I am a trained MD PhD and a Professor in Cell and Molecular Biology heading a research department in France that is working in the cancer and vascular biology fields. In the oncology, I am primary interested in the tumor microenvironment (TME) and I am working in the context on glioblastoma and renal cell carcinoma. I am also interested in vascular biology and I am conducting projects on vascular development and endothelial cell signalling and in biotechnology. I am also interested in conceptual and philosophical issues related to my scientific research.
Background. Glioblastomas are heterogeneous tumors composed of a necrotic and tumor core and an i... more Background. Glioblastomas are heterogeneous tumors composed of a necrotic and tumor core and an invasive periphery. Methods. Here, we performed a proteomics analysis of laser-capture micro-dissected glioblastoma core and inva-sive areas of patient-derived xenografts. Results. Bioinformatics analysis identified enriched proteins in central and invasive tumor areas. Novel markers of invasion were identified, the genes proteolipid protein 1 (PLP1) and Dynamin-1 (DNM1), which were subsequently validated in tumors and by functional assays. Conclusions. In summary, our results identify new networks and molecules that may play an important role in gli-oblastoma development and may constitute potential novel therapeutic targets.
Philosophers have explored the concept of causality for centuries. Here we argue that ideas about... more Philosophers have explored the concept of causality for centuries. Here we argue that ideas about causality from philosophy can help scientists to better understand how cancerous tumors grow and spread in the body. After outlining six characteristics of causality that are relevant to cancer, we emphasize the importance of feedback loops and interactions between tumor-cell-intrinsic and tumor-cell-extrinsic factors for explaining the formation and dissemination of tumors.
Most achievements to engineer blood vessels are based on multiple-step manipulations such as manu... more Most achievements to engineer blood vessels are based on multiple-step manipulations such as manual sheet rolling or sequential cell seeding followed by scaffold degradation. Here, we propose a one-step strategy using a microfluidic coextrusion device to produce mature functional blood vessels. A hollow alginate hydrogel tube is internally coated with extracellular matrix to direct the self-assembly of a mixture of endothelial cells (ECs) and smooth muscle cells (SMCs). The resulting vascular structure has the correct configuration of lumen, an inner lining of ECs, and outer sheath of SMCs. These "vesseloids" reach homeostasis within a day and exhibit the following properties expected for functional vessels (i) quiescence, (ii) perfusability, and (iii) contractility in response to vasoconstrictor agents. Together, these findings provide an original and simple strategy to generate functional artificial vessels and pave the way for further developments in vascular graft and tissue engineering and for deciphering the angiogenesis process.
This article aims at discussing some aspects of the relationship between science, truth and belie... more This article aims at discussing some aspects of the relationship between science, truth and belief. I will primarily focus on the scientific activity in the biological and medical sciences and how it relates to the notion of truth and belief and not discuss the relationship with specific religions. Science has specific methodologies to obtain knowledge. Philosophers have analyzed how scientific knowledge is acquired and have tried to identify its characteristics and to establish some general rules of how knowledge through science is gained. Radical theo- rists have disputed the value of the scientific method despite science’s indisputable successes. If science is a rational activity, it is not free from belief. Belief can have a positive and negative impact on the acquisition of scientific knowledge and the idea of human nature. These different issues will be discussed in depth in this article.
This article aims at discussing some aspects of the relationship between science, truth and belie... more This article aims at discussing some aspects of the relationship between science, truth and belief. I will primarily focus on the scientific activity in the biological and medical sciences and how it relates to the notion of truth and belief and not discuss the relationship with specific religions. Science has specific methodologies to obtain knowledge. Philosophers have analyzed how scientific knowledge is acquired and have tried to identify its characteristics and to establish some general rules of how knowledge through science is gained. Radical theorists have disputed the value of the scientific method despite science's indisputable successes. If science is a rational activity, it is not free from belief. Belief can have a positive and negative impact on the acquisition of scientific knowledge and the idea of human nature. These different issues will be discussed in depth in this article.
