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PubMed1996

Vascular endothelial growth factor and de novo mammalian angiogenesis.

The time course and potency of the de novo angiogenic response to vascular endothelial growth factor isoform 165 (VEGF165) at approximate physiologic doses was assessed using the nonsurgical mesenteric-window angiogenesis assay in adult rats. Daily i.p. injections of VEGF165 at 4.8, 48, and 480 pM were given for Days 0-4, controls receiving the vehicle. Groups of 10 animals per treatment group were sacrificed on Days 7, 14, and 21. Using microscopic morphometry and image analysis, the vascularized area, a measure of microvascular spatial extension, and the microvascular length, a measure of microvascular density, were measured. At 4.8 and 480 pM, VEGF165 induced significant angiogenesis as early as on Day 7, suggesting a direct angiogenic effect. This very rapid angiogenic response to VEGF165 is distinct from other angiogenesis reactions, including angiogenesis induced by basic fibroblast growth factor, studied using the same methodology. During the early angiogenic phase, the increase in microvascular spatial expansion dominated over the increase in microvascular density. The specific response to VEGF165 peaked on Day 7 for the 4.8 pM dose and on Day 14 for the 480 pM dose, which was the more potent. It is, moreover, noteworthy that no statistically significant response was induced by the intermediate dose of VEGF165 (48 pM) at any observation time. The data thus suggest that, although VEGF165 at near physiologic doses apparently acts as a direct angiogen, its dose-related effect in terms of angiogenesis is nonlinear.

Animals↗
PubMed1997

Interleukin-1-alpha and de novo mammalian angiogenesis.

In the literature, the role of interleukin-1 (IL-1) as an angiogen is controversial. The ability of IL-1-alpha to induce de novo angiogenesis in adult rats was studied using the mesenteric window angiogenesis assay (MWAA). Murine recombinant IL-1-alpha was injected intraperitoneally twice daily on Days 0 to 4 at 11.8 pM, 118 pM, and 1.18 nM and groups of animals were sacrificed on Days 7, 14, 21 and 28; controls received the vehicle. Angiogenesis was quantified in terms of microvascular spatial extension and density using technically independent microscopic techniques and image analysis. Compared with the vehicle control, the treatment with IL-1-alpha at doses of 118 pM and 1.18 nM induced statistically significant angiogenesis throughout the study period, whereas IL-1-alpha at 11.8 pM did not induce significant angiogenesis in statistical terms until Days 21 and 28. Compared with the previously reported angiogenic response to VEGF165, bFGF, IL-8, and TNF-alpha using the rat MWAA and the same standardized experimental protocol, the IL-1-alpha treatment displayed a higher degree of efficacy and potency than that of bFGF, IL-8, and TNF-alpha. Moreover, the duration of the significant response to IL-1-alpha exceeded that of bFGF, IL-8, and TNF-alpha. The present data indicate that IL-1-alpha at near-physiologic doses is a very effective angiogenic factor in the system used here. The response may well be multifactorially mediated, as is discussed, and the molecular mechanisms which are involved remain to be clarified.

Animals↗
PubMed2006

Effects of angiopoietin-1 on vascular endothelial growth factor-induced angiogenesis in the mouse brain.

A better understanding of angiogenic factors and their effects on angiogenesis in brain is necessary to treat cerebral vascular disorders such as ischemic brain injury. Vascular endothelial growth factor (VEGF) induces angiogenesis and increases blood-brain barrier (BBB) permeability in adult mouse brain. The effect of angiopoietin-1 on BBB leakage during the angiogenesis process is unclear. We sought to identify the effects of combining VEGF with angiopoietin-1 on cerebral angiogenesis and BBB. Adult male CD-1 mice underwent AdFc (adenoviral vector control), AdAng-1, VEGF protein, VEGF protein plus AdAng-1, or saline (negative control) injection. Brain microvessels were counted using lectin staining on tissue sections after 2 weeks of adenoviral gene transfer. The presence of zonula occludens-1 (ZO-1) was determined by Western blot analysis and immunohistochemistry. Microvessel count and augmented capillary diameter increased in mice treated with either VEGF protein or AdAng-1 plus VEGF protein compared to saline, AdFc, or AdAng-1 alone (p < 0.05). Double-labeled immunostaining demonstrated that ZO-1-positive staining was more complete on the microvessel wall in the AdAng-1 and AdAng-1 plus VEGF protein treated group compared to VEGF protein group. The results of ZO-1 expression from Western blot analysis paralleled that from immunohistochemistry (p < 0.05). We conclude that focal VEGF and angiopoietin-1 hyperstimulation in mouse brain increases microvessel density while maintaining ZO-1 protein expression, suggesting that angiopoietin-1 plays a role in synergistically inducing angiogenesis and BBB integrity.

