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• Significant UK variation exists for thymic epithelial tumour radiotherapy treatment. • Infrequent exposure limits clinician expertise managing thymic epithelial tumours. • The development of wider thymic epithelial tumour infrastructure is welcomed. Significant variation in treatment centre setup and radiotherapy practice for thymic epithelial tumours (TET) was identified through a comprehensive survey of current UK Clinical (Radiation) Oncology practice. Multi-centre collaboration and wider TET specific multidisciplinary team meetings are needed and will be essential for developing expertise in TET radiotherapy. [ABSTRACT FROM AUTHOR]

• CHART and hypofractionated accelerated radiotherapy remain deliverable, safe and effective schedules for NSCLC. • A median survival of 22.5 months and a 2-year survival of 48% demonstrate a continued need for improvement. • Earlier diagnosis and optimal treatment of co-morbidities is likely to help improve outcomes. • Dose escalation to improve outcomes is currently being investigated. Numerous fractionation regimes are used for inoperable NSCLC patients not suitable for stereotactic ablative radiotherapy. Continuous hyperfractionated accelerated radiotherapy (CHART, 54 Gy, 36 fractions over 12 days) and hypofractionated accelerated radiotherapy (55 Gy, 20 fractions over 4 weeks) are recommended UK schedules. In this single-centre retrospective analysis, we compare both fractionation schemes for patients treated at our institution from 2010 to 15. Clinical demographic, tumour and survival data were collected alongside radiotherapy dosimetric data from the Varian Eclipse Scripting application programming interface. Differences were assessed using independent samples t-tests. Multivariate survival analysis was performed using Cox regression. We identified 563 eligible patients; 43% received CHART and 57% hypofractionated radiotherapy. Median age was 71 years, 56% were male, 95% PET staged with 53% WHO performance status 0–1. 30%, 14%, 50% and 6% were stage I, II, III and IV, respectively. 38% of patients underwent induction chemotherapy. 99% completed their prescribed radiotherapy treatment. Overall response rate was 50% with a 6.5% 90-day mortality rate. Median disease-free survival was 19 months, 50% recurred locally. Median overall survival was 22.5 months with 48% alive at 2 years. Multivariate analysis identified histology, stage, performance status, chemotherapy and radiotherapy response as independent predictors of survival; no significant differences between radiotherapy regimes were observed. In our centre, CHART and hypofractionated accelerated radiotherapy produce similar outcomes. Dose escalation studies are in progress to develop these schedules to match outcomes reported in concurrent chemo-radiation studies. [ABSTRACT FROM AUTHOR]

Integrins are a family of cell-extracellular matrix adhesion molecules that play important roles in tumor angiogenesis. αvβ3-Integrin has received much attention as a potential anti-angiogenic target because it is upregulated in tumor-associated blood vessels. Agents targeting αvβ3-integrin are now showing some success in phase III clinical trails for the treatment of glioblastoma, but the exact function of this integrin in tumor angiogenesis is still relatively unknown. This review highlights some of the recent data illustrating that β3-integrins play both pro-angiogenic and anti-angiogenic roles in tumor angiogenesis depending on the context. Specifically we will discuss how the following differentially influence β3-integrin''s role in tumor angiogenesis: first, cell-matrix interactions, second, β3-integrin inhibitor doses, third, cell type, and fourth, other interacting molecules. [Copyright &y& Elsevier]

Endothelial cell migration is an essential aspect of tumor angiogenesis. Rac1 activity is needed for cell migration in vitro implying a requirement for this molecule in angiogenesis in vivo. However, a precise role for Rac1 in tumor angiogenesis has never been addressed. Here we show that depletion of endothelial Rac1 expression in adult mice, unexpectedly, has no effect on tumor growth or tumor angiogenesis. In addition, repression of Rac1 expression does not inhibit VEGF-mediated angiogenesis in vivo or ex vivo, nor does it affect chemotactic migratory responses to VEGF in 3-dimensions. In contrast, the requirement for Rac1 in tumor growth and angiogenesis becomes important when endothelial γ3-integrin levels are reduced or absent: the enhanced tumor growth, tumor angiogenesis and VEGF-mediated responses in γ3-null mice are all Rac1-dependent. These data indicate that in the presence of αvβ3-integrin Rac1 is not required for tumor angiogenesis. [ABSTRACT FROM AUTHOR]

