DigitalUM :: Browsing by Subject "Angiogenesis"

Browsing by Subject "Angiogenesis"

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Open Access
A GFP endometriosis model reveals important morphological characteristics of the angiogenic process that govern benign and malignant diseases
(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Machado, Daniel Escorsim; Júnior, Antônio Palumbo; Santos, João Marcos; Mattos, Rômulo Medina; dos Santos, Thiago Alves; Seabra, Sergio Henrique; Boldrini, Leonardo da Cunha; Machado, Jamila Alessandra Perini; Nasciutti, Luiz Eurico
Endometriosis involves the growth of endometriotic tissue outside the uterine cavity, and is frequently associated with different malignancies. A well-reported alteration in the disease microenvironment is the proliferation of new blood vessels around the lesions, as part of a necessary repertory to contribute to the invasiveness and development of infiltrating endometriosis. Therefore, the establishment of a reliable experimental model is essential to elucidate the contribution of angiogenesis and to develop new therapeutic approaches to endometriosis treatment. For this purpose we transplanted endometrial fragments from green fluorescent protein (GFP)-mice (n=20) into the peritoneal cavity of wild-type mice (n=20), and then analyzed the morphological changes and the process of angiogenesis. The lesions were cystic and vascularized, and showed morphological hallmarks such as endometrial glands and stroma. An increase in endometriotic lesion vascular density was revealed by immunostaining and RNAm expression for Vegf and its receptor Flk-1, and the lesions were confirmed as a tissue-donor source by GFP fluorescent cells. The same pattern was observed through staining of activated macrophages and an increase of about 25% in the number of macrophage-positive cells was also demonstrated in endometriotic lesions by flow cytometry, which concords with previous data that correlate endometriosis, angiogenesis and inflammation. According to our understanding, this is the first demonstration that the pattern of the angiogenic process in the GFP endometriosis model is very similar to that of cancer. These observations will be useful for investigation of the process of angiogenesis involved in the attachment and invasion of endometrial cells, as well as an in vivo platform model to study the effects of antiangiogenic drugs.
Open Access
A role for monomeric C-reactive protein in regulation of angiogenesis, endothelial cell inflammation and thrombus formation in cardiovascular/cerebrovascular disease?
(Murcia : F. Hernández, 2009) Slevin, M.; Krupinski, J.
Native CRP (nCRP) is a pentameric oligoprotein composed of identical 23 KDa subunits which can be irreversibly dissociated to form free subunits or monomeric CRP (mCRP). mCRP has a reduced aqueous solubility and a tendency to aggregate into matrix-like lattices in various tissues, in particular, blood vessel walls. A dramatic increase in expression of mCRP occurs in angiogenic blood vessels derived from stroked brain regions, atherosclerotic arteries and active vessels from other angiogenic diseases such as Alzheimer’s. Furthermore, mCRP unlike the native molecule is highly angiogenic to vascular endothelial cells in vitro and therefore might impact on the processes of vascularization and re-modelling thus affecting tissue survival and development. In this mini-review, we will discuss the differences in the biological properties between nCRP and mCRP. We will provide a brief historical background to the importance of nCRP as a biomarker for cardiovascular disease. We will explain the mechanisms of conversion of nCRP to its monomeric form and describe evidence for the role of mCRP in modulation of endothelial cell activation, promotion of inflammatory status and thrombus formation in cardio/cerebrovascular disease. Finally, we will provide evidence for the accumulation of mCRP in angiogenic microvessels from diseased tissue, and demonstrate its highly pro-angiogenic capabilities. The discovery of the existence of this tissue-associated, highly angiogenic monomeric form of CRP capable of cellular binding and intra-cellular signal transduction activation may help in our understanding of the processes responsible for modulation of angiogenesis and inflammation in disease.