Methods in molecular biology (Clifton, N.J.), 2018
We present a protocol for the specific labeling and isolation of proteins from the membrane surfa... more We present a protocol for the specific labeling and isolation of proteins from the membrane surface of endothelial cells and the surrounding extracellular matrix of organs, experimental wounds and tumors using chicken embryos. Proteins are deglycosylated on streptavidin resin and purified after gentle elution and trypsin digestion. Peptides are analyzed by spectroscopy and reverse proteomic fingerprinting. The major advantages of this protocol include reductions in both the background and overrepresentation of single proteins that would otherwise mask less well-represented proteins in the mass spectroscopy analysis. We also present methods to identify putative vascular and endothelial cell targets from isolated chicken membranes and extracellular proteins. The use of human genome and transcriptome data facilitates this analysis. Human orthologs of isolated chicken proteins are identified using best hit BLAST searches against the Human Reference Sequence Database. The expression of H...
The formation of new blood vessels, or angiogenesis, is a complex process that plays important ro... more The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.
Discoidin domain receptors 1 and 2 (DDR1 and DDR2) are members of the tyrosine kinase receptors a... more Discoidin domain receptors 1 and 2 (DDR1 and DDR2) are members of the tyrosine kinase receptors activated after binding with collagen. DDRs are implicated in numerous physiological and pathological functions such as proliferation, adhesion and migration. Little is known about the expressions of the two receptors in normal and cancer cells and most of studies focus only on one receptor. Western blot analysis of DDR1 and DDR2 expression in different tumor cell lines shows an absence of high co-expression of the two receptors suggesting a deleterious effect of their presence at high amount. To study the consequences of high DDR1 and DDR2 co-expression in cells, we over-express the two receptors in HEK 293T cells and compare biological effects to HEK cells over-expressing DDR1 or DDR2. To distinguish between the intracellular dependent and independent activities of the two receptors we over-express an intracellular truncated dominant-negative DDR1 or DDR2 protein (DDR1DN and DDR2DN). No...
CXCR3 plays important roles in angiogenesis, inflammation, and cancer. However, the precise mecha... more CXCR3 plays important roles in angiogenesis, inflammation, and cancer. However, the precise mechanism of regulation and activity in tumors is not well known. We focused on CXCR3-A conformation and on the mechanisms controlling its activity and trafficking and investigated the role of CXCR3/LRP1 cross talk in tumor cell invasion. Here we report that agonist stimulation induces an anisotropic response with conformational changes of CXCR3-A along its longitudinal axis. CXCR3-A is internalized via clathrin-coated vesicles and recycled by retrograde trafficking. We demonstrate that CXCR3-A interacts with LRP1. Silencing of LRP1 leads to an increase in the magnitude of ligand-induced conformational change with CXCR3-A focalized at the cell membrane, leading to a sustained receptor activity and an increase in tumor cell migration. This was validated in patient-derived glioma cells and patient samples. Our study defines LRP1 as a regulator of CXCR3, which may have important consequences for...
CXCL4 chemokines have antiangiogenic properties, mediated by different mechanisms, including CXCR... more CXCL4 chemokines have antiangiogenic properties, mediated by different mechanisms, including CXCR3 receptor activation. Chemokines have distinct oligomerization states that are correlated with their biological functions. CXCL4 exists as a stable tetramer under physiological conditions. It is unclear whether the oligomerization state impacts CXCL4-receptor interaction. We found that the CXCL4 tetramer is sensitive to pH and salt concentration. Residues Glu28 and Lys50 were important for tetramer formation, and the first β-strand and the C-terminal helix are critical for dimerization. By mutating the critical residues responsible for oligomerization, we generated CXCL4 mutants that behave as dimers or monomers under neutral/physiological conditions. The CXCL4 monomer acts as the minimal active unit for interacting CXCR3A, and sulfation of N-terminal tyrosine residues on the receptor is important for binding. Noticeably, CXCL4L1, a CXCL4 variant that differs by three residues in the C-terminal helix, could activate CXCR3A. CXCL4L1 showed a higher tendency to dissociate into monomers, but native CXCL4 did not. This result indicates that monomeric CXCL4 behaves like CXCL4L1. Thus, in this chemokine family, being in the monomeric state seems critical for interaction with CXCR3A.