Both vascular endothelial growth factor receptors (VEGFR) and integrins are major regulators of VEGF-induced angiogenesis. Previous work has shown that β3 integrin can regulate negatively VEGFR2 expression. Here we show that β3 integrin can regulate negatively VEGF-mediated angiogenesis by limiting the interaction of the co-receptor NRP1 (neuropilin-1) with VEGFR2. In the presence of avβ3 integrin, NRP1 contributed minimally to VEGF-induced angiogenic processes in vivo, ex vivo, and in vitro. Conversely, when β3 integrin expression is absent or low or its function is blocked with RGD-mimetic inhibitors, VEGF-mediated responses became NRP1-dependent. Indeed, combined inhibition of 133 integrin and NRP1 decreased VEGF-mediated angiogenic responses further than individual inhibition of these receptors. We also show that av133 integrin can associate with NRP1 in a VEGF-dependent fashion. Our data suggest that 133 integrin may, in part, negatively regulate VEGF signaling by sequestering NRP1 and preventing it from interacting with VEGFR2. [ABSTRACT FROM AUTHOR]

The article presents a single center retrospective analysis on the immunohistochemical prognostication in diffuse large B-cell lymphoma (DLBCL). It examines whether immunohistochemical subtyping can provide prognostic value in DLBCL, with progression-free survival and overall survival using Kaplan-Meier method. Treatments include intensive rituximab-based chemotherapy regimens, less intensive regimens or palliation, Hans algorithm for classifying diffuse large B-cell lymphoma subtypes.

Traces the presence of the White River tephra layer in peatlands to revise the known distribution of this late Holocene tephra into the Mackenzie Valley in Northwest Canada. Study of tephra-depositing events through the ash observation in peatlands; Detection of the ash species almost to the western shore of Great Slave Lake in Alaska; Use of tephra layers in chronostratigraphic marking.

Integrin trafficking to and from membrane adhesions is a crucial mechanism that dictates many aspects of a cell's behaviour, including motility, polarisation, and invasion. In endothelial cells (ECs), the intracellular traffic of α5 integrin is regulated by both neuropilin 1 (NRP1) and neuropilin 2 (NRP2), yet the redundancies in function between these co-receptors remain unclear. Moreover, the endocytic complexes that participate in NRP-directed traffic remain poorly annotated. Here we identify an important role for the GTPase-activating protein p120RasGAP in ECs, promoting the recycling of α5 integrin from early endosomes. Mechanistically, p120RasGAP enables transit of endocytosed α5 integrin-NRP1-NRP2 complexes to Rab11+ recycling endosomes, promoting cell polarisation and fibronectin (FN) fibrillogenesis. Silencing of both NRP receptors, or p120RasGAP, resulted in the accumulation of α5 integrin in early endosomes, a loss of α5 integrin from surface adhesions, and attenuated EC polarisation. Endothelial-specific deletion of both NRP1 and NRP2 in the postnatal retina recapitulated our in vitro findings, severely impairing FN fibrillogenesis and polarised sprouting. Our data assign an essential role for p120RasGAP during integrin traffic in ECs and support a hypothesis that NRP receptors co-traffic internalised cargoes. Importantly, we utilise comparative proteomics analyses to isolate a comprehensive map of NRP1-dependent and NRP2-dependent α5 integrin interactions in ECs. In vitro and in vivo data demonstrate that neuropilins regulate the trafficking of alpha5-integrin in endothelial cells. [ABSTRACT FROM AUTHOR]

Presents information on a study which described the generation and comparative phenotype of mice lacking selectins after ablation of the murine genes encoding P-, E-, and L-selectins. Construction of L-selectin targeting construct; Verification of null alleles; Discussion of the findings.

The ability to form a variety of cell‐matrix connections is crucial for angiogenesis to take place. Without stable anchorage to the extracellular matrix (ECM), endothelial cells (ECs) are unable to sense, integrate and disseminate growth factor stimulated responses that drive growth of a vascular bed. Neuropilin‐2 (NRP2) is a widely expressed membrane‐bound multifunctional non‐tyrosine kinase receptor, which has previously been implicated in influencing cell adhesion and migration by interacting with α5‐integrin and regulating adhesion turnover. α5‐integrin, and its ECM ligand fibronectin (FN) are both known to be upregulated during the formation of neo‐vasculature. Despite being descriptively annotated as a candidate biomarker for aggressive cancer phenotypes, the EC‐specific roles for NRP2 during developmental and pathological angiogenesis remain unexplored. The data reported here support a model whereby NRP2 actively promotes EC adhesion and migration by regulating dynamic cytoskeletal remodeling and by stimulating Rab11‐dependent recycling of α5‐integrin‐p‐FAK complexes to newly assembling adhesion sites. Furthermore, temporal depletion of EC‐NRP2 in vivo impairs primary tumor growth by disrupting vessel formation. We also demonstrate that EC‐NRP2 is required for normal postnatal retinal vascular development, specifically by regulating cell‐matrix adhesion. Upon loss of endothelial NRP2, vascular outgrowth from the optic nerve during superficial plexus formation is disrupted, likely due to reduced FAK phosphorylation within sprouting tip cells. [ABSTRACT FROM AUTHOR]

Purpose: To develop and apply an image acquisition and analysis strategy for spatial comparison of computed tomography (CT)-ventilation images with hyperpolarized gas magnetic resonance imaging (MRI).Methods and Materials: Eleven lung cancer patients underwent xenon-129 (129Xe) and helium-3 (3He) ventilation MRI and coregistered proton (1H) anatomic MRI. Expiratory and inspiratory breath-hold CTs were used for deformable image registration and calculation of 3 CT-ventilation metrics: Hounsfield unit (CTHU), Jacobian (CTJac), and specific gas volume change (CTSGV). Inspiration CT and hyperpolarized gas ventilation MRI were registered via same-breath anatomic 1H-MRI. Voxel-wise Spearman correlation coefficients were calculated between each CT-ventilation image and its corresponding 3He-/129Xe-MRI, and for the mean values in regions of interest (ROIs) ranging from fine to coarse in-plane dimensions of 5 × 5, 10 × 10, 15 × 15, and 20 × 20, located within the lungs as defined by the same-breath 1H-MRI lung mask. Correlation of 3He and 129Xe-MRI was also assessed.Results: Spatial correlation of CT-ventilation against 3He/129Xe-MRI increased with ROI size. For example, for CTHU, mean ± SD Spearman coefficients were 0.37 ± 0.19/0.33 ± 0.17 at the voxel-level and 0.52 ± 0.20/0.51 ± 0.18 for 20 × 20 ROIs, respectively. Correlations were stronger for CTHU than for CTJac or CTSGV. Correlation of 3He with 129Xe-MRI was consistently higher than either gas against CT-ventilation maps over all ROIs (P < .05). No significant differences were observed between CT-ventilation versus 3He-MRI and CT-ventilation versus 129Xe-MRI.Conclusion: Comparison of ventilation-related measures from CT and registered hyperpolarized gas MRI is feasible at a voxel level using a dedicated acquisition and analysis protocol. Moderate correlation between CT-ventilation and MRI exists at a regional level. Correlation between MRI and CT is significantly less than that between 3He and 129Xe-MRI, suggesting that CT-ventilation surrogate measures may not be measuring lung ventilation alone. [ABSTRACT FROM AUTHOR]

The maintenance of endothelial cell-cell junctions is vital for the control of blood vessel leakage and is known to be important in the growth and maturation of new blood vessels during angiogenesis. Here we have investigated the role of a tight junction molecule, Claudin14, in tumour blood vessel leakage, angiogenesis and tumour growth. Using syngeneic tumour models our results showed that genetic ablation of Claudin14 was not sufficient to affect tumour blood vessel morphology or function. However, and surprisingly, Claudin14-heterozygous mice displayed several blood vessel-related phenotypes including: disruption of ZO-1-positive cell-cell junctions in tumour blood vessels; abnormal distribution of basement membrane laminin around tumour blood vessels; increased intratumoural leakage and decreased intratumoural hypoxia. Additionally, although total numbers of tumour blood vessels were increased in Claudin14-heterozygous mice, and in VEGF-stimulated angiogenesis ex vivo, the number of lumenated vessels was not changed between genotypes and this correlated with no difference in syngeneic tumour growth between wild-type, Claudin14-heterozygous and Claudin14-null mice. Lastly, Claudin14-heterozygosity, but not complete deficiency, also enhanced endothelial cell proliferation significantly. These data establish a new role for Claudin14 in the regulation of tumour blood vessel integrity and angiogenesis that is evident only after the partial loss of this molecule in Claudin14-heterozyous mice but not in Claudin14-null mice. [ABSTRACT FROM AUTHOR]

Integrins are fundamental to the control of protrusion and motility in adherent cells. However, the mechanisms by which specific members of this receptor family cooperate in signaling to cytoskeletal and adhesion dynamics are poorly understood. Here, we show that the loss of .3 integrin in fibroblasts results in enhanced focal adhesion turnover and migration speed but impaired directional motility on both 2D and 3D matrices. These motility defects are coupled with an increased rate of actin-based protrusion. Analysis of downstream signaling events reveals that loss of β3 integrin results in a loss of protein kinase A-dependent phosphorylation of the actin regulatory protein vasodilator-stimulated phosphoprotein (VASP). Dephosphorylated VASP in β3-null cells is preferentially associated with Rap1-GTP-interacting adaptor molecule (RIAM) both in vitro and in vivo, which leads to enhanced formation of a VASP-RIAM complex at focal adhesions and subsequent increased binding of talin to β1 integrin. These data demonstrate a novel mechanism by which αvβ3 integrin acts to locally suppress β1 integrin activation and regulate protrusion, adhesion dynamics, and persistent migration. [ABSTRACT FROM AUTHOR]

The article presents a study on the cost effectiveness and growth rate effects of various plant container sizes for several tree species such as baldcypress, red maple, and longleaf pine. The study observes trees at two sites: Possum Branch Preserve and Brooker Creek Preserve in Pinelllas County, Florida. Oneway analysis of variance (ANOVA) was used to determine the differences among container sizes for height and canopy spread. It says that #3 container grown trees were the most-cost effective.

ADAMTS-1 is an extracellular protease with critical roles in organogenesis and angiogenesis. Here we demonstrate a functional convergence of ADAMTS-1 and the transmembrane heparan sulfate proteoglycan syndecan-4 in influencing adhesion, migration and angiogenesis. Knockdown of ADAMTS-1 in endothelial cells resulted in a parallel reduction in cell surface syndecan-4, attributable to increased matrix metalloproteinase-9 (MMP9) activity. Knockdown of either ADAMTS-1 or syndecan-4 increased cellular responses to vascular endothelial growth factor A isoformVEGFA164, and increased ex vivo aortic ring microvessel sprouting. On fibronectin, knockdown of either protein enhanced migration and promoted formation of long α5 integrin-containing fibrillar adhesions. However, integrin α5 null cells still showed increased migration in response to ADAMTS-1 and syndecan-4 siRNA treatment. Plating of naïve endothelial cells on cellconditioned matrix from ADAMTS-1 and syndecan-4 knockdown cells demonstrated that the altered adhesive behaviour was matrix dependent, and this correlated with a lack of expression of fibulin-1: an extracellular matrix co-factor for ADAMTS-1 that is known to inhibit migration. These findings support the notion that ADAMTS-1 and syndecan-4 are functionally interconnected in regulating cell migration and angiogenesis, via collaboration with MMP9 and fibulin-1. [ABSTRACT FROM AUTHOR]

Improvements in the understanding of the metabolic cross-talk between cancer and itsmicroenvironment are expected to lead to novel therapeutic approaches. Acute myeloid leukemia (AML) cells have increased mitochondria compared with nonmalignant CD34+ hematopoietic progenitor cells. Furthermore, contrary to the Warburg hypothesis, AML relies on oxidative phosphorylation to generate adenosine triphosphate. Here we report that in human AML, NOX2generates superoxide, which stimulates bonemarrow stromal cells (BMSC) toAMLblast transfer of mitochondria through AML-derived tunneling nanotubes. Moreover, inhibition of NOX2 was able to prevent mitochondrial transfer, increase AML apoptosis, and improve NSG AMLmouse survival. Although mitochondrial transfer fromBMSC to nonmalignant + cells occurs in response tooxidativestress,NOX2inhibitionhadnodetectable effectonnonmalignantCD34+cellsurvival.Taken together,we identify tumor-specific dependence on NOX2-driven mitochondrial transfer as a novel therapeutic strategy in AML. [ABSTRACT FROM AUTHOR]

Despite currently available therapies, most patients diagnosed with acute myeloid leukemia (AML) die of their disease. Tumor-host interactions are critical for the survival and proliferation of cancer cells; accordingly, we hypothesize that specific targeting of the tumor microenvironment may constitute an alternative or additional strategy to conventional tumor-directed chemotherapy. Because adipocytes have been shown to promote breast and prostate cancer proliferation, and because the bone marrow adipose tissue accounts for up to 70% of bone marrow volume in adult humans, we examined the adipocyte-leukemia cell interactions to determine if they are essential for the growth and survival of AML. Using in vivo and in vitro models of AML, we show that bone marrow adipocytes from the tumor microenvironment support the survival and proliferation of malignant cells from patients with AML. We show that AML blasts alter metabolic processes in adipocytes to induce phosphorylation of hormone-sensitive lipase and consequently activate lipolysis, which then enables the transfer of fatty acids from adipocytes to AML blasts. In addition, we report that fatty acid binding protein-4 (FABP4) messenger RNA is upregulated in adipocytes and AML when in coculture. FABP4 inhibition using FABP4 short hairpin RNA knockdown or a small molecule inhibitor prevents AML proliferation on adipocytes. Moreover, knockdown of FABP4 increases survival in Hoxa9/Meis1-driven AML model. Finally, knockdown of carnitine palmitoyltransferase IA in an AMLpatient-derived xenograft model improves survival. Here, we report the first description ofAML programming bone marrow adipocytes to generate a protumoral microenvironment. [ABSTRACT FROM AUTHOR]

Despite currently available therapies, most patients diagnosed with acute myeloid leukemia (AML) die of their disease. Tumor-host interactions are critical for the survival and proliferation of cancer cells; accordingly, we hypothesize that specific targeting of the tumor microenvironment may constitute an alternative or additional strategy to conventional tumor-directed chemotherapy. Because adipocytes have been shown to promote breast and prostate cancer proliferation, and because the bone marrow adipose tissue accounts for up to 70% of bone marrow volume in adult humans, we examined the adipocyte-leukemia cell interactions to determine if they are essential for the growth and survival of AML. Using in vivo and in vitro models of AML, we show that bone marrow adipocytes from the tumor microenvironment support the survival and proliferation of malignant cells from patients with AML. We show that AML blasts alter metabolic processes in adipocytes to induce phosphorylation of hormone-sensitive lipase and consequently activate lipolysis, which then enables the transfer of fatty acids from adipocytes to AML blasts. In addition, we report that fatty acid binding protein-4 (FABP4) messenger RNA is upregulated in adipocytes and AML when in coculture. FABP4 inhibition using FABP4 short hairpin RNA knockdown or a small molecule inhibitor prevents AML proliferation on adipocytes. Moreover, knockdown of FABP4 increases survival in Hoxa9/Meis1-driven AML model. Finally, knockdown of carnitine palmitoyltransferase IA in an AML patient-derived xenograft model improves survival. Here, we report the first description of AML programming bone marrow adipocytes to generate a protumoral microenvironment. [ABSTRACT FROM AUTHOR]

For nearly two decades now, the RGD (Arg-Gly-Asp)-binding αvβ3-integrin has been a focus of antiangiogenic drug design. These inhibitors are well-tolerated, but have shown only limited success in patients. Over the years, studies in β3-integrin-knockout mice have shed some light on possible explanations for disappointing clinical outcomes. However, studying angiogenesis in β3-integrin-knockout mice is a blunt tool to investigate β3-integrin’s role in pathological angiogenesis. Since establishing our laboratory at University of East Anglia (UEA), we have adopted more refined models of genetically manipulating the expression of the β3-integrin subunit. The present review will highlight some of our findings from these models and describe how data from them have forced us to rethink how targeting αvβ3-integrin expression affects tumour angiogenesis and cancer progression. Revisiting the fundamental biology behind how this integrin regulates tumour growth and angiogenesis, we believe, is the key not only to understanding how angiogenesis is normally co-ordinated, but also in success with drugs directed against it. [ABSTRACT FROM AUTHOR]