Open Access
A twist tale of cancer metastasis and tumor angiogenesis
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2015) Tseng, Jen-Chieh; Chen, Hsiao-Fan; Wu, Kou-Juey
Twist1 is an evolutionally conserved transcription factor. Originally identified in Drosophila as a key regulator for mesoderm development, it was later implicated in many human diseases, including Saethre-Chotzen syndrome and cancer. Twist1’s involvement in cancer has been well recognized. Driven by hypoxia-induced factor-1 (HIF-1), Twist1 has been considered as a proto-oncogene and its overexpression has been observed in a wide variety of human cancers. High expression level of Twist1 is closely related to tumor aggressiveness and metastatic potential. In cancer cells, Twist1 has been shown to function as a key regulator of epithelial-mesenchymal transition (EMT), a critical process for metastasis initiation. Twist1 has also been implicated in maintaining cancer stemness for selfrenewal and chemoresistance. This review first summarizes the roles of Twist1 in embryo development and Saethre-Chotzen syndrome followed by a discussion of Twist1’s critical functions in cancer. In particular, the review focuses on the recent discovery of Twist1’s capability to promote endothelial transdifferentiation of cancer cells beyond EMT.
Open Access
Administration of L-arginine reduces the delay of the healing process caused by ibuprofen. Implication of COX and growth factors expression
(Murcia : F. Hernández, 2005) Sánchez-Fidalgo, S.; Martín-Lacave, Inés; Illanes, M.; Bruseghini, L.; Esteras, A.; Motilva, V.
The objective of the present study has been to advance knowledge of the gastric role played by the amino acid L-Arginine (L-Arg) in the evolution of a chronic gastric ulcer. In order to clarify it, L-Arg alone or together with Ibuprofen have been administrated in an experimental acetic acid chronic ulcer, analysing characteristic parameters of an active curative process, such as PGE2 production, COX expression, and also angiogenesis, proliferation/apoptosis and growth factors expression. Our results reveal that L-Arg is favourable in the healing process improving the curative course. Ibuprofen caused a delay in ulcer healing, more evident 14 days after ulcer induction; COX-2 expression was increased at the 7th day although no signal of protein could be detected after 14 days; PGE2 production was inhibited in intact and ulcerated areas at both times assayed. In contrast, treatment with L-Arg reduced the delay of the lesion, the increment in COX-2 expression induced by Ibuprofen, and was able to maintain PGE2 levels similar to the control group after 14 days. Additionally, the histological study showed that the healing effects of L-Arg might be associated with an increased angiogenesis and FGF-2 expression. These actions could be considered key factors in the healing response associated with L-Arg administration. However, the proliferation study assayed with the PCNA-immunostaining method did not reveal significant differences, as the same as the apoptosis analysis. In conclusion, the coupling of L-Arg to Ibuprofen is an attractive alternative to Ibuprofen administration alone because it not only attenuates but also improves the evolution of chronic lesions through mechanisms that implicate endogenous PG and FGF-2- associated pathways, which allow an increase of angiogenesis process.
Open Access
Akt signaling and its role in postnatal neovascularization
(Murcia : F. Hernández, 2005) Ma, F.X.; Han, Z.C.
Postnatal neovascularization has been known to be involved in not only angiogenesis but also vasculogenesis. Several lines of evidence suggest a link between neovascularization and Akt, a family member of serine/threonine protein kinases. Akt phosphorylates endothelial NO synthase (eNOS) and thereby enhances endothelial NO synthesis and influences postnatal vessel growth. Akt signaling is activated by a variety of stimuli in endothelial cells and endothelial progenitor cells (EPCs). Activation of the Akt kinase orchestrates a number of signaling pathways potentially involved in angiogenesis. Dominant negative Akt overexpression leads to functional blocking of EPC bioactivity. Because neovascularization is implicated in the pathophysiology of a number of diseases and is becoming an important therapeutic strategy for those diseases, further dissection of the Akt pathway and elucidation of the downstream effector molecules will lead to a better understanding of postnatal neovascularization and may provide avenues for the development of novel therapeutic interventions. In this review, molecular mechanisms of Akt signal pathway will be discussed with special emphasis on its role in neovascularization.
Open Access
Angiogenesis after sintered bone implantation in rat parietal bone
(Murcia : F. Hernández, 2003) Ohtsubo, S.; Matsuda, Mikio; Takekawa, M.
