The cellular and molecular mechanisms by which a tumour cell undergoes metastasis to a predetermined location are largely unknown. Here we demonstrate that bone marrow-derived haematopoietic progenitor cells that express vascular endothelial growth factor receptor 1 (VEGFR1; also known as Flt1) home to tumour-specific pre-metastatic sites and form cellular clusters before the arrival of tumour cells. Preventing VEGFR1 function using antibodies or by the removal of VEGFR1(+) cells from the bone marrow of wild-type mice abrogates the formation of these pre-metastatic clusters and prevents tumour metastasis, whereas reconstitution with selected Id3 (inhibitor of differentiation 3)-competent VEGFR1+ cells establishes cluster formation and tumour metastasis in Id3 knockout mice. We also show that VEGFR1+ cells express VLA-4 (also known as integrin alpha4beta1), and that tumour-specific growth factors upregulate fibronectin--a VLA-4 ligand--in resident fibroblasts, providing a permissive niche for incoming tumour cells. Conditioned media obtained from distinct tumour types with unique patterns of metastatic spread redirected fibronectin expression and cluster formation, thereby transforming the metastatic profile. These findings demonstrate a requirement for VEGFR1+ haematopoietic progenitors in the regulation of metastasis, and suggest that expression patterns of fibronectin and VEGFR1+VLA-4+ clusters dictate organ-specific tumour spread.

The role of bone marrow (BM)-derived precursor cells in tumor angiogenesis is not known. We demonstrate here that tumor angiogenesis is associated with recruitment of hematopoietic and circulating endothelial precursor cells (CEPs). We used the angiogenic defective, tumor resistant Id-mutant mice to show that transplantation of wild-type BM or vascular endothelial growth factor (VEGF)-mobilized stem cells restore tumor angiogenesis and growth. We detected donor-derived CEPs throughout the neovessels of tumors and Matrigel-plugs in an Id1+/-Id3-/- host, which were associated with VEGF-receptor-1-positive (VEGFR1+) myeloid cells. The angiogenic defect in Id-mutant mice was due to impaired VEGF-driven mobilization of VEGFR2+ CEPs and impaired proliferation and incorporation of VEGFR1+ cells. Although targeting of either VEGFR1 or VEGFR2 alone partially blocks the growth of tumors, inhibition of both VEGFR1 and VEGFR2 was necessary to completely ablate tumor growth. These data demonstrate that recruitment of VEGF-responsive BM-derived precursors is necessary and sufficient for tumor angiogenesis and suggest new clinical strategies to block tumor growth.

Evidence has been gathered regarding the association between angiogenesis and inflammation in pathological situations. These two phenomena have long been coupled together in many chronic inflammatory disorders with distinct etiopathogenic origin, including psoriasis, rheumatoid arthritis, Crohn's disease, diabetes, and cancer. Lately, this concept has further been substantiated by the finding that several previously established non-inflammatory disorders, such as osteoarthritis and obesity, display both inflammation and angiogenesis in an exacerbated manner. In addition, the interplay between inflammatory cells, endothelial cells and fibroblasts in chronic inflammation sites, together with the fact that inflammation and angiogenesis can actually be triggered by the same molecular events, further strengthen this association. Therefore, elucidating the underlying cellular and molecular mechanisms that gather together the two processes is mandatory in order to understand their synergistic effect, and to develop new therapeutic approaches for the management of these disorders that cause a great deal of discomfort, disability, and in some cases death.

These data suggest that COX-2 expression is associated with angiogenesis, lymph node metastasis, and apoptosis in human breast cancer. Moreover, these results warrant further studies with larger series of patients to confirm the association with short disease free survival in patients with breast cancer.