Angiopoietin-1↗
PubMed2004

Vasculogenesis and angiogenesis.

Two distinct mechanisms, vasculogenesis and angiogenesis implement the formation of the vascular network in the embryo. Vasculogenesis gives rise to the heart and the first primitive vascular plexus inside the embryo and in its surrounding membranes, as the yolk sac circulation. Angiogenesis is responsible for the remodeling and expansion of this network. While vasculogenesis refers to in situ differentiation and growth of blood vessels from mesodermal derived hemangioblasts, angiogenesis comprises two different mechanisms: endothelial sprouting and intussusceptive microvascular growth (IMG). The sprouting process is based on endothelial cell migration, proliferation and tube formation. IMG divides existing vessel lumens by formation and insertion of tissue folds and columns of interstitial tissue into the vessel lumen. The latter are termed interstitial or intervascular tissue structures (ITSs) and tissue pillars or posts. Intussusception also includes the establishment of new vessels by in situ loop formation in the wall of large veins. The molecular regulation of these distinct mechanisms is discussed in respect to the most important positive regulators, VEGF and its receptors flk-1 (KDR) and flt-1, the Angiopoietin/tie system and the ephrin-B/EpH-B system. The cellular mechanisms and the molecular regulation of angiogenesis in the pathological state are summarized and the differences of physiological and pathological angiogenesis elaborated.

Angiopoietin-1↗
PubMed2004

Angiogenesis and invasion in gliomas.

Angiogenesis and tumor cell invasion are pathophysiological processes playing a pivotal role in glioma development and growth since the earliest phase. Angiogenesis and tumor invasion both can be considered as an invasive process in which cells are activated, and move away from their initial location, by modyfing the adhesiveness with the extracellular matrix, expressing new adhesion molecules, and degrading the extracellular matrix components by the active secretion of proteases. This process requires a complex cross-talking between endothelial and tumor cells, extracellular matrix components, and cellular elements of the host microenviroment. Both processes are under the tight regulation of a balance between stimulating and inhibiting factors. The existence of common mechanisms of regulation and the presence of naturally occurring factors that inihibit angiogenesis and invasion, makes the inhibition of both processes possible. Tumor cells may develop adapting mechanims that can allow the tumor to partially escape to the treatment, particularly when only one mechanism or one process is inhibited. The ideal treatment should simultaneously affect both angiogenesis and invasion, by the isolation or development of novel therapeutics capable of influencing both processes. As their efficacy seems also be dependent on the mode of delivery, additional studies are also needed to improve these modalities, in order to ultimately improve the extent and the duration of the therapeutic response. The most widely used in vitro and in vivo models to study angiogenesis and invasion are also discussed.

Animals↗
PubMed1995

Biological and clinical role of angiogenesis in breast cancer.

Angiogenesis, the process leading to the formation of new blood vessels, plays a central role in tumor progression of solid neoplasia. The switch from the avascular to the vascular phase is generally accompanied by rapid primary tumor growth and local invasiveness. Furthermore, angiogenesis is also necessary both at the beginning and at the end of the development of distant metastasis and is implicated in the phenomenon of dormant micrometastases. The angiogenic activity of both the primary tumor and its metastases is the result of the net balance between angiogenic peptides and natural inhibitors, and it is regulated by multiple biochemical and genetic mechanisms. In normal tissues of the adult, unlike invasive cancers, the angiogenic inhibitory pathway predominates. Several experimental and clinico-pathologic studies have confirmed that angiogenesis is specifically involved in transformation and progression of human breast cancer. In particular, clinicopathologic studies have found that the degree of vascularization of primary invasive human breast cancer is heterogeneous and correlates with the prognosis of patients. A number of antiangiogenic agents have been recently discovered, and some are under early clinical evaluation. Thus, angiogenic activity of the tumors represents a potentially novel anticancer therapeutic target. This issue of Breast Cancer Research and Treatment reports on the most relevant basic biological aspects of angiogenesis, on its clinical role in breast cancer prognosis, and on the implications of inhibition of angiogenesis for future novel anticancer therapeutic approaches.

