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ADAM12, (A Disintegrin and metalloproteinase domain-containing protein 12), is upregulated in epithelial cancers and contributes to increased tumor proliferation, metastasis, and endocrine resistance. However, its role in tumor angiogenesis is unknown. Here, we report that ADAM12 is upregulated in the vessels of aggressive breast tumors and exerts key regulatory functions. ADAM12 significantly increases bFGF-mediated angiogenesis in vivo and ADAM12 levels are upregulated in tumors that have undergone a switch to the angiogenic phenotype. Importantly, ADAM12-overexpressing breast tumors display a higher microvessel density (MVD). Our goal was to identify the mechanisms by which tumor-associated ADAM12 promotes angiogenesis. ADAM12 expression in breast tumor cells correlated with a significant upregulation of proangiogenic factors such as VEGF and MMP-9 and downregulation of antiangiogenic factors such as Thrombospondin-1 (THBS1/TSP1) and Tissue Inhibitor of Metalloproteinases-2 (TIMP-2). Co-culture with ADAM12-expressing tumor cells promoted endothelial cell (EC) recruitment and capillary tube formation. Conversely, downregulation of endogenous ADAM12 in breast cancer cell lines resulted in reduction of pro-angiogenic factors and EC recruitment. These ADAM12-mediated effects are driven by the activation of EGFR, STAT3 and Akt signaling. Blockade of EGFR/STAT3 or silencing of ADAM12 reversed the proangiogenic tumor phenotype, significantly downregulated pro-angiogenic mitogens and reduced EC recruitment. In human breast cancer tissues, ADAM12 expression was significantly positively correlated with pro-angiogenic factors including VEGF and MMP-9 but negatively associated with TSP1.Implications: These novel findings suggest that ADAM12 regulates EC function and facilitates a proangiogenic microenvironment in a STAT3-dependent manner. A combined approach of targeting ADAM12 and STAT3 signaling in breast cancer may represent a promising strategy to inhibit tumor neovascularization. Mol Cancer Res; 15(11); 1608–22. ©2017 AACR.

Supplementary file includes the following Extended methods: Immunohistochemitry and Chondrosarcoma model Supplementary Table I: Reference genes and genes of interest for qRT-PCR analysis Supplementary Table II: List of differentially expressed angiogenic-regulator genes in ADAM12-expressing breast tumor cells (BTC) Suppl. Fig. 1: ADAM12 expression in EC Suppl. Fig. 2: Effect of metalloprotease inhibitor on EC recruitment by ADAM12-expressing BTC Suppl. Fig. 3: Effect of ADAM12 silencing on angiogenic regulator expression levels in BTC Suppl. Fig. 4: ADAM12 expression in T47-D cells results in upregulated VEGF levels and downregulated TSP1 and TIMP-2 levels Suppl. Fig. 5: Downregulation of endogenous ADAM12 expression in MDA-MB-436 Suppl. Fig. 6: mRNA expression correlation analysis of ADAM12 with angiogenic regulators in human breast tumor tissue Suppl. Fig. 7: pSTAT3 levels are upregulated in ADAM12-expressing T47-D and MDA-MB-231 BTC Suppl. Fig. 8: Downregulation of STAT3 and EGFR results in significant downregulation of EC recruitment by ADAM12-expressing BTC