AC133 is a member of a novel family of cell surface proteins with 5 transmembrane domains. The function of AC133 is unknown. Although AC133 mRNA is detected in different tissues, its expression in the hematopoietic system is restricted to CD34 ؉ stem cells. AC133 is also expressed on stem cells of other tissues, including endothelial progenitor cells. However, despite the potential importance of AC133 to the field of stem cell biology, nothing is known about the transcriptional regulation of AC133 expression. In this report we showed that the human AC133 gene has at least 9 distinctive 5-untranslated region (UTR) exons, resulting in the formation of at least 7 alternatively spliced 5-UTR isoforms of AC133 mRNA, which are expressed in a tissue-dependent manner. We found that transcription of these AC133 isoforms is controlled by 5 alternative promoters, and we demonstrated their activity on AC133-expressing cell lines using a luciferase reporter system. We also showed that in vitro methylation of 2 of these AC133 promoters completely suppresses their activity, suggesting that methylation plays a role in their regulation. Identification of tissue-specific AC133 promoters may provide a novel method to isolate tissuespecific stem and progenitor cells. (Blood.

Erectile dysfunction (ED) is a common complication of diabetes, affecting up to 75% of all diabetic men. Although the aetiology of diabetic ED is multifactorial, endothelial dysfunction is recognized as a mainstay in the pathophysiology of the disease. Endothelial dysfunction is induced by the detrimental actions of high glucose levels and increased oxidative stress on endothelial cells that make up the vascular lining. Besides directly injuring the endothelium, diabetes might also hamper vascular repair mechanisms of angiogenesis and vasculogenesis. These states exacerbate and maintain endothelial dysfunction, impairing vasorelaxation events and cavernosal blood perfusion, which are crucial for normal erectile function.

Introduction The endothelial monolayer plays a crucial role in the vasodilation and hemodynamic events involved in erection physiology. Due to its relevant functions, a close link has been established between endothelial integrity and erectile dysfunction (ED). Endothelial dysfunction is induced by the detrimental actions of vascular risk factors (VRFs), identified as common correlates for the development of cardiovascular disease and ED. It is currently recognized that ED is the early harbinger of a more generalized vascular systemic disorder, and, therefore, an evaluation of endothelial health in ED patients should be of prime relevance. Several noninvasive methods for endothelial function assessment have been proposed, including the Penile Nitric Oxide Release Test (PNORT). Aim To highlight the most recent gathered knowledge on basic and clinical mechanisms underlying loss of cavernosal endothelial function promoted by VRFs and to discuss local and systemic methods for endothelial function assessment in ED individuals, focusing on the PNORT. Main Outcome Measures A complete revision on the novel basic and clinical links between endothelial and ED. Methods A systematic review of the literature regarding the aforementioned issues. Results Risk factor-associated cavernosal endothelial dysfunction is mostly induced by unifying mechanisms, including oxidative stress and impaired endothelial nitric oxide functional activities, which present clinically as ED. Several techniques to evaluate endothelial dysfunction were revised, with advantages and limitations debated, focusing on our detailed expertise using the PNORT method. Conclusions The established endothelial–erectile dysfunction connection was thoroughly revised, from basic mechanisms to the clinical importance of endothelial dysfunction assessment as diagnosis for generalized vascular disease. Further studies are required to disclose efficient approaches to repair disabled endothelium and both restore and prevent endothelial dysfunction.

Quantifying the impact of air pollution on the public's health has become an increasingly critical component in policy discussion. Recent data indicate that more than 70% of the world population lives in cities. Several studies reported that current levels of air pollutants in urban areas are associated with adverse health risks, namely, cardiovascular diseases and lung cancer. IARC recently classified outdoor air pollution and related particulate matter (PM) as carcinogenic to humans. Despite the air quality improvements observed over the last few years, there is still continued widespread exceedance within Europe, particularly regarding PM and nitrogen oxides (NOx). The European Air Quality Directive 2008/50/EC requires Member States to design appropriate air quality plans for zones where air quality does not comply with established limit values. However, in most cases, air quality is only quantified using a combination of monitored and modeled data and no health impact assessment is carried out. An integrated approach combining the effects of several emission abatement measures on air quality, impacts on human health, and associated implementation costs enables an effective cost-benefit analysis and an added value to the decision-making process. Hence, this review describes the basic steps and tools for integrating health into air quality assessment (health indicators, exposure-response functions). In addition, consideration is given to two major outdoor pollutants: PM and NO2. A summary of the health metrics used to assess the health impact of PM and NO2 and recent epidemiologic data are also described.