Adult↗
PubMed1995

Oncogenes as inducers of tumor angiogenesis.

Dominantly acting transforming oncogenes are generally considered to contribute to tumor development and progression by their direct effects on tumor cell proliferation and differentiation. However, the growth of solid tumors beyond 1-2 mm in diameter requires the induction and maintenance of a tumor blood vessel supply, which is attributed in large part to the production of angiogenesis promoting growth factors by tumor cells. The mechanisms which govern the expression of angiogenesis growth factors in tumor cells are largely unknown, but dominantly acting oncogenes may have a much greater impact than hitherto realized. An example of this is the induction of expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) by mutant H- or K-ras oncogenes, as well as v-src and v-raf, in transformed fibroblasts or epithelial cells. Besides VEGF/VPF, mutant ras genes are known to upregulate the expression of a variety of other growth factors thought to have direct or indirect stimulating effects on angiogenesis, e.g. TGF-beta and TGF-alpha. This effect may be mediated through the ras-raf-MAP kinase signal transduction pathway, resulting in activation of transcription factors such as AP1, which can then bind to relevant sites in the promoter regions of genes encoding angiogenesis growth factors. In principle, similar events could take place after activation or overexpression of many other oncogenes, especially those which can mediate their function through ras-dependent signal transduction pathways. The regulatory effect of oncogenes on mediators of angiogenesis has some potentially important therapeutic consequences. For example, it strengthens the rationale of pharmacologically targeting oncogene products, such as mutant RAS proteins, as an anti-tumor therapeutic strategy. Such drugs may attack the source of one or more angiogenic growth factors and by doing so, function, at least in part, as anti-angiogenic agents in vivo.

Genes, Tumor Suppressor↗
PubMed1996

Tumor angiogenesis in primary and metastatic colorectal cancers.

PURPOSE: Angiogenesis is needed to sustain growth of both primary and metastatic lesions; however, comparisons in microvessel density between a primary tumor and its metastases have not been widely performed. We studied microvessel density in primary colorectal cancers and their liver metastases. METHODS: Sections from 32 primary lesions and 53 hepatic metastases were immunostained with a monoclonal antibody for von Willebrand's factor, an endothelial cell marker. Blood vessels were quantified under x 100 magnification using both conventional light microscopy and computer-assisted image analysis. Primary and metastatic angiogenesis scores (AS), i.e., vessel counts, were analyzed with respect to tumor size, hepatic multicentricity, synchronicity, resectability, and patient survival. Using computer-assisted calculations, the same analyses were performed using blood vessel to tumor surface area ratios, vessel wall thickness, and intensity of immunostaining. RESULTS: Angiogenesis scores were significantly lower in metastatic lesions compared with their primary tumors (P < 0.0001). Primary AS did not correlate with metastatic tumor size, resectability, multicentricity, or patient survival. Metastatic AS strongly predicted patient survival (P < 0.0009) but with a negative coefficient, i.e., higher scores were associated with improved survival. Metastatic AS were higher in resectable than in nonresectable metastases and in solitary than in multiple metastases; however, these trends were not statistically significant. Metachronous liver lesions had significantly higher angiogenesis scores than synchronous metastases (P < 0.04). Similar trends were seen using computer-assisted image analysis. CONCLUSIONS: These results indicate that in presence of an established metastasis, there is a weak angiogenic relationship between a primary tumor and its metastasis. Heterogeneity in metastatic lesions cannot be explained solely by studying angiogenesis in primary tumors. Microvessel density in a primary tumor may not be useful as an independent prognostic indicator in late stages of disease. In such cases, assessment of microvessel density in a metastatic tumor whenever possible may be an indicator of prognosis.

Biomarkers, Tumor↗
PubMed1995

Breast cancer angiogenesis: a quantitative morphologic and Doppler imaging study.

BACKGROUND: Tumor growth and metastases require the development of new vessels (angiogenesis). Angiogenesis, assessed by microvessel count using immunocytochemical stain of endothelial cells, has been shown to predict metastases and correlate with early death. Recently developed color Doppler mapping can detect the "tumor flow signals" in breast cancer and help to distinguish it from benign lesions. The question is, does this tumor vascularization assessed by color Doppler mapping correlate with the angiogenesis assessed by immunocytochemistry? METHODS: Eighty-four patients admitted for breast surgery were studied. The final diagnosis was made by pathology for 52 malignancies and 32 benign lesions. The color Doppler mapping of the breast lesion was made preoperatively. The following parameters were assessed: (a) vessel location (peripheral or central); (b) density of color Doppler signals; and (c) maximum systolic velocity. Tumor angiogenesis was assessed by microvessel count under light microscopy using the platelet/endothelial cell adhesion molecule antibodies (CD31) method. The correlation between maximum velocity and microvessel count of breast cancer was examined. The clinical significance of maximum flow velocity of breast cancer with various clinicopathologic factors was assessed. RESULTS: Color signals were detected in 48 cases of 52 malignancies (92%). All tumors demonstrated signals at the periphery of the lesion but in only 13 (27%) were the signals detected within the tumor. Color signals were scored as + + or + + + in 44 (92%) patients. Pulsed wave blood flow was shown in all these 48 tumors, with maximum velocities varying from 4 to 36 cm/s. Among the 32 benign lesions, color signals were detected in 10 (31%) and all were peripheral and scored subjectively as +. Evaluation of these color Doppler mapping parameters shows no significant correlation with microvessel counts using CD31 monoclonal antibodies. However, there was a positive association (p < 0.05) between nodal metastases and higher tumor flow velocity in T1 (< 2 cm) breast tumors but not in larger tumors. CONCLUSION: Although the color Doppler mapping has been shown to be useful in distinguishing benign from malignant breast lesions, the intensity of signal and velocity of flow had no correlation with the extent of angiogenesis of breast cancer. The presence of high-flow tumor signal in early breast carcinoma is significantly associated with the presence of axillary lymph node metastases.

Adult↗
PubMed2002

Role of angiogenesis in the development and growth of liver metastasis.

Cancer metastasis is a highly complex process that involves aberrations in gene expression by cancer cells leading to transformation, growth, angiogenesis, invasion, dissemination, survival in the circulation, and subsequent attachment and growth in the organ of metastasis. Angiogenesis facilitates metastasis formation by providing a mechanism to (1) increase the likelihood of tumor cells entering the blood circulation and (2) provide nutrients and oxygen for growth at the metastatic site. The formation and establishment of metastatic lesions depend on the activation of multiple angiogenic pathways at both primary and metastatic sites. A variety of factors involved in the angiogenesis of liver metastasis have been identified and may serve as prognostic markers and targets for therapy. Vascular endothelial growth factor, interleukin-8, and platelet-derived endothelial cell growth factor are all proangiogenic factors that have been associated with liver metastasis from various primary tumor types. Inhibition of the activity of these factors is a promising therapeutic approach for patients with liver metastases. In addition, inhibition of integrins that mediate endothelial cell survival may also serve as a component of therapeutic regimens for liver metastases. This review focuses on the biology of angiogenesis in liver metastasis formation and growth. Because colorectal carcinoma is the most common tumor to metastasize to the liver, this disease will serve as a paradigm for the study of angiogenesis in liver metastases.

Endothelial Growth Factors↗
PubMed1997

Angiogenesis in Endocrine Neoplasms.

Angiogenesis promotes the growth of tumors, because it both facilitates oxygenation and nutrient flow, and removes metabolic waste. During the past two decades, as the importance of tumor vascularity became recognized, angiogenesis and the relationship between blood vessels and tumor progression received increasing attention. It was found that isolated tumor tissues failed to expand beyond few millimeters unless vascularized, whereupon vascularization they exhibited a rapid growth. Extensive research focusing on the relationship between tumor proliferation and the formation of new vessels has initially been undertaken to assess the role of angiogenesis in the progression of breast carcinomas. Significant results emerged from these investigations, and similar studies were extended to other tumor types, such as melanomas, cervical and pulmonary carcinomas, and so on. It is of note that angiogenesis as it relates to endocrine tumors has so far been limited to pituitary neoplasms, thyroid carcinomas, and pheochromocytomas. The purpose of the article is to provide a brief review of angiogenesis and to summarize available data regarding its role in the growth off endocrine neoplasms.

Journal Article↗
PubMed1998

Current concepts of tumor-induced angiogenesis.