We studied the effect of bone substitutes on revascularization and the restart of blood supply after sintered bone implantation in comparison with synthetic hydroxyapatite implantation and fresh autogenous bone transplantation (control) in rat parietal bones. Methods for the study included the microvascular corrosion cast method and immunohistochemical techniques were also used. The revascularization of the control group was the same as that for usual wound healing in the observations of the microvascular corrosion casts. The sintered bone implantation group was quite similar to that of the control group. In the synthetic hydroxyapatite group, immature newly-formed blood vessels existed even on the 21st day after implantation and the physiological process of angiogenesis was interrupted. Immunohistochemically, vascular endothelial growth factor (VEGF), which activates angiogenesis, appeared at the early stages of both the control group and the sintered bone implantation group. VEGF reduced parallel with the appearance of the transforming growth factor factor-beta-1 (TGF-beta-1), which obstructs angiogenesis, and the angiogenesis passed gradually into the mature stage. In the hydroxyapatite implantation group, TGF-beta-1 appeared at the early stage of the implants. The appearance of VEGF lagged and it existed around the pores of hydroxyapatite even on the 21st day of the implantation. Proliferation and wandering of endothelial cells continued without any maturing of the vessels. These findings suggest that the structure and the components of the implant material affect angiogenesis after implantation as well as new bone formation.
Open Access
Angiogenesis and expression of tenascin after transmural laser revascularization
(Murcia : F. Hernández, 1999) Gassler, N.; Rastar, F.; Hentz, M.W.
Transmyocardial revascularization (TMR) with CO2-laser equipment is an alternative approach in the treatment of patients with severe ischemic cardiac disease. Several studies concerning morphological features after TMR document a strong transmyocardial injury, but little is known about wound healing in laserinduced alterations of the cardiac skeleton and their putative role for angiogenesis and endothelialization. The present study was conducted to establish a useful immunohistochemical marker for detection of these laser-induced injuries and to analyze starting points of angiogenesis in human myocardium after TMR. Our data show that tenascin labeling is a useful immunohistochemical approach to detect laser-alterated segments of the cardiac skeleton as well as laser-induced fibrosis. Starting points of the angiogenetic process are seen throughout the margins of laser-induced lesions, where myocardial capillaries are found. Disrupted vessels located within laser-alterated connective tissue septa are not major starting points for endothelialization of laser-induced lesions and for capillary sprouts. In comparison to laser-induced fibrosis, induction and promotion of angiogenesis by laser radiation is weak.
Open Access
Angiogenesis and liver fibrogenesis
(Murcia : F. Hernández, 2009) Valfrè di Bonzo, Lorenzo; Novo, Erica; Cannito, Stefania; Busletta, Chiara; Paternostro, Claudia; Povero, Davide; Parola, Maurizio
Angiogenesis is a dynamic, hypoxiastimulated and growth factor-dependent process, eventually leading to the formation of new vessels from pre-existing blood vessels. In the last decade experimental and clinical studies have described the occurrence of hepatic angiogenesis in a number of different pathophysiological conditions, including those involving inflammatory, fibrotic and ischemic features. In particular, the literature evidence indicates that hepatic angiogenesis is strictly associated with, and may even favour fibrogenic progression of chronic inflammatory liver diseases of different aetiology. In this review, current “in vivo” and “in vitro” evidence supporting the potential pathogenetic role of angiogenesis in chronic liver diseases will be reviewed in an attempt to outline cellular and molecular mechanisms involved, with a specific emphasis on the crucial role of hypoxic conditions and hepatic stellate cells (HSCs), particularly when activated to the myofibroblast-like pro-fibrogenic phenotype.
Open Access
Angiogenesis in rheumatoid arthritis
(Murcia : F. Hernández, 2006) Maruotti, Nicola; Cantatore, F.P.; Crivellato, E.; Vacca, A.; Ribatti, Doménico
There is much evidence that rheumatoid arthritis is closely linked to angiogenesis. Important angiogenic mediators have been demonstrated in synovium and tenosynovium of rheumatoid joints. VEGF (Vascular Endothelial Growth Factor), expressed in response to soluble mediators such as cytokines and growth factors and its receptors are the best characterized system in the angiogenesis regulation of rheumatoid joints. Moreover, other angiogenic mediators such as platelet-derived growth factor (PDGF), fibroblast growth factor-2 (FGF-2), epidermal growth factor (EGF), insulin-like growth factor (IGF), hepatocyte growth factor (HGF), transforming growth factor beta (TGF-ß), tumor necrosis factor alpha (TNF- a), interleukin-1 (IL-1), IL-6, IL-8, IL-13, IL-15, IL-18, angiogenin, platelet activating factor (PAF), angiopoietin, soluble adhesion molecules, endothelial mediator (endoglin) play an important role in angiogenesis in rheumatoid arthritis. On the other hand, endostatin, thrombospondin-1 and -2 are angiogenic inhibitors in rheumatoid arthritis. The persistence of inflammation in rheumatoid joints is a consequence of an imbalance between these inducers and inhibitors of angiogenesis.