ADAM12, (A Disintegrin and metalloproteinase domain-containing protein 12), is upregulated in epithelial cancers and contributes to increased tumor proliferation, metastasis, and endocrine resistance. However, its role in tumor angiogenesis is unknown. Here, we report that ADAM12 is upregulated in the vessels of aggressive breast tumors and exerts key regulatory functions. ADAM12 significantly increases bFGF-mediated angiogenesis in vivo and ADAM12 levels are upregulated in tumors that have undergone a switch to the angiogenic phenotype. Importantly, ADAM12-overexpressing breast tumors display a higher microvessel density (MVD). Our goal was to identify the mechanisms by which tumor-associated ADAM12 promotes angiogenesis. ADAM12 expression in breast tumor cells correlated with a significant upregulation of proangiogenic factors such as VEGF and MMP-9 and downregulation of antiangiogenic factors such as Thrombospondin-1 (THBS1/TSP1) and Tissue Inhibitor of Metalloproteinases-2 (TIMP-2). Co-culture with ADAM12-expressing tumor cells promoted endothelial cell (EC) recruitment and capillary tube formation. Conversely, downregulation of endogenous ADAM12 in breast cancer cell lines resulted in reduction of pro-angiogenic factors and EC recruitment. These ADAM12-mediated effects are driven by the activation of EGFR, STAT3 and Akt signaling. Blockade of EGFR/STAT3 or silencing of ADAM12 reversed the proangiogenic tumor phenotype, significantly downregulated pro-angiogenic mitogens and reduced EC recruitment. In human breast cancer tissues, ADAM12 expression was significantly positively correlated with pro-angiogenic factors including VEGF and MMP-9 but negatively associated with TSP1. Implications: These novel findings suggest that ADAM12 regulates EC function and facilitates a proangiogenic microenvironment in a STAT3-dependent manner. A combined approach of targeting ADAM12 and STAT3 signaling in breast cancer may represent a promising strategy to inhibit tumor neovascularization. Mol Cancer Res; 15(11); 1608–22. ©2017 AACR.

No previous studies have evaluated arts based recovery college courses. Yet arts may assist in personal recovery, as often defined by service users, through social connection and personal meaning. This interdisciplinary study evaluated (i) whether self-reported wellbeing and arts activities increased following arts based recovery college courses, and (ii) how students, peer trainers and artist-trainers understood courses&rsquo, impact. The design was mixed-methods. Of 42 service user students enrolling, 39 completed a course and 37 consented to provide data. Of these, 14 completed pre and post course questionnaires on mental wellbeing and 28 on arts participation. Post course focus groups were held with six of eight peer trainers and five of seven artist-trainers, and 28 students gave written feedback. Twenty-four students were interviewed up to three times in the subsequent nine months. There were statistically significant increases in self-reported mental wellbeing and range of arts activities following course attendance. At follow-up 17 of 24 students reported improved mental wellbeing, while seven reported little or no change. Some spoke of increased social inclusion and continuing to use skills learned in the course to maintain wellbeing. Initial in-course experience of &lsquo, artistic growth&rsquo, predicted follow-up reports of improvement. Future controlled studies should employ standardized measures of social inclusion and arts participation.

Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer.

An angiogenesis inhibitor named Beta-35 has been identified and purified from the conditioned medium of mouse pancreatic β cells tumor cells. Beta-35 has a molecular weight of 35 kDa and inhibits DNA synthesis of bovine capillary endothelial cells at a half-maximal concentration of approximately 5 nM. It shows anti-angiogenic activity in the chick embryo chorioallantoic membrane at a dose of about 1 μg/embryo. Amino acid microsequencing and mass spectrometric analysis of the purified protein demonstrate that Beta-35 contains the first 314 residues of the N-terminal sequence of bovine transferrin. We have cloned and expressed this protein in Escherichia coli using the corresponding gene segment of Beta-35 contained in the cDNA of human transferrin. The recombinant protein of Beta-35 shows significant anti-tumor activity at a dose of 5 mg/kg/day against human pancreatic cancer or melanoma implanted subcutaneously in SCID mice.

The epicardium makes essential cellular and paracrine contributions to the growth of the fetal myocardium and the formation of the coronary vasculature. However, whether the epicardium has similar roles postnatally in the normal and injured heart remains enigmatic. Here, we have investigated this question using genetic fate-mapping approaches in mice. In uninjured postnatal heart, epicardial cells were quiescent. Myocardial infarction increased epicardial cell proliferation and stimulated formation of epicardium-derived cells (EPDCs), which remained in a thickened layer on the surface of the heart. EPDCs did not adopt cardiomyocyte or coronary EC fates, but rather differentiated into mesenchymal cells expressing fibroblast and smooth muscle cell markers. In vitro and in vivo assays demonstrated that EPDCs secreted paracrine factors that strongly promoted angiogenesis. In a myocardial infarction model, EPDC-conditioned medium reduced infarct size and improved heart function. Our findings indicate that epicardium modulates the cardiac injury response by conditioning the subepicardial environment, potentially offering a new therapeutic strategy for cardiac protection.