Tumor induced angiogenesis is responsible for the nutrition of the growing tumor and can also increase the probability of hematogenous tumor dissemination. Data obtained from morphological analysis of tumor angiogenesis can contribute to the development of new anti-angiogenic therapies. Based on in vitro and in vivo observations several models of angiogenesis were introduced, explaining the mechanism of lumen formation and the timing of basement membrane depositon. (1) Lumen is formed either by cell body curving or by fusion of intracellular vacuoles of nonpolarized endothelial cells. New basement membrane is deposited after lumen formation. (2) Slit-like lumen is immediately formed by migrating polarized endothelial cells. Basement membrane is continuously deposited during endothelial cell migration, only cellular processes of the endothelial cell migrating on the tip of the growing capillary are free of deposited basement membrane material. (3) Development of transluminal bridges in larger vessels a process called intussusceptive growth leads to the division of the vessels. These models, however, describe angiogenesis in tissues rich in connective tissue. Different processes of angiogenesis take place in organs such as liver, lungs, adrenals, which are the most frequent sites of metastasis having high vessel density without sufficient space for capillary sprouting. In the case of liver metastases of Lewis lung carcinoma the proliferation of endothelial cells was elicited only by direct contact between tumor and endothelial cells, leading to the development of large convoluted vessels inside the metastases. These vessels were continuous with the sinusoidal system, suggesting that these metastases have dual blood supply. This observation, among others, is in contrast to the generally accepted view that liver tumors have arterial blood supply. The increasing number of data demonstrating the dual or venous blood supply of liver metastases should be taken into consideration in the therapy of liver metastasis.

Animals↗
PubMed2001

Role of hematopoietic stem cells in angiogenesis.

Angiogenesis is an important event for embryonic organogenesis as well as for tissue repair in the adult. Here we show that hematopoietic stem cells (HSCs) are essential for angiogenesis during embryogenesis. To investigate the role of HSCs in endothelial cell (EC) development, we analyzed AML1-deficient embryos, which lack definitive hematopoiesis. These embryos showed defective angiogenesis in the head, pericardium, and fetal liver. Para-aortic splanchnopleural (P-Sp) explant cultures on stromal cells (P-Sp cultures) did not generate definitive hematopoietic cells and showed defective angiogenesis in the AML1-null embryo. Disrupted angiogenesis in P-Sp cultures from AML1-null embryos was rescued by addition of HSCs. HSCsspecifically produce angiopoietin-1 (Ang1). Thus HSCs,which expressAng1, directly promoted migration of ECs. These findings suggest that HSCs alone prepare the hematopoietic microenvironment.

Angiopoietin-1↗
PubMed1997

Clinicopathologic study of angiogenesis in Japanese patients with breast cancer.

To evaluate the clinicopathologic significance of angiogenesis as a prognostic factor and the objective methods for evaluating angiogenesis, we immunohistochemically stained a representative section of breast tumors with factor VIII-related antigen staining. There were 109 patients with primary breast cancer from 1971 to 1979. The two methods of identifying angiogenesis were the average microvessel count per square millimeter (AMC) and the highest microvessel count per square millimeter (HMC). There was no relation between microvessel count (AMC or HMC) or age, menopausal status, clinical tumor size (T), histologic classification, nuclear grade, node status, histologic grade (HG), mitosis index, or lymphatic invasion (LI). There was a relation between microvessel count and blood vessel invasion (BVI) (HMC:p = 0.0007) and tumor necrosis (TN) (HMC:p = 0.0050). Univariate analysis showed that AMC or HMC was a statistically significant predictor of overall survival in all patients (p = 0.0086 and p = 0.0307, respectively). Multivariate analysis showed that AMC was an independent predictor of node status when we fitted a model with node status, BVI, and either AMC or HMC; but HMC was not independent. However, when we fitted a model including all 11 of the other indicators and AMC or HMC, the node status, HG, and LI were independent predictors, but AMC and HMC were not. Although AMC was a better method than HMC for evaluating angiogenesis, we cannot confirm angiogenesis as a significant independent prognostic factor associated with long-term survival in Japanese breast cancer patients.

Adult↗
PubMed2000

Successful use of the "patch, drain, and wait" laparotomy approach to perforated necrotizing enterocolitis: is hypoxia-triggered "good angiogenesis" involved?

