, which were originally identified by Metchnikoff on account of their phagocytic nature, are ancient cells in metazoan phylogeny. In adult mammals, they are found in all tissues where they [...], Macrophages, the most plastic cells of the haematopoietic system, are found in all tissues and show great functional diversity. They have roles in development, homeostasis, tissue repair and immunity. Although tissue macrophages are anatomically distinct from one another, and have different transcriptional profiles and functional capabilities, they are all required for the maintenance of homeostasis. However, these reparative and homeostatic functions can be subverted by chronic insults, resulting in a causal association of macrophages with disease states. In this Review, we discuss how macrophages regulate normal physiology and development, and provide several examples of their pathophysiological roles in disease. We define the 'hallmarks' of macrophages according to the states that they adopt during the performance of their various roles, taking into account new insights into the diversity of their lineages, identities and regulation. It is essential to understand this diversity because macrophages have emerged as important therapeutic targets in many human diseases.

To understand the origin of macrophages in primary tumours and their metastatic sites, we measured monocyte trafficking. Mouse monocytes were identified by their expression of CD11b and CD115 (Supplementary Fig. [...], Macrophages, which are abundant in the tumour microenvironment, enhance malignancy [1]. At metastatic sites, a distinct population of metastasis-associated macrophages promotes the extravasation, seeding and persistent growth of tumour cells [2]. Here we define the origin of these macrophages by showing that Gr1-positive inflammatory monocytes are preferentially recruited to pulmonary metastases but not to primary mammary tumours in mice. This process also occurs for human inflammatory monocytes in pulmonary metastases of human breast cancer cells. The recruitment of these inflammatory monocytes, which express CCR2 (the receptor for chemokine CCL2), as well as the subsequent recruitment of metastasis-associated macrophages and their interaction with metastasizing tumour cells, is dependent on CCL2 synthesized by both the tumour and the stroma. Inhibition of CCL2-CCR2 signalling blocks the recruitment of inflammatory monocytes, inhibits metastasis invivoand prolongs the survival of tumour-bearing mice. Depletion of tumour-cell-derived CCL2 also inhibits metastatic seeding. Inflammatory monocytes promote the extravasation of tumour cells in a process that requires monocyte-derived vascular endothelial growth factor. CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer [3-6]. Our data provide the mechanistic link between these two clinical associations and indicate new therapeutic targets for treating metastatic breast cancer.

Placental viviparity, a mode of reproduction during which nutrients are supplied to the embryo directly from the mother via the placenta, poses a number of challenges. The first is the [...], Successful embryo implantation requires complex interactions between the uterus and embryo, including the establishment of maternal immunologic tolerance of fetal material. The maternal-fetal interface is dynamically populated by a wide variety of innate immune cells; however, the relevance of uterine DCs (uDCs) within the decidua to the success of implantation has remained unclear. In this issue of the JCI, Plaks et al. show, in a transgenic mouse model, that uDCs are essential for pregnancy, as their ablation results in a failure of decidualization, impaired implantation, and embryonic resorption (see the related article beginning on page 3954). Depletion of uDCs altered decidual angiogenesis, suggesting that uDCs contribute to successful implantation via their effects on decidual tissue remodeling, including angiogenesis, and independent of their anticipated role in the establishment of maternal-fetal tolerance.

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2006.01.007 Byline: John Condeelis (1)(2), Jeffrey W. Pollard (3)(4) Abstract: Macrophages within the tumor microenvironment facilitate angiogenesis and extracellular-matrix breakdown and remodeling and promote tumor cell motility. Recent studies reveal that direct communication between macrophages and tumor cells leads to invasion and egress of tumor cells into the blood vessels (intravasation). Thus, macrophages are at the center of the invasion microenvironment and are an important drug target for cancer therapy. Author Affiliation: (1) Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA (2) Analytical Imaging Facility, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA (3) Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA (4) Department of Obstetrics & Gynecology and Women's Health, Center for the Study of Reproductive Biology and Women's Health, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA