Rotary Cell Culture System

The rotary cell culture system is a device designed to grow 3D cells clusters (tissue, cancer tumors and virus cultures) in microgravity (outside the body). The advantage here is to obtain larger and 3D cell cultures with structural and chemical characteristics similar to normal tissue, in comparison with lab-grown cell cultures.

It allows to test chemotherapy agents on a patient’s own cancer cells ex vivo.

Hematology

Our Hematology Center is:

  • A tertiary academic hematology center involved in quality clinical care for patients, in academic and industry-driven clinical research and in major international disease-oriented academic networks
  • The second major Hematopoietic Stem Cell (HSC) transplant center in Belgium, performing autologous and allogeneic transplantation with unmanipulated or purified HSC from the bone marrow, peripheral blood or cord blood after myeloablative or non-myeloablative conditioning, with a strong emphasis on clinical and translational research

It encompasses:

  • 24-bed hematology ward, 7-bed transplant ward, 40-bed oncology daycare facility (shared with oncology), > 30 half-days of consultation
  • > 8.500 inpatient hospitalization days, > 5.500 daycare hospital visits & >14.500 outpatient consultations on a yearly basis
  • > 50 allogeneic HSC transplantations and > 35 autologous HSC transplantations per year
  • Collection, processing and storage of autologous or allogeneic: bone marrow (35/year); apheresis products (200/year); cord blood units (500-1.000/year)
  • Minimal processing of cellular products: red cell removal, cell selection (CD34, AC133, Treg) and depletion (CD8, CD2), freezing & thawing
  • Production of cellular ATMP (Advanced Therapeutic Medicinal Products): mesenchymal stem cells, preosteoblasts, dendritic cells

Looking for clinical advice or support, or preparing for a clinical study? We will help you set up a cost-effective and time-efficient study! Get in touch with our experts [info@b2h.be].

Hematopoietic stem cell transplantation (HSCT) remains the treatment of choice for many hematological malignancies. The success of HSCT relies on a long-term complete immune reconstitution in the patient after the transplantation.

Several factors can affect the efficacy of HSCT such as the patient’s age and the initial disease, the source of cells and the degree of compatibility of the transplant. In fact, a suboptimal degree of compatibility may cause the emergence of graft-versus-host disease, a possible adverse effect of HSCT. Following transplantation a de novo production of mature lymphocytes will occur. This process is called immune recovery.

Unfortunately, thyme recovery, a central part of the immune recovery process, is a slow process and the degree at which it occurs is affected by the conditioning regimen administered to the patient before the transplantation procedure and by the occurrence of graft-versus-host disease.

IGF-1 is a key mediator of the somatotropic axis (Ghrh-GH-IGF-1) and plays crucial roles in many metabolic processes. Interestingly, IGF-1 can also act on the thymus and influence lymphocyte production.

Researchers at GIGA and CHU are investigating the impact of IGF-1 on thymic recovery in the context of allogeneic HCST.

The second part of their research is focused on the treatment of chronic GVHD with different immunosuppressive drugs. After treatment, clinicians aim at making a distinction between the effects of these drugs on thymic recovery and on cGVHD itself.

This will lead to a better insight into how these drugs function in patients with cGVHD.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward to collaborating with you!

Allogeneic hematopoietic cell transplantation (allo-HCT) following a high or reduced dose-conditioning regimen is an usual treatment option for many patients with hematological disorders. Unfortunately, two major complications, infections and/or graft-versus-host disease (GVHD), compromise too frequently the survival or the quality of life of these patients.

Clinicians at CHU are studying the immune reconstitution after conventional or mini – Allo-HSCT in several trials comparing different kinds of conditioning or immunosuppressive treatments…

The goal of these studies is to develop new treatment strategies to improve thymo-dependent immune recovery (in particular in older patients) and so to reduce the infection rate and the GVHD risk.

Another part of their research focus is on the implication of T-reg in GVHD. In particular, a clinical trial is ongoing to compare the clinical and immunological impact on steroid refractory chronic GVHD of the infusion (or not) of donor T-reg after a treatment with rapamycin. This project is realized in collaboration with the KU Leuven.

Looking for clinical advice or support, or preparing for a clinical study? We will help you set up a cost-effective and time-efficient study! Get in touch with our experts [info@b2h.be].

Hematopoietic stem cell transplantation offers potential curative treatment for a wide range of hematological diseases. This therapeutic approach must face multiple challenges. The primary aim is obviously to control the underlying disease. However, the success of hematopoietic stem cell transplantation also relies on complete recovery of hematopoietic functions, limitation of transplant-related toxicity and morbidity and reconstitution of a fully efficient adaptive immune system at long-term. Several pre-transplant factors (such as patient-, disease-, transplant or graft-related factors) may condition the long-term success of hematopoietic stem cell transplantation.

Researchers at GIGA and CHU assess the effects of 1) graft’s source (bone marrow versus peripheral blood versus cord blood), 2) donor’s characteristics, 3) graft’s composition and 4) graft’s modulation on post-transplant outcomes.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward to collaborating with you!

Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective treatment for many hematological malignancies, but patients have prolonged anemia after transplantation. This anemia is facilitated by a relative erythropoietin (Epo) deficiency and patients may benefit from treatment with recombinant human erythropoietin (RhEPO).

Iron metabolism has not been extensively studied after HSC transplantation, with only a few publications including hepcidin (the key regulator of iron metabolism). Post-transfusional iron overload decreases only slowly after transplantation. In addition, after conditioning, ferritin levels are markedly elevated before progressively declining. Iron overload has also been associated with early and late hepatic complications, veno-occlusive disease, infections, relapse and decreased survival.

Researchers and clinicians at GIGA aim at determining the predictive factors of response to RhEPO in patients undergoing allo-HCT. In addition, they (1) analyze hepcidin evolution following allo-HCT (after conditioning, during aplasia, during erythropoiesis recovery; relationships with iron overload and inflammation); (2) evaluate the prognostic value of pre-transplant ferritin values on various transplant outcome and toxicities, in relation with the type of conditioning (myeloablative or not); (3) follow the evolution of iron overload after allo-HCT and the impact of iron chelation; (4) evaluate the pathophysiological significance of ferritin levels following allo-HCT. Several parts of this project are undertaken in collaboration with the Hospital Center of Lyon-Sud.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward to collaborating with you!

Clinicians at CHU have developed the ULICE program for autologous and allogeneic Hematopoietic Stem Cell (HSC) transplantation with family or unrelated marrow, peripheral blood or cord blood for malignant, genetic and other hematological disorders. The program is the second in size in Belgium (±100 transplants/year) and has received the international JACIE accreditation.

Clinicians have also expertise in the investigation of immune functions after HSC transplantation or in certain forms of cell therapy. For more information, click here.

Looking for clinical advice or support, or preparing for a clinical study? We will help you set up a cost-effective and time-efficient study! Get in touch with our experts [info@b2h.be].

Tumor growth

After irradiation, the tumor is daily measured to determine the mean diameter, or volume. Unirradiated tumors will grow continuously whereas irradiated tumors show some shrinkage or delayed growth, then regrow. The measured score is growth delay or time to grow to a specified size in function of the received dose.

Contact [info@b2h.be] us to discuss how these capabilities can forward your projects! We will help you develop tailored solutions.

Tumor control (TCD50 assay) provides data of most obvious relevance to radiotherapy. In experiments, animals with tumors of uniform size are irradiated locally with graded doses. The tumors subsequently are observed regularly for recurrence or local control. The proportion of tumors that are locally controlled can be plotted as a function of dose, and data of this kind are amenable to a statistical analysis to determine the TCD50, the dose at which 50% of the tumors are locally controlled.

Contact [info@b2h.be] us to discuss how these capabilities can forward your projects! We will help you develop tailored solutions.

Angiogenesis

ear sponge assayIn this model, a polymer matrix (in the form of a sponge or a Matrigel gel/plug) containing cells and/or an angiogenic factor is implanted between the two skin layers of mice ear.

The test substance is directly injected into the sponge.

Neovascularization can then be assessed by a variety of methods including immunohistological staining or by evaluation of the blood/hemoglobin content of the sponge.

Contact [info@b2h.be] us to discuss how these capabilities can forward your projects! We will help you develop tailored solutions.

choroidal neovascularization modelThe Choroidal neovascularization model relies on laser injury to perforate Bruch’s membrane, resulting in subretinal blood vessel recruitment from the choroid.

By recapitulating the main features of the exudative form of human age-related macular degeneration, this assay serves for the backbone for testing antiangiogenic therapies.

The protocol is outlined in the published article Lambert V. et al., Nature protocols (2013), 8.

Contact [info@b2h.be] us to discuss how these capabilities can forward your projects! We will help you develop tailored solutions.

Glioblastoma

Researchers at GIGA have demonstrated the role of osteopontin in the tumorigenicity of glioblastoma cells and its importance in the maintenance of the stem characters.

Their recent studies focused on the potential role of osteopontin in the resistance of glioblastoma cells to radiotherapy and its implication in the initiation of Double Strand Breaks repair mechanism.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have identified a novel histone deacetylase inhibitor (HDACi) (N-Hydroxy-6-(5-nitro-naphtalimide)-hexanamide: ES8) that efficiently inhibits angiogenesis in relevant ex vivo models (Human umbilical vein endothelial cells (HUVEC), 3D aortic ring assay) and in vivo (chick chorioallantoic membrane (CAM), Zebrafish).

Transcriptomic profiling reveals a set of ES8 specific genes that are not affected by the prototypical HDACi suberoylanilide hydroxamic acid (SAHA).

In addition, they have shown that ES8 also reduced tumor growth in small cell lung cancer mouse models.

Availability of a novel compound not centered exclusively on inhibition of angiogenic factors and inducing a characteristic transcription profile may be of interest to overcome resistance to currently used chemotherapies.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

The anti-angiogenic effect of IK9 was demonstrated in vivo in a choroidal neovascularization mice model and additionally ex vivo in a rat aortic ring assay where it was more active than the known matrix metalloproteinase inhibitor Ro 28-2653. IK9 did not affect apoptosis, proliferation, or endothelial cell invasiveness in vitro.

These findings suggest its potential use as a therapeutic agent.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen molecules by excising the aminopropeptide.

Researchers at GIGA demonstrated that ADAMTS-2 is able to reduce proliferation of endothelial cells in vitro and to induce their retraction and detachment from the substrate resulting in apoptosis.

In 3-D culture models, ADAMTS-2 strongly reduced branching of capillary-like structures formed by endothelial cells and their long-term maintenance and inhibited vessels formation in embryos bodies.

The anti-angiogenic properties of ADAMTS-2 were also observed in vivo, in a choroidal neovascularization model in which a reproducible and significant increase of neovascularization was observed in ADAMTS-2-/- mice compared to wild-type animals.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have shown by knocking down the urokinase plasminogen activator receptor (uPAR) in human umbilical vein endothelial cells (HUVECs) impaired VEGFR2 signaling.

In addition, they demonstrated that upon exposure of HUVECs to VEGF, uPAR recruited the low-density lipoprotein receptor-related protein 1 (LRP-1) inducing VEGFR2 internalization.

Researchers have also observed that uPAR deficiency in mice prevented VEGF-induced angiogenesis.

Taken together these data demonstrated that uPAR is crucial for VEGF signaling and that this interaction promoted angiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Exosomes are small vesicles composed of RNAs, microRNAs and soluble and membranous proteins. These organelles seem to play a key role in intercellular communication via the transfer of their molecular contents. Moreover, tumor exosomes are able to modulate the tumor microenvironment by activating angiogenesis, promoting the formation of cancer-associated fibroblasts (CAFs) and modulating the immune response. We can produce, isolate, purify and characterize exosomes, thanks to various differential centrifugation techniques.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Dentin matrix protein 1 (DMP1) is a member of the Small Integrin-Binding LIgand N-linked Glycoproteins (SIBLINGs) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis.

Researchers at GIGA demonstrated that this extracellular matrix protein induced the expression of VE-cadherin, a key regulator of intercellular junctions and contact inhibition of growth endothelial cells growth.

They showed that DMP1 induced VE-cadherin and p27(Kip1) expression followed by cell cycle arrest in human umbilical vein endothelial cells (HUVEC) in a CD44-dependent manner.

VEGF-induced proliferation, migration and tubulogenesis responses were specifically blocked upon DMP1 pre-treatment of HUVEC.

In vivo, the researchers observed that DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis.