Anti-angiogenic and mammalian target of rapamycin inhibitors have shown efficacy in solid tumours... more Anti-angiogenic and mammalian target of rapamycin inhibitors have shown efficacy in solid tumours. Reported combination of both drugs was deemed to be too toxic. Due to a potential favourable safety profile of axitinib (AX), a phase I study combining everolimus (EV) and AX for solid tumours was explored. Patients (pts) with advanced cancers were enrolled in an escalation phase I study to investigate the safety of the combination. Pharmacokinetic profile and functional vascular imaging were performed. An extension to pts with naive metastatic renal cell carcinoma (MRCC) was explored. 15 pts were included over three different dose levels (DLs); DL 0: AX 3 mg BID (twice daily)/EV 5 mg OD (once daily); DL 1: AX 5 mg BID/EV 5 mg OD and DL 2: AX 5 mg BID/EV 10 mg OD for 28 d. One dose-limiting toxicity (DLT) was reported at DL 0: grade (Gr) III diarrhoea and one DLT at DL 2: Gr III asthenia. Three severe adverse events (AEs) in two pts were unexpected: jaw osteonecrosis, recurrent renal failure and cardiomyopathy. Maximum tolerated dose (MTD) was level 2. After 1st cycle, Gr III or Gr II AEs of interest were mainly asthenia, diarrhoea and anorexia. All pts but one showed tumour shrinkage. Partial responses (PRs) were seen in one pt with bladder carcinoma and in one pt in 1st line MRCC in the escalating phase. In the extension phase in naive MRCC treated at MTD, five pts had a PR and one pt had a prolonged stable disease. The recommended dose for phase II is AX 5 mg BID/EV 10 mg OD.
While live 3D high resolution microscopy techniques are developing rapidly, their use for biologi... more While live 3D high resolution microscopy techniques are developing rapidly, their use for biological applications is partially hampered by practical difficulties such as the lack of a versatile sample chamber. Here, we propose the design of a multi-usage observation chamber adapted for live 3D bio-imaging. We show the usefulness and practicality of this chamber, which we named the UniverSlide, for live imaging of two case examples, namely multicellular systems encapsulated in sub-millimeter hydrogel shells and zebrafish larvae. We also demonstrate its versatility and compatibility with all microscopy devices by using upright or inverted microscope configurations after loading the UniverSlide with fixed or living samples. Further, the device is applicable for medium/high throughput screening and automatized multi-position image acquisition, providing a constraint-free but stable and parallelized immobilization of the samples. The frame of the UniverSlide is fabricated using a stereol...
Vascular biology is an important scientific domain that has gradually penetrated many medical and... more Vascular biology is an important scientific domain that has gradually penetrated many medical and scientific fields. Scientists are most often focused on present problems in their daily scientific work and lack awareness regarding the evolution of their domain throughout history and of how philosophical issues are related to their research field. In this article, I provide a personal view with an attempt to conceptualize vascular development research that articulates lessons taken from history, philosophy, biology and medicine. I discuss selected aspects related to the history and the philosophy of sciences that can be extracted from the study of vascular development and how conceptual progress in this research field has been made. I will analyze paradigm shifts, cross-fertilization of different fields, technological advances and its impact on angiogenesis and discuss issues related to evolutionary biology, proximity of different molecular systems and scientific methodologies. Final...