Tissue inhibitors of metalloproteinases (TIMPs) regulate tumor growth, progression, and angiogenesis in a variety of experimental cancer models and in human malignancies. Results from numerous studies have revealed important differences between TIMP family members in their ability to inhibit angiogenic processes in vitro and angiogenesis in vivo despite their universal ability to inhibit matrix metalloproteinase (MMP) activity. To address these differences, a series of structure-function studies were conducted to identify and to characterize the anti-angiogenic domains of TIMP-2, the endogenous MMP inhibitor that uniquely inhibits capillary endothelial cell (EC) proliferation as well as angiogenesis in vivo. We demonstrate that the COOH-terminal domain of TIMP-2 (T2C) inhibits the proliferation of capillary EC at molar concentrations comparable with those previously reported for intact TIMP-2, while the NH2-terminal domain (T2N), which inhibits MMP activity, has no significant anti-proliferative effect. Interestingly, although both T2N and T2C inhibited embryonic angiogenesis, only T2C resulted in the potent inhibition of angiogenesis driven by the exogenous addition of angiogenic mitogen, suggesting that MMP inhibition alone may not be sufficient to inhibit the aggressive neovascularization characteristic of aberrant angiogenesis. We further mapped the anti-proliferative activity of T2C to a 24-amino acid peptide corresponding to Loop 6 of TIMP-2 and show that Loop 6 is a potent inhibitor of both embryonic and mitogen-stimulated angiogenesis in vivo. These findings demonstrate that TIMP-2 possesses two distinct types of anti-angiogenic activities which can be uncoupled from each other, the first represented by its MMP-dependent inhibitory activity which can inhibit only embryonic neovascularization and the second represented by an MMP-independent activity which inhibits both normal angiogenesis and mitogen-driven angiogenesis in vivo. In addition, we report, for the first time, the discovery of Loop 6 as a novel and potent inhibitor of angiogenesis.

Objectives:Several observations reported earlier indicated that the selectins, in particular E-selectin, might be involved in angiogenesis; however, mice deficient in the endothelial selectins develop normally. To clarify the role of endothelial selectins in angiogenesis, we have studied experimentally induced angiogenesis in selectin-deficient mice. Methods:Hydron pellets containing either basic fibroblast growth factor or the inflammatory cytokine tumor necrosis factor α were implanted into the corneas of wild-type and P- and/or E-selectin-deficient mice. Results:The lengths and circumferential range of the newly formed blood vessels in the corneas of the endothelial selectin-deficient mice were similar to those of wild-type mice. Conclusion:The endothelial selectins are not essential in experimentally induced angiogenesis in vivo.

Epoxyeicosatrienoic acids (EETs), lipid mediators produced by cytochrome P450 epoxygenases, regulate inflammation, angiogenesis, and vascular tone. Despite pleiotropic effects on cells, the role of these epoxyeicosanoids in normal organ and tissue regeneration remains unknown. EETs are produced predominantly in the endothelium. Normal organ and tissue regeneration require an active paracrine role of the microvascular endothelium, which in turn depends on angiogenic growth factors. Thus, we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.