Taken together these data identify this protein as a new specific inhibitor of VEGF-induced angiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have identified that shorter peptides derived from 16k prolactin can also inhibit angiogenesis in vivo and in vitro.

The ability of 16K prolactin to prevent neovascularization was analyzed in several models of physiological angiogenesis (CAM assay), pathological (retinopathy) and several tumor models.

Furthermore the 16K prolactin treatment was shown to prevent the development of a normally functioning tumor vasculature by impairing vessel maturation and disrupting lymphangiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

The development of blood vessels inside tumors is required to provide the nutrients and oxygen is needed for tumor growth and to allow the spread of cancer cells at a distance to form metastasis.

Researchers at CIRM have identified a new anti-angiogenic potency of coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9) as a new potent inhibitor of angiogenesis and suggested its potential use as a therapeutic agent.

Pancreas cancer

Researchers at GIGA have identified a novel histone deacetylase inhibitor (HDACi) (N-Hydroxy-6-(5-nitro-naphtalimide)-hexanamide: ES8) that efficiently inhibits angiogenesis in relevant ex vivo models (Human umbilical vein endothelial cells (HUVEC), 3D aortic ring assay) and in vivo (chick chorioallantoic membrane (CAM), Zebrafish).

Transcriptomic profiling reveals a set of ES8 specific genes that are not affected by the prototypical HDACi suberoylanilide hydroxamic acid (SAHA).

In addition, they have shown that ES8 also reduced tumor growth in small cell lung cancer mouse models.

Availability of a novel compound not centered exclusively on inhibition of angiogenic factors and inducing a characteristic transcription profile may be of interest to overcome resistance to currently used chemotherapies.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

DUSP3, also called Vaccinia-H1 Related (VHR) is a small dual specificity phosphatase dephosphorylating both tyrosine and serine/threonine phosphorylated residues. DUSP3 plays an important role in cell cycle regulation and is up-regulated in several human cancers. The physiological role of this phosphatase is, however, poorly understood.

Researchers at GIGA have generated a DUSP3 knockout mouse by homologous recombination.

Using this transgenic mouse model, they have observed that DUSP3 plays an important role in metastatic dissemination/growth by a mechanism involving the control of chemokine ligand 2 (CCR2) – chemokine receptor 2 (CCL2) chemoattraction axis in macrophages.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Pancreatic ductal adenocarcinoma is the fourth leading cause of cancer death worldwide, with no satisfactory treatment to date.

Researchers at GIGA have tested the potential anti-tumoral activity of combined inhibition of cyclooxygenase-2 (COX-2) and class I histone deacetylase (HDAC).

They showed that combination of HDAC1/3 and COX-2 inhibition significantly impaired proliferation of BxPC-3 cells in vitro and stalled entirely the BxPC-3 cells tumor growth onto the chorioallantoic membrane in vivo. The combination was more effective than either drug used alone.

Consistently, they showed that both HDAC1 and HDAC3 inhibition induced the expression of COX-2 via the NF-kB pathway.

These data demonstrate, for the first time in a Pancreatic Ductal Adenocarcinoma model, a significant action of HDAC and COX-2 inhibitors on cancer cell growth, which sets the basis for the development of potentially effective new combinatory therapies for pancreatic ductal adenocarcinoma patients.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at CIRM have identified a new anti-angiogenic potency of coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9).

The anti-angiogenic effect of IK9 was demonstrated in vivo in a choroidal neovascularization mice model and additionally ex vivo in a rat aortic ring assay where it was more active than the known matrix metalloproteinase inhibitor Ro 28-2653. IK9 did not affect apoptosis, proliferation, or endothelial cell invasiveness in vitro.

These findings suggest its potential use as a therapeutic agent.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen molecules by excising the aminopropeptide.

Researchers at GIGA demonstrated that ADAMTS-2 is able to reduce proliferation of endothelial cells in vitro and to induce their retraction and detachment from the substrate resulting in apoptosis.

In 3-D culture models, ADAMTS-2 strongly reduced branching of capillary-like structures formed by endothelial cells and their long-term maintenance and inhibited vessels formation in embryos bodies.

The anti-angiogenic properties of ADAMTS-2 were also observed in vivo, in a choroidal neovascularization model in which a reproducible and significant increase of neovascularization was observed in ADAMTS-2-/- mice compared to wild-type animals.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have shown by knocking down the urokinase plasminogen activator receptor (uPAR) in human umbilical vein endothelial cells (HUVECs) impaired VEGFR2 signaling.

In addition, they demonstrated that upon exposure of HUVECs to VEGF, uPAR recruited the low-density lipoprotein receptor-related protein 1 (LRP-1) inducing VEGFR2 internalization.

Researchers have also observed that uPAR deficiency in mice prevented VEGF-induced angiogenesis.

Taken together these data demonstrated that uPAR is crucial for VEGF signaling and that this interaction promoted angiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Exosomes are small vesicles composed of RNAs, microRNAs and soluble and membranous proteins. These organelles seem to play a key role in intercellular communication via the transfer of their molecular contents. Moreover, tumor exosomes are able to modulate the tumor microenvironment by activating angiogenesis, promoting the formation of cancer-associated fibroblasts (CAFs) and modulating the immune response. We can produce, isolate, purify and characterize exosomes, thanks to various differential centrifugation techniques.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Dentin matrix protein 1 (DMP1) is a member of the Small Integrin-Binding LIgand N-linked Glycoproteins (SIBLINGs) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis.

Researchers at GIGA demonstrated that this extracellular matrix protein induced the expression of VE-cadherin, a key regulator of intercellular junctions and contact inhibition of growth endothelial cells growth.

They showed that DMP1 induced VE-cadherin and p27(Kip1) expression followed by cell cycle arrest in human umbilical vein endothelial cells (HUVEC) in a CD44-dependent manner.

VEGF-induced proliferation, migration and tubulogenesis responses were specifically blocked upon DMP1 pre-treatment of HUVEC.

In vivo, the researchers observed that DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis.

Taken together these data identify this protein as a new specific inhibitor of VEGF-induced angiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have identified that shorter peptides derived from 16k prolactin can also inhibit angiogenesis in vivo and in vitro.

The ability of 16K prolactin to prevent neovascularization was analyzed in several models of physiological angiogenesis (CAM assay), pathological (retinopathy) and several tumor models.

Furthermore the 16K prolactin treatment was shown to prevent the development of a normally functioning tumor vasculature by impairing vessel maturation and disrupting lymphangiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

CD39 is an ectoenzyme, present on different immune cell subsets, which mediates immunosuppressive functions catalyzing ATP degradation. It is not known whether CD39 is expressed and implicated in the activity of CD8+ regulatory T lymphocytes (T-reg).

Researchers at GIGA have analyzed CD39 expression and function in both CD8+ and CD4+CD25(hi) T-reg from the peripheral blood of healthy donors as well as from tumor specimens.

CD39 was found expressed by both CD8+ (from the majority of healthy donors and tumor patients) and CD4+CD25(hi) T-reg and CD39 expression correlated with suppression activity mediated by CD8+ T-reg.

Importantly, CD39 counteraction remarkably inhibited the suppression activity of CD8+ T-reg (both from peripheral blood and tumor microenvironment) suggesting that CD39-mediated inhibition constitutes a prevalent hallmark of their function.

Collectively, these findings, unveiling a new mechanism of action for CD8+ T-reg, provide new knowledge on intratumoral molecular pathways related to tumor immune escape, which could be exploited in the future for designing new biological tools for anticancer immune intervention.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

The development of blood vessels inside tumors is required to provide the nutrients and oxygen is needed for tumor growth and to allow the spread of cancer cells at a distance to form metastasis.

Researchers at CIRM have identified a new anti-angiogenic potency of coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9) as a new potent inhibitor of angiogenesis and suggested its potential use as a therapeutic agent (M. HEMMER et al., Drug Dev. Res. (2010), 71, 209–218).

Liver cancer

Researchers at GIGA have identified a novel histone deacetylase inhibitor (HDACi) (N-Hydroxy-6-(5-nitro-naphtalimide)-hexanamide: ES8) that efficiently inhibits angiogenesis in relevant ex vivo models (Human umbilical vein endothelial cells (HUVEC), 3D aortic ring assay) and in vivo (chick chorioallantoic membrane (CAM), Zebrafish).

Transcriptomic profiling reveals a set of ES8 specific genes that are not affected by the prototypical HDACi suberoylanilide hydroxamic acid (SAHA).

In addition, they have shown that ES8 also reduced tumor growth in small cell lung cancer mouse models.

Availability of a novel compound not centered exclusively on inhibition of angiogenic factors and inducing a characteristic transcription profile may be of interest to overcome resistance to currently used chemotherapies.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

DUSP3, also called Vaccinia-H1 Related (VHR) is a small dual specificity phosphatase dephosphorylating both tyrosine and serine/threonine phosphorylated residues. DUSP3 plays an important role in cell cycle regulation and is up-regulated in several human cancers. The physiological role of this phosphatase is, however, poorly understood.

Researchers at GIGA have generated a DUSP3 knockout mouse by homologous recombination.

Using this transgenic mouse model, they have observed that DUSP3 plays an important role in metastatic dissemination/growth by a mechanism involving the control of chemokine ligand 2 (CCR2) – chemokine receptor 2 (CCL2) chemoattraction axis in macrophages.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at CIRM have identified a new anti-angiogenic potency of coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9).

The anti-angiogenic effect of IK9 was demonstrated in vivo in a choroidal neovascularization mice model and additionally ex vivo in a rat aortic ring assay where it was more active than the known matrix metalloproteinase inhibitor Ro 28-2653. IK9 did not affect apoptosis, proliferation, or endothelial cell invasiveness in vitro.

These findings suggest its potential use as a therapeutic agent.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen molecules by excising the aminopropeptide.

Researchers at GIGA demonstrated that ADAMTS-2 is able to reduce proliferation of endothelial cells in vitro and to induce their retraction and detachment from the substrate resulting in apoptosis.

In 3-D culture models, ADAMTS-2 strongly reduced branching of capillary-like structures formed by endothelial cells and their long-term maintenance and inhibited vessels formation in embryos bodies.

The anti-angiogenic properties of ADAMTS-2 were also observed in vivo, in a choroidal neovascularization model in which a reproducible and significant increase of neovascularization was observed in ADAMTS-2-/- mice compared to wild-type animals.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have shown by knocking down the urokinase plasminogen activator receptor (uPAR) in human umbilical vein endothelial cells (HUVECs) impaired VEGFR2 signaling.

In addition, they demonstrated that upon exposure of HUVECs to VEGF, uPAR recruited the low-density lipoprotein receptor-related protein 1 (LRP-1) inducing VEGFR2 internalization.

Researchers have also observed that uPAR deficiency in mice prevented VEGF-induced angiogenesis.

Taken together these data demonstrated that uPAR is crucial for VEGF signaling and that this interaction promoted angiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Exosomes are small vesicles composed of RNAs, microRNAs and soluble and membranous proteins. These organelles seem to play a key role in intercellular communication via the transfer of their molecular contents. Moreover, tumor exosomes are able to modulate the tumor microenvironment by activating angiogenesis, promoting the formation of cancer-associated fibroblasts (CAFs) and modulating the immune response. We can produce, isolate, purify and characterize exosomes, thanks to various differential centrifugation techniques.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Dentin matrix protein 1 (DMP1) is a member of the Small Integrin-Binding LIgand N-linked Glycoproteins (SIBLINGs) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis.

Researchers at GIGA demonstrated that this extracellular matrix protein induced the expression of VE-cadherin, a key regulator of intercellular junctions and contact inhibition of growth endothelial cells growth.

They showed that DMP1 induced VE-cadherin and p27(Kip1) expression followed by cell cycle arrest in human umbilical vein endothelial cells (HUVEC) in a CD44-dependent manner.

VEGF-induced proliferation, migration and tubulogenesis responses were specifically blocked upon DMP1 pre-treatment of HUVEC.

 In vivo, the researchers observed that DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis.

Taken together these data identify this protein as a new specific inhibitor of VEGF-induced angiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have identified that shorter peptides derived from 16k prolactin can also inhibit angiogenesis in vivo and in vitro.

The ability of 16K prolactin to prevent neovascularization was analyzed in several models of physiological angiogenesis (CAM assay), pathological (retinopathy) and several tumor models.

Furthermore the 16K prolactin treatment was shown to prevent the development of a normally functioning tumor vasculature by impairing vessel maturation and disrupting lymphangiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

CD39 is an ectoenzyme, present on different immune cell subsets, which mediates immunosuppressive functions catalyzing ATP degradation. It is not known whether CD39 is expressed and implicated in the activity of CD8+ regulatory T lymphocytes (T-reg).

Researchers at GIGA have analyzed CD39 expression and function in both CD8+ and CD4+CD25(hi) T-reg from the peripheral blood of healthy donors as well as from tumor specimens.

CD39 was found expressed by both CD8+ (from the majority of healthy donors and tumor patients) and CD4+CD25(hi) T-reg and CD39 expression correlated with suppression activity mediated by CD8+ T-reg.

Importantly, CD39 counteraction remarkably inhibited the suppression activity of CD8+ T-reg (both from peripheral blood and tumor microenvironment) suggesting that CD39-mediated inhibition constitutes a prevalent hallmark of their function.

Collectively, these findings, unveiling a new mechanism of action for CD8+ T-reg, provide new knowledge on intratumoral molecular pathways related to tumor immune escape, which could be exploited in the future for designing new biological tools for anticancer immune intervention.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

The development of blood vessels inside tumors is required to provide the nutrients and oxygen is needed for tumor growth and to allow the spread of cancer cells at a distance to form metastasis.

Researchers at CIRM have identified a new anti-angiogenic potency of coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9) as a new potent inhibitor of angiogenesis and suggested its potential use as a therapeutic agent (M. HEMMER et al., Drug Dev. Res. (2010), 71, 209–218).

Breast cancer

Researchers at GIGA have identified a novel histone deacetylase inhibitor (HDACi) (N-Hydroxy-6-(5-nitro-naphtalimide)-hexanamide: ES8) that efficiently inhibits angiogenesis in relevant ex vivo models (Human umbilical vein endothelial cells (HUVEC), 3D aortic ring assay) and in vivo (chick chorioallantoic membrane (CAM), Zebrafish).

Transcriptomic profiling reveals a set of ES8 specific genes that are not affected by the prototypical HDACi suberoylanilide hydroxamic acid (SAHA).

In addition, they have shown that ES8 also reduced tumor growth in small cell lung cancer mouse models.

Availability of a novel compound not centered exclusively on inhibition of angiogenic factors and inducing a characteristic transcription profile may be of interest to overcome resistance to currently used chemotherapies.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

DUSP3, also called Vaccinia-H1 Related (VHR) is a small dual specificity phosphatase dephosphorylating both tyrosine and serine/threonine phosphorylated residues. DUSP3 plays an important role in cell cycle regulation and is up-regulated in several human cancers. The physiological role of this phosphatase is, however, poorly understood.

Researchers at GIGA have generated a DUSP3 knockout mouse by homologous recombination.

Using this transgenic mouse model, they have observed that DUSP3 plays an important role in metastatic dissemination/growth by a mechanism involving the control of chemokine ligand 2 (CCR2) – chemokine receptor 2 (CCL2) chemoattraction axis in macrophages.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

MT4-MMP (MMP-17) is a glycosylphosphatidyl inositol-anchored matrix metalloprotease expressed on the surface of cancer cells.

It emerged recently as a key intrinsic feature of breast cancer cells that stimulates tumor growth and metastasis into the lung.

Researchers at GIGA have established an unexpected functional link between MT4-MMP (MMP-17) and the growth factor receptor EGFR and provide clear evidence that MT4-MMP controls EGFR phosphorylation and signaling.

Their data also indicate that MT4-MMP is internalized by the CLIC/GEEC pathway, a mechanism that differs from other MT-MMP members. Although MT4-MMP localizes with caveolin-1, MT4-MMP internalization was not affected by inhibitors of caveolin-1 or clathrin endocytosis pathways but was reduced by cdc42 or RhoA silencing with siRNA.

These data open new opportunities for designing novel therapies targeting the non-proteolytic functions of MT4-MMP (MMP-17) and the new mechanistic insight into the regulatory mechanisms of MT4-MMP may have implications in the design of novel therapeutic strategies.

Moreover, researchers have shown clinically that MT4-MMP and EGFR expressions were correlated in human triple-negative breast cancer specimens. Based on these observations, they have developed reliable tools to screen for combined therapies and to perform a patient selection, as a first step towards personalized medicine. (see our Licensing Opportunity)

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have reported, for the first time, that asporin is overexpressed in the stroma of most human breast cancers and is not expressed in normal breast tissue.

Their in vitro findings show that soluble IL-1beta, secreted by Triple Negative Breast Cancer (TNBC) cells, is responsible for inhibiting asporin in normal and cancer-associated fibroblasts.

In two in vivo murine models of TNBC, they observed that tumors expressing asporin exhibit significantly reduced growth and metastatic properties.

A retrospective IHC study performed on human breast carcinoma demonstrates that asporin expression is lowest in TNBC and HER2+ tumors, while HR+ tumors have significantly higher asporin expression. Assessment of asporin expression and patient outcome shows that low protein levels in the primary breast lesion significantly delineate patients with bad outcome regardless of the tumor HR status. Survival analysis, based on gene expression, confirmed that low asporin levels are associated with a reduced likelihood of survival.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

The interaction between tumor cells and their microenvironment is an essential aspect of tumor development. Therefore, understanding how this microenvironment communicates with tumor cells is crucial for the development of new anti-cancer therapies.

MicroRNAs (miRNAs), small non-coding RNAs, are secreted into the extracellular medium in vesicles called exosomes, which allow communication between cells via the transfer of their cargo.

Using exogenous miRNA, researchers at GIGA demonstrated that endothelial cells can transfer miRNA to tumor cells via exosomes.

Using miRNA profiling, they identified miR-503, which exhibited downregulated levels in exosomes released from endothelial cells cultured under tumoral conditions.

The modulation of miR-503 in breast cancer cells altered their proliferative and invasive capacities.

Two targets of miR-503 were identified: CCND2 and CCND3. Moreover, increased plasmatic miR-503 was measured in breast cancer patients after neoadjuvant chemotherapy, which could be partly due to increased miRNA secretion by endothelial cells.

These data are the first to reveal the involvement of the endothelium in the modulation of tumor development via the secretion of circulating miR-503 in response to chemotherapy treatment.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Myoferlin is a member of the ferlin family of proteins that participate in plasma membrane fusion, repair and endocytosis.

Researchers at GIGA have shown that myoferlin is overexpressed in human breast cancers and its critical role in controlling degradation of the EGFR after its activation and internalization in breast cancer cells.

Myoferlin depletion blocked EGF-induced cell migration and epithelial-to-mesenchymal transition. Both effects were induced as a result of impaired degradation of phosphorylated EGFR via dysfunctional plasma membrane caveolae and alteration of caveolin homooligomerization.

In parallel, they demonstrated that myoferlin depletion reduced tumor development in a chicken chorioallantoic membrane xenograft model of human breast cancer.

Considering the therapeutic significance of EGFR targeting, our findings identify myoferlin as a novel target for future drug development.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at CIRM have identified a new anti-angiogenic potency of coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9).

The anti-angiogenic effect of IK9 was demonstrated in vivo in a choroidal neovascularization mice model and additionally ex vivo in a rat aortic ring assay where it was more active than the known matrix metalloproteinase inhibitor Ro 28-2653. IK9 did not affect apoptosis, proliferation, or endothelial cell invasiveness in vitro.

These findings suggest its potential use as a therapeutic agent.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen molecules by excising the aminopropeptide.

Researchers at GIGA demonstrated that ADAMTS-2 is able to reduce proliferation of endothelial cells in vitro and to induce their retraction and detachment from the substrate resulting in apoptosis.

In 3-D culture models, ADAMTS-2 strongly reduced branching of capillary-like structures formed by endothelial cells and their long-term maintenance and inhibited vessels formation in embryos bodies.

The anti-angiogenic properties of ADAMTS-2 were also observed in vivo, in a choroidal neovascularization model in which a reproducible and significant increase of neovascularization was observed in ADAMTS-2-/- mice compared to wild-type animals.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have shown by knocking down the urokinase plasminogen activator receptor (uPAR) in human umbilical vein endothelial cells (HUVECs) impaired VEGFR2 signaling.

In addition, they demonstrated that upon exposure of HUVECs to VEGF, uPAR recruited the low-density lipoprotein receptor-related protein 1 (LRP-1) inducing VEGFR2 internalization.

Researchers have also observed that uPAR deficiency in mice prevented VEGF-induced angiogenesis.

Taken together these data demonstrated that uPAR is crucial for VEGF signaling and that this interaction promoted angiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Exosomes are small vesicles composed of RNAs, microRNAs and soluble and membranous proteins. These organelles seem to play a key role in intercellular communication via the transfer of their molecular contents. Moreover, tumor exosomes are able to modulate the tumor microenvironment by activating angiogenesis, promoting the formation of cancer-associated fibroblasts (CAFs) and modulating the immune response. We can produce, isolate, purify and characterize exosomes, thanks to various differential centrifugation techniques.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Dentin matrix protein 1 (DMP1) is a member of the Small Integrin-Binding LIgand N-linked Glycoproteins (SIBLINGs) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis.

Researchers at GIGA demonstrated that this extracellular matrix protein induced the expression of VE-cadherin, a key regulator of intercellular junctions and contact inhibition of growth endothelial cells growth.

They showed that DMP1 induced VE-cadherin and p27(Kip1) expression followed by cell cycle arrest in human umbilical vein endothelial cells (HUVEC) in a CD44-dependent manner.

VEGF-induced proliferation, migration and tubulogenesis responses were specifically blocked upon DMP1 pre-treatment of HUVEC.

In vivo, the researchers observed that DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis.

Taken together these data identify this protein as a new specific inhibitor of VEGF-induced angiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have identified that shorter peptides derived from 16k prolactin can also inhibit angiogenesis in vivo and in vitro.

The ability of 16K prolactin to prevent neovascularization was analyzed in several models of physiological angiogenesis (CAM assay), pathological (retinopathy) and several tumor models.

Furthermore the 16K prolactin treatment was shown to prevent the development of a normally functioning tumor vasculature by impairing vessel maturation and disrupting lymphangiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

CD39 is an ectoenzyme, present on different immune cell subsets, which mediates immunosuppressive functions catalyzing ATP degradation. It is not known whether CD39 is expressed and implicated in the activity of CD8+ regulatory T lymphocytes (T-reg).

Researchers at GIGA have analyzed CD39 expression and function in both CD8+ and CD4+CD25(hi) T-reg from the peripheral blood of healthy donors as well as from tumor specimens.

CD39 was found expressed by both CD8+ (from the majority of healthy donors and tumor patients) and CD4+CD25(hi) T-reg and CD39 expression correlated with suppression activity mediated by CD8+ T-reg.

Importantly, CD39 counteraction remarkably inhibited the suppression activity of CD8+ T-reg (both from peripheral blood and tumor microenvironment) suggesting that CD39-mediated inhibition constitutes a prevalent hallmark of their function.

Collectively, these findings, unveiling a new mechanism of action for CD8+ T-reg, provide new knowledge on intratumoral molecular pathways related to tumor immune escape, which could be exploited in the future for designing new biological tools for anticancer immune intervention.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

The development of blood vessels inside tumors is required to provide the nutrients and oxygen is needed for tumor growth and to allow the spread of cancer cells at a distance to form metastasis.

Researchers at CIRM have identified a new anti-angiogenic potency of coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9) as a new potent inhibitor of angiogenesis and suggested its potential use as a therapeutic agent (M. HEMMER et al., Drug Dev. Res. (2010), 71, 209–218).

Colorectal cancer

Researchers at GIGA have identified a novel histone deacetylase inhibitor (HDACi) (N-Hydroxy-6-(5-nitro-naphtalimide)-hexanamide: ES8) that efficiently inhibits angiogenesis in relevant ex vivo models (Human umbilical vein endothelial cells (HUVEC), 3D aortic ring assay) and in vivo (chick chorioallantoic membrane (CAM), Zebrafish).

Transcriptomic profiling reveals a set of ES8 specific genes that are not affected by the prototypical HDACi suberoylanilide hydroxamic acid (SAHA).

In addition, they have shown that ES8 also reduced tumor growth in small cell lung cancer mouse models.

Availability of a novel compound not centered exclusively on inhibition of angiogenic factors and inducing a characteristic transcription profile may be of interest to overcome resistance to currently used chemotherapies.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

DUSP3, also called Vaccinia-H1 Related (VHR) is a small dual specificity phosphatase dephosphorylating both tyrosine and serine/threonine phosphorylated residues. DUSP3 plays an important role in cell cycle regulation and is up-regulated in several human cancers. The physiological role of this phosphatase is, however, poorly understood.