Down’s syndrome (DS) is a genetic disorder caused by full or partial trisomy of human chromosome 21 and presents with many clinical phenotypes including a reduced incidence of solid tumours. Recent work with the Ts65Dn model of DS, which has orthologues of about 50% of the genes on chromosome 21 (Hsa21), has indicated that three copies of the ETS2 (ref. 3) or DS candidate region 1 (DSCR1) genes (a previously known suppressor of angiogenesis) is sufficient to inhibit tumour growth. Here we use the Tc1 transchromosomic mouse model of DS to dissect the contribution of extra copies of genes on Hsa21 to tumour angiogenesis. This mouse expresses roughly 81% of Hsa21 genes but not the human DSCR1 region. We transplanted B16F0 and Lewis lung carcinoma tumour cells into Tc1 mice and showed that growth of these tumours was substantially reduced compared with wild-type littermate controls. Furthermore, tumour angiogenesis was significantly repressed in Tc1 mice. In particular, in vitro and in vivo angiogenic responses to vascular endothelial growth factor (VEGF) were inhibited. Examination of the genes on the segment of Hsa21 in Tc1 mice identified putative anti-angiogenic genes (ADAMTS1and ERG) and novel endothelial cell-specific genes, never previously shown to be involved in angiogenesis (JAM-B and PTTG1IP), that, when overexpressed, are responsible for inhibiting angiogenic responses to VEGF. Three copies of these genes within the stromal compartment reduced tumour angiogenesis, explaining the reduced tumour growth in DS. Furthermore, we expect that, in addition to the candidate genes that we show to be involved in the repression of angiogenesis, the Tc1 mouse model of DS will permit the identification of other endothelium-specific anti-angiogenic targets relevant to a broad spectrum of cancer patients. [ABSTRACT FROM AUTHOR]

Sprouting angiogenesis and lymphatic-blood vessel segregation both involve the migration of endothelial cells, but the precise migratory molecules that govern the decision of blood vascular endothelial cells to segregate into lymphatic vasculature are unknown. Here, we deleted endothelial Rac1 in mice (Tie1-Cre+;Rac1fl/fl) and revealed, unexpectedly, that whereas blood vessel morphology appeared normal, lymphatic-blood vessel separation was impaired, with corresponding edema, haemorrhage and embryonic lethality. Importantly, normal levels of Rac1 were essential for directed endothelial cell migratory responses to lymphatic-inductive signals. Our studies identify Rac1 as a crucial part of the migratory machinery required for endothelial cells to separate and form lymphatic vasculature. [ABSTRACT FROM AUTHOR]

Inhibitors of αvβ3 and αvβ5 integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic αvβ3 and αvβ5 inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering αvβ3 integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans. [ABSTRACT FROM AUTHOR]

Effective reepithelialization after injury is essential for correct wound healing. The upregulation of keratinocyte alpha3beta1 integrin during reepithelialization suggests that this adhesion molecule is involved in wound healing; however, its precise role in this process is unknown. We have shown here that retarded reepithelialization in Itga3(-/-) mouse skin wounds is due predominantly to repressed TGF-beta1-mediated responses. Specifically, expression of the inhibitor of TGF-beta1-signaling Smad7 was elevated in Itga3(-/-) keratinocytes. Indeed, in vivo blockade of Smad7 increased the rate of reepithelialization in Itga3(-/-) and WT wounds to similar levels. Our data therefore indicate that the function of alpha3beta1 integrin as a mediator of keratinocyte migration is not essential for reepithelialization but suggest instead that alpha3beta1 integrin has a major new in vivo role as an inhibitor of Smad7 during wound healing. Moreover, our study may identify a previously undocumented function for Smad7 as a regulator of reepithelialization in vivo and implicates Smad7 as a potential novel target for the treatment of cutaneous wounds. [ABSTRACT FROM AUTHOR]