Open Access
Angiogenesis in the central nervous system: a role for vascular endothelial growth factor/vascular permeability factor and tenascin-C. Common molecular effectors in cerebral neoplastic and non-neoplastic “angiogenic diseases”
(Murcia : F. Hernández, 2002) Zagzag, D.; Capo, V.
Human pathological conditions of the central nervous system (CNS) associated with angiogenesis (i.e. neovascularization) include neoplastic, as well as infectious, ischemic, and traumatic processes. Upregulation of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) and tenascin-C (TN-C) is spatially and temporally related to neovascularization. Spatially, VEGF/VPF and TN-C are both found at the site of neovascularization, but they are not detected in areas of normal brain or in areas without neovascularization. Te m p o r a l l y, VEGF/VPF and TN-C are found at the peak of angiogenesis and are not detected when angiogenesis had ceased.
Open Access
Angiogenesis: an update
(Murcia : F. Hernández, 1994) Díaz-Flores, Lucio; Gutiérrez, Ricardo; Varela, H.
Angiogenesis is the neovascularization or formation of new blood vessels from the established microcirculation. It is particularly important and indispensable in a large number of normal and pathological processes during pre- and post-natal life, including neoplasia, inflammation, wound repair and collaterization in response to ischemic stimuli. The current interest in the role of neovascularization in the transition from hyperplasia to neoplasia, as well as in the tumour growth and metastasis, has brought about a large number of studies on angiogenesis. The complex processes of neovascularization, quiescent in the adult organism, may occur rapidly in several circumstances, with the implication of the following events: a) endothelial cell (EC) and pericyte activation; b) basal lamina degradation; c) migration and proliferation of EC and pericytes; d) formation of a new capillary vessel lumen; e) appearance of pericytes around the new capillaries; f) development of a new basal lamina; g) capillary loop formation; h) persistence or involution, and differentiation of the new vessels; and i) capillary network formation and, eventually, organization into larger microvessels. The use of numerous "in vivo" and "in vitro" systems has facilitated the assessment of angiogenesis control, in which angiogenic (fibroblast growth factors, vascular endothelial growth factor, platelet endothelial growth factor, E series prostaglandin, angiogenin, monobutyrin) and antiangiogenic (cartilagederived angiogenic inhibitor, thrombospondin, protamine, platelet factor-4, interferon, angiostatic antibiotics, steroids) substances intervene. Heparin and heparin sulphate also play a key role in these mechanisms. A greater knowledge of angiogenesis control may lead to the development of a potential therapy in angiogenesis-related processes.
Open Access
Angiopoietin-1Tie2 receptor signaling in vascular quiescence and angiogenesis
(Murcia : F. Hernández, 2010) Fukuhara, Shigetomo; Sako, Keisuke; Noda, Kazuomi; Zhang, Jianghui; Minami, Masayoshi; Mochizuki , Naoki
Angiopoietin (Ang) 1 is a ligand forendothelium-specific receptor tyrosine kinase Tie-2. Inadult vasculature, Ang1/Tie2 signaling is thought toregulate both maintenance of vascular quiescence andpromotion of angiogenesis. However, it has beenunknown how Tie2 signal regulates these distinctbiological functions. Recently, we and Alitalo’s grouphave clarified that Ang1 assembles distinct Tie2signaling complexes in either presence or absence ofendothelial cell-cell adhesions. Ang1 induces trans-association of Tie2 at cell-cell contacts, whereas Tie2 isanchored to the extracellular matrix (ECM) by Ang1 atthe cell-substratum interface. Trans-associated Tie2 andECM-anchored Tie2 activate distinct signalingpathways. In this review, we discuss how Ang1/Tie2signal regulates both maintenance of vascular quiescenceand promotion of angiogenesis, especially focusing onthe roles of trans-associated Tie2 and ECM-anchoredTie2
Open Access
Antiangiogenic and radiotherapy for cancer treatment
(Murcia : F. Hernández, 2006) Kobayashi, H.; Lin, P.C.
Tumor growth and progression depends on tumor angiogenesis, the growth of tumor blood vessels, therefore, targeting tumor angiogenesis is a very promising approach for controlling tumor growth and/or causing regression. Tumor blood vessels have been recognized as a critical component of radiation response to the point of being independent of tumor oxygenation during radiation. An anti-angiogenic approach has been considered less likely to develop drug resistance. But recent findings suggest that anti-angiogenesis causes hypoxia that selects tumor cells (due to genetic instability) that are less dependent on blood supply and leads to drug resistance. The approach of combination of anti-angiogenesis with ionizing radiation by targeting both endothelial and tumor cells should minimize this possibility. The combination may produce a synergistic anti-tumor effect.
Open Access
Arterial wall neovascularization induced by glycerol
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2001) Díaz Flores, L.; Madrid, J. F.; Gutierrez, R.; Valladares, F.; Díaz, M.; Valera, H.; Díaz Flores Jr, L.
An int e nse a nd sig ni fica nt neo - vascul ari za tion, with numerous capillaries growing into th e med ia laye r o f th e rat femo ra l art e ry, was demonstrated when glycero l was administered into the interstitium be tween the femoral ve in and the femoral a rt e ry. Th e max imum mi c rovasc ul a ri za ti o n was obse rved at days 7 and 9 after glyce rol administration. Afterwards, invo lution of th e majo rit y of the new lyfo rmed microvessels in the art erial wall occurred. Other substances containing glyce rol in their molecul es, such as tri ace tyl-glyce rol and tri butyril-glyce rol, fa il ed to produce significant neovascul ari zation in the medi a laye r of the femora l art ery. Neova cul ariza tion of the art eri al wa ll was preceded by a co nside rab le dec rease in the number of the smooth muscle ce lls, whi ch ex perienced apoptosis and necrobiosis, disappearing in extense areas of the arteri al segment affected by glyce rol. Coinciding with neovascul ariza tion and mi crovascul ar in volu tion, repopul ation of the med ia laye r by smooth mu 'cle cells was observed.
Open Access
Astragaloside IV induces endothelial progenitor cell angiogenesis in deep venous thrombosis through inactivation of PI3K/AKT signaling
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Lyu, Xiaojiang; Yi, Zhigang; He, Yun; Zhang, Chunfeng; Zhu, Ping; Liu, Chonghai
Background. Deep vein thrombosis (DVT), referred to as venous thromboembolism, is the third most frequent cardiovascular disease. Endothelial progenitor cells (EPCs) contribute to the recanalization of DVT. Astragaloside IV (AS-IV) has been suggested to have angiogenesis-enhancing effects. Here, we investigate the roles and mechanisms of AS-IV in EPCs and DVT. Methods. The experimental DVT model was established by inferior vena cava stenosis in rats. EPCs were collected from patients with DVT. Transwell assays were performed to detect cell migration. Tube formation was determined using Matrigel basement membrane matrix and ImageJ software. The thrombus weight and length were measured. Pathological changes were examined by hematoxylin-eosin staining. The production of proinflammatory cytokines was estimated by ELISA. The level of PI3K/AKT-related proteins was measured by western blotting. Results. AS-IV administration facilitated the migrative and angiogenic functions of human EPCs in vitro. Additionally, AS-IV inhibited thrombosis and repressed the infiltration of leukocytes into the thrombus and the production of proinflammatory cytokines in rats. Mechanistically, AS-IV inactivated PI3K/AKT signaling in rats. Conclusion. AS-IV prevents thrombus in an experimental DVT model by facilitating EPC angiogenesis and decreasing inflammation through inactivation of PI3K/AKT signaling.
Open Access
ATM gene expression is associated with differentiation and angiogenesis in infiltrating breast carcinomas
(Murcia : F. Hernández, 2006) Cuatrecasas, M.; Santamaria, G.; Velasco, M.; Camacho, E.; Hernandez, L.; Sanchez, M.; Orrit, C.; Murcia, C.; Cardesa, Antonio; Campo, Elías; Fernandez, P.L.
The product of the ATM gene, mutated in the human genetic disorder ataxia-telangiectasia (A-T) plays a key role in the detection and repair of DNA doublestrand breaks. A-T is defined by progressive cerebellar ataxia, telangiectasia, sensitivity to ionising radiation and genomic instability with cancer predisposition. On the other hand, increased angiogenesis is essential for tumor growth and metastasis. The aim of this study was to investigate ATM expression in breast carcinomas and its relationship to neoangiogenesis. Methods and Results: Fifty-two breast tumors from 51 patients, 38 of them with concomitant in situ component (CIS), were analyzed by immunohistochemistry for the expression of ATM. CD34 expression was used for the morphometric evaluation of vasculature. ATM was positive in 1 to 10% of normal epithelial cells. ATM expression was reduced in 55.8% of infiltrating carcinomas, non-reduced in 34.6%, and increased in 9.6%. Expression of ATM in CIS was similar to the infiltrating component in 71% of cases and reduced in 23.7% of them. High-grade ductal infiltrating carcinomas showed lower ATM expression than lowgrade ones. Reduced ATM expression also correlated with increased microvascular area. Conclusions: Reduced ATM expression in breast carcinomas correlated with tumor differentiation and increased microvascular parameters, supporting its role in neoangiogenesis and tumor progression in breast carcinogenesis.
Open Access
Blood vessel morphometry in human colorectal lesions
(Murcia : F. Hernández, 1995) Tipoe, G.L.; White, F.H,
Neovascularisation in tumours of different cell origins has been well documented qualitatively. In this report, we have assessed vascular architecture in different pathological lesions of the colorectum by quantifying blood vessel parameters in order to detect subtle morphological changes using objective methods. Colorectal tissue samples were obtained from resected large bowels containing malignant tumours. Biopsies were taken from defined sites in the resected specimen and were classified as normal (N), potentially premalignant mucosa (PPM), adenomatous polyp (P) and adenocarcinoma (ADCA). Al1 tissues were fixed in modified Karnovsky's fixative for 4 hrs and postfixed in 1% Oso4 for 1 hr. Samples were processed for EM under standardized procedures and embedded in Epon. 0.5 pm semithin sections from five patients per group were stained with toluidine blue. A multistage systematic sampling procedure was adopted. The imer outlines of al1 blood vessels in the lamina propria (LP) were digitised using a Zeiss VIDAS Image Analyzer at a final magnification of ~1,050T. he area of the reference (LP) was also measured. No attempt was made to distinguish between the different types of vessel. The morphometric blood vessels parameters quantified were volume density (V,), numerical density (NA), length density (LV) and mean transverse sectional area (A). Statistically significant differences in Vv and A were detected between al1 groups except between N and PPM and between P and ADCA. No significant differences in NA and LV were present in any group comparisons. The mean values of al1 parameters were the highest in ADCA. Our results suggest that vasodilatation occurred in order to provide an increased supply of nutrients to support active growth and division of the transforming cells. Such vasodilatation might also reflect the inflammatory response to the presence of actively growing malignant cells since activated immune cells are able to release vasoactive substances.
Open Access
Bone marrow angiogenesis: methods of quantification and changes evolving in chronic myeloproliferative disorders
(Murcia : F. Hernández, 2004) Kvasnicka, H.M.; Thiele, J.