Sunitinib is one of the first-line standard treatments for metastatic clear cell renal cell carci... more Sunitinib is one of the first-line standard treatments for metastatic clear cell renal cell carcinoma (ccRCC) with a median time to progression shorter than 1 year. The objective is to discover predictive markers of response to adapt the treatment at diagnosis. Prospective phase 2 multi-centre trials were conducted in ccRCC patients initiating sunitinib (54 patients) or bevacizumab (45 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). The plasmatic level of CXCL7 at baseline was correlated with progression-free survival (PFS). The cut-off value of CXCL7 for PFS was 250 ng ml(-1). Patients with CXCL7 plasmatic levels above the cut-off at baseline (250 ng ml(-1)) had a significantly longer PFS (hazard ratio 0.323 (95% confidence interval 0.147-0.707), P=0.001). These results were confirmed in a retrospective validation cohort. The levels of CXCL7 did not influence PFS of the bevacizumab-treated patients. CXCL7 may be considered as a predictive marker of sunit...
Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (... more Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (RCC). While treatment improves progression-free survival, most patients relapse. We hypothesized that patient relapse can stem from the development of a lymphatic network driven by the production of the main growth factor for lymphatic endothelial cells, vascular endothelial growth factor C (VEGFC). In this study, we found that sunitinib can stimulate VEGFC gene transcription and increase VEGFC mRNA half-life. Additionally, sunitinib activated p38 MAP kinase, which resulted in the upregulation/activity of HuR and inactivation of tristetraprolin, two AU-rich-element binding proteins. Sunitinib stimulated a VEGFC-dependent development of lymphatic vessels in experimental tumors. This may explain our findings of increased lymph node invasion and new metastatic sites in 30% of sunitinib-treated patients and increased lymphatic vessels found in 70% of neoadjuvant treated patients. In summary,...
Malignant glioma are especially difficult to model in vivo. Here we review the most recent strate... more Malignant glioma are especially difficult to model in vivo. Here we review the most recent strategies for designing relevant models of glioma. These should greatly contribute to identification of new tumor regulating molecules and facilitate testing of inhibitors to be used in therapeutical trials as well as the drug resistance that they might confer.
Background. Glioblastomas are heterogeneous tumors composed of a necrotic and tumor core and an i... more Background. Glioblastomas are heterogeneous tumors composed of a necrotic and tumor core and an invasive periphery. Methods. Here, we performed a proteomics analysis of laser-capture micro-dissected glioblastoma core and inva-sive areas of patient-derived xenografts. Results. Bioinformatics analysis identified enriched proteins in central and invasive tumor areas. Novel markers of invasion were identified, the genes proteolipid protein 1 (PLP1) and Dynamin-1 (DNM1), which were subsequently validated in tumors and by functional assays. Conclusions. In summary, our results identify new networks and molecules that may play an important role in gli-oblastoma development and may constitute potential novel therapeutic targets.
Philosophers have explored the concept of causality for centuries. Here we argue that ideas about... more Philosophers have explored the concept of causality for centuries. Here we argue that ideas about causality from philosophy can help scientists to better understand how cancerous tumors grow and spread in the body. After outlining six characteristics of causality that are relevant to cancer, we emphasize the importance of feedback loops and interactions between tumor-cell-intrinsic and tumor-cell-extrinsic factors for explaining the formation and dissemination of tumors.
Most achievements to engineer blood vessels are based on multiple-step manipulations such as manu... more Most achievements to engineer blood vessels are based on multiple-step manipulations such as manual sheet rolling or sequential cell seeding followed by scaffold degradation. Here, we propose a one-step strategy using a microfluidic coextrusion device to produce mature functional blood vessels. A hollow alginate hydrogel tube is internally coated with extracellular matrix to direct the self-assembly of a mixture of endothelial cells (ECs) and smooth muscle cells (SMCs). The resulting vascular structure has the correct configuration of lumen, an inner lining of ECs, and outer sheath of SMCs. These "vesseloids" reach homeostasis within a day and exhibit the following properties expected for functional vessels (i) quiescence, (ii) perfusability, and (iii) contractility in response to vasoconstrictor agents. Together, these findings provide an original and simple strategy to generate functional artificial vessels and pave the way for further developments in vascular graft and tissue engineering and for deciphering the angiogenesis process.
This article aims at discussing some aspects of the relationship between science, truth and belie... more This article aims at discussing some aspects of the relationship between science, truth and belief. I will primarily focus on the scientific activity in the biological and medical sciences and how it relates to the notion of truth and belief and not discuss the relationship with specific religions. Science has specific methodologies to obtain knowledge. Philosophers have analyzed how scientific knowledge is acquired and have tried to identify its characteristics and to establish some general rules of how knowledge through science is gained. Radical theo- rists have disputed the value of the scientific method despite science’s indisputable successes. If science is a rational activity, it is not free from belief. Belief can have a positive and negative impact on the acquisition of scientific knowledge and the idea of human nature. These different issues will be discussed in depth in this article.
This article aims at discussing some aspects of the relationship between science, truth and belie... more This article aims at discussing some aspects of the relationship between science, truth and belief. I will primarily focus on the scientific activity in the biological and medical sciences and how it relates to the notion of truth and belief and not discuss the relationship with specific religions. Science has specific methodologies to obtain knowledge. Philosophers have analyzed how scientific knowledge is acquired and have tried to identify its characteristics and to establish some general rules of how knowledge through science is gained. Radical theorists have disputed the value of the scientific method despite science's indisputable successes. If science is a rational activity, it is not free from belief. Belief can have a positive and negative impact on the acquisition of scientific knowledge and the idea of human nature. These different issues will be discussed in depth in this article.
Methods in molecular biology (Clifton, N.J.), 2018
We present a protocol for the specific labeling and isolation of proteins from the membrane surfa... more We present a protocol for the specific labeling and isolation of proteins from the membrane surface of endothelial cells and the surrounding extracellular matrix of organs, experimental wounds and tumors using chicken embryos. Proteins are deglycosylated on streptavidin resin and purified after gentle elution and trypsin digestion. Peptides are analyzed by spectroscopy and reverse proteomic fingerprinting. The major advantages of this protocol include reductions in both the background and overrepresentation of single proteins that would otherwise mask less well-represented proteins in the mass spectroscopy analysis. We also present methods to identify putative vascular and endothelial cell targets from isolated chicken membranes and extracellular proteins. The use of human genome and transcriptome data facilitates this analysis. Human orthologs of isolated chicken proteins are identified using best hit BLAST searches against the Human Reference Sequence Database. The expression of H...
The formation of new blood vessels, or angiogenesis, is a complex process that plays important ro... more The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.
Discoidin domain receptors 1 and 2 (DDR1 and DDR2) are members of the tyrosine kinase receptors a... more Discoidin domain receptors 1 and 2 (DDR1 and DDR2) are members of the tyrosine kinase receptors activated after binding with collagen. DDRs are implicated in numerous physiological and pathological functions such as proliferation, adhesion and migration. Little is known about the expressions of the two receptors in normal and cancer cells and most of studies focus only on one receptor. Western blot analysis of DDR1 and DDR2 expression in different tumor cell lines shows an absence of high co-expression of the two receptors suggesting a deleterious effect of their presence at high amount. To study the consequences of high DDR1 and DDR2 co-expression in cells, we over-express the two receptors in HEK 293T cells and compare biological effects to HEK cells over-expressing DDR1 or DDR2. To distinguish between the intracellular dependent and independent activities of the two receptors we over-express an intracellular truncated dominant-negative DDR1 or DDR2 protein (DDR1DN and DDR2DN). No...
CXCR3 plays important roles in angiogenesis, inflammation, and cancer. However, the precise mecha... more CXCR3 plays important roles in angiogenesis, inflammation, and cancer. However, the precise mechanism of regulation and activity in tumors is not well known. We focused on CXCR3-A conformation and on the mechanisms controlling its activity and trafficking and investigated the role of CXCR3/LRP1 cross talk in tumor cell invasion. Here we report that agonist stimulation induces an anisotropic response with conformational changes of CXCR3-A along its longitudinal axis. CXCR3-A is internalized via clathrin-coated vesicles and recycled by retrograde trafficking. We demonstrate that CXCR3-A interacts with LRP1. Silencing of LRP1 leads to an increase in the magnitude of ligand-induced conformational change with CXCR3-A focalized at the cell membrane, leading to a sustained receptor activity and an increase in tumor cell migration. This was validated in patient-derived glioma cells and patient samples. Our study defines LRP1 as a regulator of CXCR3, which may have important consequences for...
CXCL4 chemokines have antiangiogenic properties, mediated by different mechanisms, including CXCR... more CXCL4 chemokines have antiangiogenic properties, mediated by different mechanisms, including CXCR3 receptor activation. Chemokines have distinct oligomerization states that are correlated with their biological functions. CXCL4 exists as a stable tetramer under physiological conditions. It is unclear whether the oligomerization state impacts CXCL4-receptor interaction. We found that the CXCL4 tetramer is sensitive to pH and salt concentration. Residues Glu28 and Lys50 were important for tetramer formation, and the first β-strand and the C-terminal helix are critical for dimerization. By mutating the critical residues responsible for oligomerization, we generated CXCL4 mutants that behave as dimers or monomers under neutral/physiological conditions. The CXCL4 monomer acts as the minimal active unit for interacting CXCR3A, and sulfation of N-terminal tyrosine residues on the receptor is important for binding. Noticeably, CXCL4L1, a CXCL4 variant that differs by three residues in the C-terminal helix, could activate CXCR3A. CXCL4L1 showed a higher tendency to dissociate into monomers, but native CXCL4 did not. This result indicates that monomeric CXCL4 behaves like CXCL4L1. Thus, in this chemokine family, being in the monomeric state seems critical for interaction with CXCR3A.
Anti-angiogenic and mammalian target of rapamycin inhibitors have shown efficacy in solid tumours... more Anti-angiogenic and mammalian target of rapamycin inhibitors have shown efficacy in solid tumours. Reported combination of both drugs was deemed to be too toxic. Due to a potential favourable safety profile of axitinib (AX), a phase I study combining everolimus (EV) and AX for solid tumours was explored. Patients (pts) with advanced cancers were enrolled in an escalation phase I study to investigate the safety of the combination. Pharmacokinetic profile and functional vascular imaging were performed. An extension to pts with naive metastatic renal cell carcinoma (MRCC) was explored. 15 pts were included over three different dose levels (DLs); DL 0: AX 3 mg BID (twice daily)/EV 5 mg OD (once daily); DL 1: AX 5 mg BID/EV 5 mg OD and DL 2: AX 5 mg BID/EV 10 mg OD for 28 d. One dose-limiting toxicity (DLT) was reported at DL 0: grade (Gr) III diarrhoea and one DLT at DL 2: Gr III asthenia. Three severe adverse events (AEs) in two pts were unexpected: jaw osteonecrosis, recurrent renal failure and cardiomyopathy. Maximum tolerated dose (MTD) was level 2. After 1st cycle, Gr III or Gr II AEs of interest were mainly asthenia, diarrhoea and anorexia. All pts but one showed tumour shrinkage. Partial responses (PRs) were seen in one pt with bladder carcinoma and in one pt in 1st line MRCC in the escalating phase. In the extension phase in naive MRCC treated at MTD, five pts had a PR and one pt had a prolonged stable disease. The recommended dose for phase II is AX 5 mg BID/EV 10 mg OD.