Effective reepithelialization after injury is essential for correct wound healing. The upregulation of keratinocyte α3β1 integrin during reepithelialization suggests that this adhesion molecule is involved in wound healing; however, its precise role in this process is unknown. We have shown here that retarded reepithelialization in Itga3-/- mouse skin wounds is due predominantly to repressed TGF-β1-mediated responses. Specifically, expression of the inhibitor of TGF-β1-signaling Smad7 was elevated in Itga3-/- keratinocytes. Indeed, in vivo blockade of Smad7 increased the rate of reepithelialization in Itga3-/- and WT wounds to similar levels. Our data therefore indicate that the function of α3β1 integrin as a mediator of keratinocyte migration is not essential for reepithelialization but suggest instead that α3β1 integrin has a major new in vivo role as an inhibitor of Smad7 during wound healing. Moreover, our study may identify a previously undocumented function for Smad7 as a regulator of reepithelialization in vivo and implicates Smad7 as a potential novel target for the treatment of cutaneous wounds. [ABSTRACT FROM AUTHOR]

Inhibition of αvβ3 or αvβ5 integrin function has been reported to suppress neovascularization and tumor growth, suggesting that these integrins are critical modulators of angiogenesis. Here we report that mice lacking β3 integrins or both β3 and β5 integrins not only support tumorigenesis, but have enhanced tumor growth as well. Moreover, the tumors in these integrin-deficient mice display enhanced angiogenesis, strongly suggesting that neither β3 nor β5 integrins are essential for neovascularization. We also observed that angiogenic responses to hypoxia and vascular endothelial growth factor (VEGF) are augmented significantly in the absence of β3 integrins. We found no evidence that the expression or functions of other integrins were altered as a consequence of the β3 deficiency, but we did observe elevated levels of VEGF receptor-2 (also called Flk-1) in β3-null endothelial cells. These data indicate that αvβ3 and αvβ5 integrins are not essential for vascular development or pathological angiogenesis and highlight the need for further evaluation of the mechanisms of action of αv-integrin antagonists in anti-angiogenic therapeutics. [ABSTRACT FROM AUTHOR]

Enhanced blood vessel (BV) formation is thought to drive tumor growth through elevated nutrient delivery. However, this observation has overlooked potential roles for mural cells in directly affecting tumor growth independent of BV function. Here we provide clinical data correlating high percentages of mural-β3-integrin-negative tumor BVs with increased tumor sizes but no effect on BV numbers. Mural-β3-integrin loss also enhances tumor growth in implanted and autochthonous mouse tumor models with no detectable effects on BV numbers or function. At a molecular level, mural-cell β3-integrin loss enhances signaling via FAK-p-HGFR-p-Akt-p-p65, driving CXCL1, CCL2, and TIMP-1 production. In particular, mural-cell-derived CCL2 stimulates tumor cell MEK1-ERK1/2-ROCK2-dependent signaling and enhances tumor cell survival and tumor growth. Overall, our data indicate that mural cells can control tumor growth via paracrine signals regulated by β3-integrin, providing a previously unrecognized mechanism of cancer growth control. • Low mural-β3-integrin in tumor BVs is associated with poor prognosis in human cancers • Mural-β3-integrin loss enhances tumor growth in tumor models without vascular changes • Mural-β3-integrin loss upregulates FAK-p-HGFR-p-Akt-p-p65-driven cytokine production • Mural cell-derived CCL2 activates MEK1-ROCK2-dependent tumor growth Although enhanced blood vessel formation is thought to drive cancer via nutrient delivery, tumor-associated vasculature can directly regulate tumor cell growth via pericyte-derived "pericrine" signals without affecting blood vessel function. [ABSTRACT FROM AUTHOR]

The article discusses the role of alpha, gamma, beta3-integrin in controlling the tumour angiogenesis as angiogenesis is necessary for the growth of the tumour. It mentions that the findings of research have shown that endothelially-expressed beta3-integrin remains an authentic target of antiangiogenic tumour therapy. It also discusses the impact of the timing and length of exposure to beta3-integrin endothelial genetic inhibition on the angiogenic response.

A correction to the affiliation address of one of the authors in the article "Tumour angiogenesis is reduced in the Tc1 mouse model of Down's syndrome" that was published in the 2010 issue is presented.