Until now little information is available about bone marrow (BM) angiogenesis in chronic myeloproliferative disorders (CMPDs). Amongst the various immunohistochemical markers for endothelial cells CD34 and CD105 have proven to be most reliable since they exhibit no relevant co-staining. Determination of vascularity has to include pathophysiological aspects of perfusion. Therefore, quantification of the microvascular density (MVD) by the so-called hot spot method has to be improved by parameters that characterize blood flow more properly like microvessel area (luminal distension), shape (form factor), tortuosity, and branching (maximal vessel length). In comparison to the normal BM chronic myeloid leukemia (CML) revealed a significant increase in MVD which was functionally associated with elevated levels of angiogenic cytokines. Structure of vessels was significantly altered by showing an enhanced irregularity of shape and tortuosity and increase in fibers was conspicuously accompanied by a higher degree of MVD. Contrasting the group of patients with Imatinib (STI571) therapy interferon failed to reduce the number of vessels. Following bone marrow transplantation a significant enhancement of the MVD was found in the early posttransplant period, but after about 6 months normalization occurred. Anomalies of microvascular architecture were easily demonstrable by three-dimensional reconstruction and consisted of a complex branching network of irregular shaped sinuses. Chronic idiopathic myelofibrosis displayed a significant increase in the MVD only in the advanced fibrosclerotic stages. This feature was accompanied by an enhanced luminal distension and tortuosity, thus contrasting the prefibrotic and early fibrotic phases of this disorder. Similar to CML a relationship between evolving myelofibrosis and change in vascular architecture was encountered. This feature may present a possible target for future antiangiogenic antiangiogenic therapy. In essential thrombocythemia there is only a mild increase in MVD detectable while in polycythemia vera besides an enlarged number, a luminal dilation due to the densely packed erythrocytes is recognizable. In conclusion, contrasting the usually applied quantification technique more elaborate morphometrical methods are warranted to obtain a better insight into the vascular architecture of the BM. In CMPDs angiogenesis is significantly associated with the evolution of myelofibrosis and may be altered by therapeutic regimens probably due to changes in cytokine release.
Open Access
Cancer progression and substance P
(F. Hernández y Juan F. Madrid. Universidad de Murcia. Departamento de Biología Celular e Histología, 2014) Coveñas, Rafael; Muñoz, Miguel
The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in cancer. After binding to the NK-1 receptor, SP induces tumor cell proliferation, migration of tumor cells (invasion, infiltration and metastasis) and angiogenesis. In contrast, NK-1 receptor antagonists inhibit tumor cell proliferation (tumor cells die by apoptosis), block the migratory activity of tumor cells, and exert antiangiogenic properties. The induction of apoptosis offers an appropriate method for cancer treatment. The NK-1 receptor can be considered as a target in cancer treatment. A common mechanism for cancer cell proliferation mediated by SP and the NK-1 receptor occurs and NK-1 receptor antagonists are broadspectrum antineoplastic drugs. The NK-1 receptor antagonist aprepitant is used in clinical practice and exerts an antitumor action against a large number of different human tumor cells. In the future, such antitumor action should be tested in human clinical trials.
Open Access
Clinical, pathological and immunological features of psoriatic-like lesions affecting keratin 14-vascular endothelial growth factor transgenic mice
(Murcia: F. Hernández, 2011) Canavese, M.; Altruda, F.; Silengo, L.; Castiglioni, V.; Scanziani, E.; Radaelli, E.
Up-regulation of vascular endothelial growth factor (VEGF) plays a primary role in the pathogenesis of psoriasis. Transgenic mice over-expressing VEGF under the Keratin 14 (K14) promoter develop an inflammatory skin condition with many of the pathobiological features of human psoriasis. In this work, the development of spontaneous psoriatic-like dermatitis in K14-VEGF transgenic mice was monitored from week 6 to week 44 and skin lesions were characterized clinically (application of a clinical score system comparable to the human Psoriasis Area and Severity Index), microscopically (histopathology, leukocyte subset and neoangiogensis) and immunologically (evaluation of local and systemic cytokine/chemokine profiles). Based on PASI score system, three progressive clinical phases were identified: mild acute (8-14 weeks of age), moderate subacute (15-21 weeks of age) and severe chronic-active (22-44 weeks of age) dermatitis. Microscopically, skin lesions consisted of progressive proliferative psoriatic-like dermatitis dominated by dermo-epidermal infiltrates of CD3-positive lymphocytes, an increased number of mast cells and neoangiogenesis. Both local and systemic up-regulation of pro-inflammatory (IL-12, TNF-alpha, IL-6, MCP-1 and IL-8) and regulatory (IL-10) cytokines/chemokines was observed, mainly during the later stages of disease development. The results obtained in this study further confirm the central role of VEGF over-expression in the development of psoriatic-like dermatitis. Similarly to what is reported for human psoriasis, both the local and systemic immunologic profiles observed in K14-VEGF transgenic mice suggest that a combined Th1 and Th17 response may be implicated in lesion development. The identification of three progressive stages of disease, each with peculiar clinicopathological features, renders the K14-VEGF transgenic mouse a valuable model to study novel immunotherapies for psoriasis.