Lipocalin 2 (Lcn2), a member of the lipocalin family, is up-regulated in a variety of epithelial cancers. We have previously reported that Lcn2 induces the epithelial to mesenchymal transition in breast cancer through the estrogen receptor α/Slug axis and that it is a potential noninvasive biomarker of this disease. Here, we report the novel finding that Lcn2 regulates breast cancer angiogenesis. Vascular endothelial growth factor (VEGF), a key angiogenic activator, was significantly increased with Lcn2 expression in MCF-7 human breast cancer cells as well as in an angiogenic line derived from MDA-MB-436 cells. Treatment with a VEGF-neutralizing antibody demonstrates that VEGF is essential for the angiogenic activity of Lcn2. We further demonstrate that Lcn2-induced VEGF is mediated through hypoxia-inducible factor 1α (HIF-1α) and that Lcn2 regulates HIF-1α through extracellular signal-regulated kinase (Erk). The regulation of HIF-1α and VEGF by Lcn2 was also demonstrated in the aggressive MDA-MB-231 cell line. Using the mouse corneal pocket assay, we found that Lcn2 significantly enhanced the angiogenesis induced by VEGF. Taken together, these results are the first to demonstrate that Lcn2 promotes angiogenesis in vitro and in vivo and suggest a novel mechanism through which Lcn2 may promote tumor progression.—Yang, J., McNeish, B., Butterfield, C., Moses, M. A. Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer.

We investigated the use of dietary omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) in the treatment of neuroblastoma both as a sole agent and in combination with sunitinib, a broad-spectrum tyrosine kinase receptor inhibitor.Substitution of all dietary fat with menhaden oil (ω-3 PUFA rich) resulted in a 40-70% inhibition of tumor growth and a statistically significant difference in the levels of several PUFAs (18:2 ω-6, 20:4 ω-6, 22:4 ω-6, 20:5 ω-3) as compared with a control diet. Furthermore, tumors from animals on the ω-3 fatty acid (FA)-enriched diet had an elevated triene/tetraene ratio suggestive of a change in local eicosanoid metabolism in these tissues similar to that seen with essential fatty acid deficiency. The ω-3 FA-enriched diet also decreased tumor-associated inflammatory cells and induced mitochondrial changes suggestive of mitochondrial damage. Combination treatment with sunitinib resulted in further reduction in tumor proliferation and microvessel density.These findings suggest a potential role for ω-3 PUFAs in the combination treatment of neuroblastoma.We used a murine model of orthotopic and subcutaneous human neuroblastoma and diets that differ in the FA content to define the optimal dietary ω-3/omega-6 (ω-6) FA ratio required for the inhibition of these tumors.

The chemotherapeutic agent etoposide is a topoisomerase II inhibitor widely used for cancer therapy. Low-dose oral etoposide, administered at close regular intervals, has potent anti-tumor activity in patients who are refractory to intravenous etoposide; however, the mechanism remains unclear. Since endothelial cells may be more sensitive than tumor cells to chemotherapy agents, we determined the effects of etoposide alone and in combination with oral cyclooxygenase-2 inhibitors and peroxisome-proliferator activated receptor γ ligands on angiogenesis and tumor growth in xenograft tumor models. Optimal anti-angiogenic (metronomic) and anti-tumor doses of etoposide on angiogenesis, primary tumor growth and metastasis were established alone and in combination therapy. Etoposide inhibited endothelial and tumor cell proliferation, decreased vascular endothelial growth factor (VEGF) production by tumor cells and suppressed endothelial tube formation at non-cytotoxic concentrations. In our in vivo studies, oral etoposide inhibited fibroblast growth factor 2 and VEGF-induced corneal neovascularization, VEGF-induced vascular permeability and increased levels of the endogenous angiogenesis inhibitor endostatin in mice. In addition, etoposide inhibited Lewis lung carcinoma (LLC) and human glioblastoma (U87) primary tumor growth as well as spontaneous lung metastasis in a LLC resection model. Furthermore, etoposide had synergistic anti-tumor activity in combination with celecoxib and rosiglitazone, which are also oral anti-angiogenic and anti-tumor agents. Etoposide inhibits angiogenesis in vitro and in vivo by indirect and direct mechanisms of action. Combining etoposide with celecoxib and rosiglitazone increases its efficacy and merits further investigation in future clinical trials to determine the potential usefulness of etoposide in combinatory anti-angiogenic chemotherapy.

Angiogenesis and inflammation are central processes through which the tumor microenvironment influences tumor growth. We have demonstrated recently that peroxisome proliferator-activated receptor (PPAR)alpha deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of thrombospondin (TSP)-1 and prevents tumor growth. Hence, we speculated that pharmacologic activation of PPARalpha would promote tumor growth. Surprisingly, the PPARalpha agonist fenofibrate potently suppressed primary tumor growth in mice. This effect was not mediated by cancer-cell-autonomous antiproliferative mechanisms but by the inhibition of angiogenesis and inflammation in the host tissue. Although PPARalpha-deficient tumors were still susceptible to fenofibrate, absence of PPARalpha in the host animal abrogated the potent antitumor effect of fenofibrate. In addition, fenofibrate suppressed endothelial cell proliferation and VEGF production, increased TSP-1 and endostatin, and inhibited corneal neovascularization. Thus, both genetic abrogation of PPARalpha as well as its activation by ligands cause tumor suppression via overlapping antiangiogenic pathways. These findings reveal the potential utility of the well tolerated PPARalpha agonists beyond their use as lipid-lowering drugs in anticancer therapy. Our results provide a mechanistic rationale for evaluating the clinical benefits of PPARalpha agonists in cancer treatment, alone and in combination with other therapies.

Inflammation in the tumor bed can either promote or inhibit tumor growth. Peroxisome proliferator-activated receptor (PPAR)alpha is a central transcriptional suppressor of inflammation, and may therefore modulate tumor growth. Here we show that PPARalpha deficiency in the host leads to overt inflammation that suppresses angiogenesis via excess production of the endogenous angiogenesis inhibitor thrombospondin-1 and prevents tumor growth. Bone marrow transplantation and granulocyte depletion show that PPARalpha expressing granulocytes are necessary for tumor growth. Neutralization of thrombospondin-1 restores tumor growth in PPARalpha-deficient mice. These findings suggest that the absence of PPARalpha activity renders inflammatory infiltrates tumor suppressive and, thus, may provide a target for inhibiting tumor growth by modulating stromal processes, such as angiogenesis.

Spatio-temporal studies on the growth of capillary blood vessels and capillary lymphatic vessels in tissue remodeling have suggested that lymphangiogenesis is angiogenesis-dependent. We revisited this concept by using fibroblast growth factor 2 (FGF-2) (80 ng) to stimulate the growth of both vessel types in the mouse cornea. When we lowered the dose of FGF-2 in the cornea 6.4-fold (12.5 ng), the primary response was lymphangiogenic. Further investigation revealed that vascular endothelial growth factor-C and -D are required for this apparent lymphangiogenic property of FGF-2, and when the small amount of accompanying angiogenesis was completely suppressed, lymphangiogenesis remained unaffected. Our findings demonstrate that there is a dose-dependent response of FGF-2 for lymphangiogenesis, and lymphangiogenesis can occur in the absence of a preexisting or developing vascular bed, i.e., in the absence of angiogenesis, in the mouse cornea.

The synthesis of a tris(hydroxymethyl)acrylamidomethane (THAM)-derived cotelomer endowed with thalidomide units and a preliminary assessment of its biological activity are described. 4-Carboxy thalidomide and 4-(N-acryloyl) lysine thalidomide derivatives were prepared. The polymerization of these compounds with THAM in the presence of octanethiol as transfer reagent provided a water-soluble telomer bearing several thalidomide units. The ability of this telomer to inhibit angiogenesis in a mouse model of corneal neovascularization was compared to 4-carboxy thalidomide and thalidomide. A significant inhibition in area of neovascularization stimulated by a bFGF pellet was observed only in the mice treated with the telomer.

Plaque angiogenesis promotes the growth of atheromas, but the functions of plaque capillaries are not fully determined. Neovascularization may act as a conduit for the entry of leukocytes into sites of chronic inflammation. We observe vasa vasorum density correlates highly with the extent of inflammatory cells, not the size of atheromas in apolipoprotein E-deficient mice. We show atherosclerotic aortas contain activities that promote angiogenesis. The angiogenesis inhibitor angiostatin reduces plaque angiogenesis and inhibits atherosclerosis. Macrophages in the plaque and around vasa vasorum are reduced, but we detect no direct effect of angiostatin on monocytes. After angiogenesis blockade in vivo , the angiogenic potential of atherosclerotic tissue is suppressed. Activated macrophages stimulate angiogenesis that can further recruit inflammatory cells and more angiogenesis. Our findings demonstrate that late-stage inhibition of angiogenesis can interrupt this positive feedback cycle. Inhibition of plaque angiogenesis and the secondary reduction of macrophages may have beneficial effects on plaque stability.