Researchers at GIGA have generated a DUSP3 knockout mouse by homologous recombination.

Using this transgenic mouse model, they have observed that DUSP3 plays an important role in metastatic dissemination/growth by a mechanism involving the control of chemokine ligand 2 (CCR2) – chemokine receptor 2 (CCL2) chemoattraction axis in macrophages.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

MT4-MMP (MMP-17) is a glycosylphosphatidyl inositol-anchored matrix metalloprotease expressed on the surface of cancer cells.

Researchers at GIGA have established an unexpected functional link between MT4-MMP (MMP-17) and the growth factor receptor EGFR and provide clear evidence that MT4-MMP controls EGFR phosphorylation and signaling.

Their data also indicate that MT4-MMP is internalized by the CLIC/GEEC pathway, a mechanism that differs from other MT-MMP members. Although MT4-MMP localizes with caveolin-1, MT4-MMP internalization was not affected by inhibitors of caveolin-1 or clathrin endocytosis pathways but was reduced by cdc42 or RhoA silencing with siRNA.

These data open new opportunities for designing novel therapies targeting the non-proteolytic functions of MT4-MMP (MMP-17) and the new mechanistic insight into the regulatory mechanisms of MT4-MMP may have implications in the design of novel therapeutic strategies.

Moreover, researchers have shown clinically that MT4-MMP and EGFR expressions were correlated in human triple-negative breast cancer specimens. Based on these observations, they have developed reliable tools to screen for combined therapies and to perform a patient selection, as a first step towards personalized medicine. (see our Licensing Opportunity)

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at CIRM have identified a new anti-angiogenic potency of coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9).

The anti-angiogenic effect of IK9 was demonstrated in vivo in a choroidal neovascularization mice model and additionally ex vivo in a rat aortic ring assay where it was more active than the known matrix metalloproteinase inhibitor Ro 28-2653. IK9 did not affect apoptosis, proliferation, or endothelial cell invasiveness in vitro.

These findings suggest its potential use as a therapeutic agent.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen molecules by excising the aminopropeptide.

Researchers at GIGA demonstrated that ADAMTS-2 is able to reduce proliferation of endothelial cells in vitro and to induce their retraction and detachment from the substrate resulting in apoptosis.

In 3-D culture models, ADAMTS-2 strongly reduced branching of capillary-like structures formed by endothelial cells and their long-term maintenance and inhibited vessels formation in embryos bodies.

The anti-angiogenic properties of ADAMTS-2 were also observed in vivo, in a choroidal neovascularization model in which a reproducible and significant increase of neovascularization was observed in ADAMTS-2-/- mice compared to wild-type animals.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have shown by knocking down the urokinase plasminogen activator receptor (uPAR) in human umbilical vein endothelial cells (HUVECs) impaired VEGFR2 signaling.

In addition, they demonstrated that upon exposure of HUVECs to VEGF, uPAR recruited the low-density lipoprotein receptor-related protein 1 (LRP-1) inducing VEGFR2 internalization.

Researchers have also observed that uPAR deficiency in mice prevented VEGF-induced angiogenesis.

Taken together these data demonstrated that uPAR is crucial for VEGF signaling and that this interaction promoted angiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Exosomes are small vesicles composed of RNAs, microRNAs and soluble and membranous proteins. These organelles seem to play a key role in intercellular communication via the transfer of their molecular contents. Moreover, tumor exosomes are able to modulate the tumor microenvironment by activating angiogenesis, promoting the formation of cancer-associated fibroblasts (CAFs) and modulating the immune response. We can produce, isolate, purify and characterize exosomes, thanks to various differential centrifugation techniques.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Dentin matrix protein 1 (DMP1) is a member of the Small Integrin-Binding LIgand N-linked Glycoproteins (SIBLINGs) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis.

Researchers at GIGA demonstrated that this extracellular matrix protein induced the expression of VE-cadherin, a key regulator of intercellular junctions and contact inhibition of growth endothelial cells growth.

They showed that DMP1 induced VE-cadherin and p27(Kip1) expression followed by cell cycle arrest in human umbilical vein endothelial cells (HUVEC) in a CD44-dependent manner.

VEGF-induced proliferation, migration and tubulogenesis responses were specifically blocked upon DMP1 pre-treatment of HUVEC.

In vivo, the researchers observed that DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis.

Taken together these data identify this protein as a new specific inhibitor of VEGF-induced angiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have identified that shorter peptides derived from 16k prolactin can also inhibit angiogenesis in vivo and in vitro.

The ability of 16K prolactin to prevent neovascularization was analyzed in several models of physiological angiogenesis (CAM assay), pathological (retinopathy) and several tumor models.

Furthermore the 16K prolactin treatment was shown to prevent the development of a normally functioning tumor vasculature by impairing vessel maturation and disrupting lymphangiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

CD39 is an ectoenzyme, present on different immune cell subsets, which mediates immunosuppressive functions catalyzing ATP degradation. It is not known whether CD39 is expressed and implicated in the activity of CD8+ regulatory T lymphocytes (T-reg).

Researchers at GIGA have analyzed CD39 expression and function in both CD8+ and CD4+CD25(hi) T-reg from the peripheral blood of healthy donors as well as from tumor specimens.

CD39 was found expressed by both CD8+ (from the majority of healthy donors and tumor patients) and CD4+CD25(hi) T-reg and CD39 expression correlated with suppression activity mediated by CD8+ T-reg.

Importantly, CD39 counteraction remarkably inhibited the suppression activity of CD8+ T-reg (both from peripheral blood and tumor microenvironment) suggesting that CD39-mediated inhibition constitutes a prevalent hallmark of their function.

Collectively, these findings, unveiling a new mechanism of action for CD8+ T-reg, provide new knowledge on intratumoral molecular pathways related to tumor immune escape, which could be exploited in the future for designing new biological tools for anticancer immune intervention.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

The development of blood vessels inside tumors is required to provide the nutrients and oxygen is needed for tumor growth and to allow the spread of cancer cells at a distance to form metastasis.

Researchers at CIRM have identified a new anti-angiogenic potency of coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9) as a new potent inhibitor of angiogenesis and suggested its potential use as a therapeutic agent (M. HEMMER et al., Drug Dev. Res. (2010), 71, 209–218).