While live 3D high resolution microscopy techniques are developing rapidly, their use for biologi... more While live 3D high resolution microscopy techniques are developing rapidly, their use for biological applications is partially hampered by practical difficulties such as the lack of a versatile sample chamber. Here, we propose the design of a multi-usage observation chamber adapted for live 3D bio-imaging. We show the usefulness and practicality of this chamber, which we named the UniverSlide, for live imaging of two case examples, namely multicellular systems encapsulated in sub-millimeter hydrogel shells and zebrafish larvae. We also demonstrate its versatility and compatibility with all microscopy devices by using upright or inverted microscope configurations after loading the UniverSlide with fixed or living samples. Further, the device is applicable for medium/high throughput screening and automatized multi-position image acquisition, providing a constraint-free but stable and parallelized immobilization of the samples. The frame of the UniverSlide is fabricated using a stereol...
Vascular biology is an important scientific domain that has gradually penetrated many medical and... more Vascular biology is an important scientific domain that has gradually penetrated many medical and scientific fields. Scientists are most often focused on present problems in their daily scientific work and lack awareness regarding the evolution of their domain throughout history and of how philosophical issues are related to their research field. In this article, I provide a personal view with an attempt to conceptualize vascular development research that articulates lessons taken from history, philosophy, biology and medicine. I discuss selected aspects related to the history and the philosophy of sciences that can be extracted from the study of vascular development and how conceptual progress in this research field has been made. I will analyze paradigm shifts, cross-fertilization of different fields, technological advances and its impact on angiogenesis and discuss issues related to evolutionary biology, proximity of different molecular systems and scientific methodologies. Final...
Sunitinib is one of the first-line standard treatments for metastatic clear cell renal cell carci... more Sunitinib is one of the first-line standard treatments for metastatic clear cell renal cell carcinoma (ccRCC) with a median time to progression shorter than 1 year. The objective is to discover predictive markers of response to adapt the treatment at diagnosis. Prospective phase 2 multi-centre trials were conducted in ccRCC patients initiating sunitinib (54 patients) or bevacizumab (45 patients) in the first-line metastatic setting (SUVEGIL and TORAVA trials). The plasmatic level of CXCL7 at baseline was correlated with progression-free survival (PFS). The cut-off value of CXCL7 for PFS was 250 ng ml(-1). Patients with CXCL7 plasmatic levels above the cut-off at baseline (250 ng ml(-1)) had a significantly longer PFS (hazard ratio 0.323 (95% confidence interval 0.147-0.707), P=0.001). These results were confirmed in a retrospective validation cohort. The levels of CXCL7 did not influence PFS of the bevacizumab-treated patients. CXCL7 may be considered as a predictive marker of sunit...
Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (... more Sunitinib is an antiangiogenic therapy given as a first-line treatment for renal cell carcinoma (RCC). While treatment improves progression-free survival, most patients relapse. We hypothesized that patient relapse can stem from the development of a lymphatic network driven by the production of the main growth factor for lymphatic endothelial cells, vascular endothelial growth factor C (VEGFC). In this study, we found that sunitinib can stimulate VEGFC gene transcription and increase VEGFC mRNA half-life. Additionally, sunitinib activated p38 MAP kinase, which resulted in the upregulation/activity of HuR and inactivation of tristetraprolin, two AU-rich-element binding proteins. Sunitinib stimulated a VEGFC-dependent development of lymphatic vessels in experimental tumors. This may explain our findings of increased lymph node invasion and new metastatic sites in 30% of sunitinib-treated patients and increased lymphatic vessels found in 70% of neoadjuvant treated patients. In summary,...
Malignant glioma are especially difficult to model in vivo. Here we review the most recent strate... more Malignant glioma are especially difficult to model in vivo. Here we review the most recent strategies for designing relevant models of glioma. These should greatly contribute to identification of new tumor regulating molecules and facilitate testing of inhibitors to be used in therapeutical trials as well as the drug resistance that they might confer.
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Papers by Andreas Bikfalvi