Among the earliest and most important stages during tumorigenesis is the activation of the angiogenic process, an event that is termed the “switch to the angiogenic phenotype.” We have developed an in vivo system that can reliably recapitulate the stages in tumor development that represent this transition. Using this model, we have harvested and studied tumor nodules that can be distinguished from each other on the basis of their degree of vascularization. Angiogenic tumor nodules were characterized by the presence of capillary vessels as determined by factor VIII immunohistochemistry, and both angiogenic and proteolytic activities in vitro . In contrast, preangiogenic nodules were devoid of microvessels and showed little angiogenic or proteolytic activity in vitro . Addition of a specific metalloproteinase inhibitor resulted in the abrogation of both angiogenic and proteolytic activities of the angiogenic nodules in vitro . Comparative substrate gel electrophoresis detected the presence of a prominent matrix metalloproteinase (MMP-2) in the angiogenic nodules when compared with the preangiogenic ones. Suppression of MMP-2 activity by antisense oligonucleotides in the vascular nodules resulted in the loss of angiogenic potential both in vitro and in vivo in the chick chorioallantoic membrane assay. Moreover, this suppression of MMP-2 activity in angiogenic nodules inhibited tumor growth in vivo by approximately 70%. These results strongly implicate the activity of MMP-2 as a requirement for the switch to the angiogenic phenotype and validate this model as a reliable and reproducible tool by which to study other cellular and biochemical factors involved in the acquisition of the angiogenic phenotype.

Using high-voltage and conventional electron microscopy of cell whole mounts, we have investigated the effects of tumor-conditioned medium and hypothalmus-derived growth factor on the structure of capillary endothelial cells during their attachment and spreading in tissue culture. Cells were cultured in A, Dulbecco's Modified Eagle's Medium (DMEM) and 10% calf serum; B, equal parts of A and 48 hr mouse sarcoma conditioned medium; and C, A containing 10 units of hypothalamus-derived growth factor. Cells cultured in all three media were fully spread, and to the same extent, by 4 hr after plating. While spreading, cells cultured in DMEM alone developed prominent stress fibers and contained numerous bundles of microtubules which formed radical tracts along which mitochondria and other organelles rapidly moved to the cell periphery. Stress fibers were thinner and microtubule tracts fewer in number in cells cultured in tumor-conditioned medium. In 4 hr, organelles moved only part of the distance to the cell margin. Stress fibers were rudimentary and microtubules randomly orientated in cells exposed to hypothalamus-derived growth factor. Most organelles remained near the cell nucleus. The dramatic decrease in stress fibers and microtubule tracts in cells grown in tumor-conditioned medium and hypothalamus-derived growth factor and the subsequent decreased capacity of the cells to move organelles toward their periphery could have some functional significance relative to the growth-promoting activity of these substances.

The need to strengthen health capacity in developing countries is widely documented. The World Health Organization has called for an increase in the number of health workers in all countries experiencing critical shortages, a significant scaling-up of training and more efficient use of existing health workers. Health Links, long-term mutually beneficial partnerships between UK health institutions and their counterparts in developing countries, are helping to fill these gaps. Links allow for the reciprocal transfer of knowledge and skills between partners, enabling the UK's expertise in health service delivery and training to be channelled towards the needs of those in developing countries, while also bringing a wide range of benefits to the UK. Examples of Health Links in Ethiopia demonstrate such benefits. An increasingly supportive policy environment is enabling a significant expansion in the number of Links. However, the quality of these Links is critical to their impact and thus there is a need both to continue to support those engaging in Links to develop sustainable, mutually beneficial strategic partnerships, and to strengthen the body of evidence of their impacts.