Lung cancer

Researchers at GIGA have identified a novel histone deacetylase inhibitor (HDACi) (N-Hydroxy-6-(5-nitro-naphtalimide)-hexanamide: ES8) that efficiently inhibits angiogenesis in relevant ex vivo models (Human umbilical vein endothelial cells (HUVEC), 3D aortic ring assay) and in vivo (chick chorioallantoic membrane (CAM), Zebrafish).

Transcriptomic profiling reveals a set of ES8 specific genes that are not affected by the prototypical HDACi suberoylanilide hydroxamic acid (SAHA).

In addition, they have shown that ES8 also reduced tumor growth in small cell lung cancer mouse models.

Availability of a novel compound not centered exclusively on inhibition of angiogenic factors and inducing a characteristic transcription profile may be of interest to overcome resistance to currently used chemotherapies.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

DUSP3, also called Vaccinia-H1 Related (VHR) is a small dual specificity phosphatase dephosphorylating both tyrosine and serine/threonine phosphorylated residues. DUSP3 plays an important role in cell cycle regulation and is up-regulated in several human cancers. The physiological role of this phosphatase is, however, poorly understood.

Researchers at GIGA have generated a DUSP3 knockout mouse by homologous recombination.

Using this transgenic mouse model, they have observed that DUSP3 plays an important role in metastatic dissemination/growth by a mechanism involving the control of chemokine ligand 2 (CCR2) – chemokine receptor 2 (CCL2) chemoattraction axis in macrophages.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at CIRM have identified a new anti-angiogenic potency of coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9).

The anti-angiogenic effect of IK9 was demonstrated in vivo in a choroidal neovascularization mice model and additionally ex vivo in a rat aortic ring assay where it was more active than the known matrix metalloproteinase inhibitor Ro 28-2653. IK9 did not affect apoptosis, proliferation, or endothelial cell invasiveness in vitro.

These findings suggest its potential use as a therapeutic agent.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen molecules by excising the aminopropeptide.

Researchers at GIGA demonstrated that ADAMTS-2 is able to reduce proliferation of endothelial cells in vitro and to induce their retraction and detachment from the substrate resulting in apoptosis.

In 3-D culture models, ADAMTS-2 strongly reduced branching of capillary-like structures formed by endothelial cells and their long-term maintenance and inhibited vessels formation in embryos bodies.

The anti-angiogenic properties of ADAMTS-2 were also observed in vivo, in a choroidal neovascularization model in which a reproducible and significant increase of neovascularization was observed in ADAMTS-2-/- mice compared to wild-type animals.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have shown by knocking down the urokinase plasminogen activator receptor (uPAR) in human umbilical vein endothelial cells (HUVECs) impaired VEGFR2 signaling.

In addition, they demonstrated that upon exposure of HUVECs to VEGF, uPAR recruited the low-density lipoprotein receptor-related protein 1 (LRP-1) inducing VEGFR2 internalization.

Researchers have also observed that uPAR deficiency in mice prevented VEGF-induced angiogenesis.

Taken together these data demonstrated that uPAR is crucial for VEGF signaling and that this interaction promoted angiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Exosomes are small vesicles composed of RNAs, microRNAs and soluble and membranous proteins. These organelles seem to play a key role in intercellular communication via the transfer of their molecular contents. Moreover, tumor exosomes are able to modulate the tumor microenvironment by activating angiogenesis, promoting the formation of cancer-associated fibroblasts (CAFs) and modulating the immune response. We can produce, isolate, purify and characterize exosomes, thanks to various differential centrifugation techniques.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Dentin matrix protein 1 (DMP1) is a member of the Small Integrin-Binding LIgand N-linked Glycoproteins (SIBLINGs) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis.

Researchers at GIGA demonstrated that this extracellular matrix protein induced the expression of VE-cadherin, a key regulator of intercellular junctions and contact inhibition of growth endothelial cells growth.

They showed that DMP1 induced VE-cadherin and p27(Kip1) expression followed by cell cycle arrest in human umbilical vein endothelial cells (HUVEC) in a CD44-dependent manner.

VEGF-induced proliferation, migration and tubulogenesis responses were specifically blocked upon DMP1 pre-treatment of HUVEC.

 In vivo, the researchers observed that DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis.

Taken together these data identify this protein as a new specific inhibitor of VEGF-induced angiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

Researchers at GIGA have identified that shorter peptides derived from 16k prolactin can also inhibit angiogenesis in vivo and in vitro.

The ability of 16K prolactin to prevent neovascularization was analyzed in several models of physiological angiogenesis (CAM assay), pathological (retinopathy) and several tumor models.

Furthermore the 16K prolactin treatment was shown to prevent the development of a normally functioning tumor vasculature by impairing vessel maturation and disrupting lymphangiogenesis.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

CD39 is an ectoenzyme, present on different immune cell subsets, which mediates immunosuppressive functions catalyzing ATP degradation. It is not known whether CD39 is expressed and implicated in the activity of CD8+ regulatory T lymphocytes (T-reg).

Researchers at GIGA have analyzed CD39 expression and function in both CD8+ and CD4+CD25(hi) T-reg from the peripheral blood of healthy donors as well as from tumor specimens.

CD39 was found expressed by both CD8+ (from the majority of healthy donors and tumor patients) and CD4+CD25(hi) T-reg and CD39 expression correlated with suppression activity mediated by CD8+ T-reg.

Importantly, CD39 counteraction remarkably inhibited the suppression activity of CD8+ T-reg (both from peripheral blood and tumor microenvironment) suggesting that CD39-mediated inhibition constitutes a prevalent hallmark of their function.

Collectively, these findings, unveiling a new mechanism of action for CD8+ T-reg, provide new knowledge on intratumoral molecular pathways related to tumor immune escape, which could be exploited in the future for designing new biological tools for anticancer immune intervention.

Interested in these projects? Drop us an email [info@b2h.be]. We are looking forward collaborating with you!

#Link – Benzopyrans – New anti-angiogenic product

The development of blood vessels inside tumors is required to provide the nutrients and oxygen is needed for tumor growth and to allow the spread of cancer cells at a distance to form metastasis.

Researchers at CIRM have identified a new anti-angiogenic potency of coumarinic derivative, 3-bromophenyl 6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylate (IK9) as a new potent inhibitor of angiogenesis and suggested its potential use as a therapeutic agent (M. HEMMER et al., Drug Dev. Res. (2010), 71, 209–218).