The traditional and most frequently employed surgical approach to perforated necrotizing enterocolitis (NEC), laparotomy and bowel resection with enterostomy creation, has been associated with an unacceptably high mortality and major morbidity (sepsis, short-gut syndrome, strictures, long-term total parenteral nutrition (TPN), prolonged and costly hospitalizations with multiple operations, the inevitable open-and-close procedure for "hopeless" extensive gut ischemia in approximately 10% of laparotomy cases, etc.). The use of the laparotomy "patch, drain, and wait" (PD&W) approach to this serious of NEC complication has provided a simple, direct, and effective means of dealing with this problem. The basic principle is to resect no gut and do no enterostomies. The details are presented here as well as the multiple types of "patching" and the importance of use of extensive direct-vision draining with bilateral small Penrose drains from the undersurfaces of both diaphragms into the pelvis with exit sites in both lower quadrants. Proper and effective patching and draining cannot be done blindly,but requires direct vision (laparotomy or laparoscopy). The critical components and timing of the "waiting" are emphasized, including the vital importance of strict avoidance of early post-drainage laparotomy in the 7- to 14-day post-drainage period (whether the drainage is percutaneous, laparotomy PD&W, or laparoscopy PD&W) due to the early, life-threatening-ending hypervascularity that occurs at this time and if left unmolested will function beneficially as life- and gut-saving "good angiogenesis". The bilateral Penrose drains capture fecal fistulas and function quite well as de-facto enterostomies as the peritoneal cavity is rapidly obliterated by adhesions and massive, florid hypervascularity/gut hypoxia triggered "good angiogenesis" (no peritoneal cavity, no peritonitis). Broad-spectrum triple antibiotics and the routine use of TPN contribute to favorable results. The lessons/experiments of nature encountered in newborns with midgut atresia(s) and remarkable levels of gut survival, in the occasional case with only meconium peritonitis and no obstruction ("auto-anastomosis") are pertinent here as the TPN of PD&W is provided in atresia(s) by the maternal-placental circulation and the sterile peritoneal cavity of atresia(s) is simulated by the combination of antibiotics and peritoneal-cavity obliteration. Life- and gut-saving "good angiogenesis" is common to both situations. A 15-year personal experience with the PD&W laparotomy approach to perforated NEC in 23 cases is reported here with no mortality in the initial 60 postoperative days, no major morbidity, and no second operation required in 70% (spontaneous "auto-anastomosis") of cases. All infants with extensive gut ischemia/necrosis (NEC totalis) who would otherwise be classified as "hopeless" and managed by open-and-close only were managed in this experience successfully by PD&W with preservation of both life and an adequate amount of gut, although a second operation was required in these cases to re-establish intestinal continuity. A particularly striking observation was the rapid transition of these infants from profound illness to near-normalcy in a matter of hours after the initiation of PD&W--much like the rapid clinical changes accompanying the lancing of a boil or an abscess. An involvement of hypoxia-induced "good angiogenesis" with marked hypervascularity and involving molecules, genes, and receptors of the vascular endothelial growth factor family of hypoxia-induced angiogenesis molecules is speculated upon, and clinical studies to document these speculations are suggested as well as studies evaluating the potential of laparoscopic PD&W. The usefulness of Argyle chest-tube "venting" and "stenting" by trans-anal passage above colonic "patched" areas as seen in 2 cases is worthy of further study and use.

Anti-Bacterial Agents↗
PubMed2003

[Hypoxia and angiogenesis in rheumatic diseases].

The important role of angiogenesis for the pathogenesis of most tumors has gained much interest into the mechanisms of new vessel formation during recent years. Hypoxia induces angiogenesis via stabilization of the transcription factor HIF-1alpha. After dimerization of HIF-1alpha with HIF-1beta/ARNT, HIF-1 binds to the hypoxia-responsive elements in the regulatory regions of proangiogenic molecules such as VEGF. Hypoxia-mediated angiogenesis also plays a part in the pathogenesis of rheumatoid arthritis. For instance, intraarticular application of the angiostatic molecule angiostatin reduces the severity of collagen-induced arthritis in mice. Moreover, recent data indicate that the expression of HIF-1alpha in myeloid cells is important for the initiation of the inflammatory infiltrate in rheumatoid arthritis. In contrast to rheumatoid arthritis, the therapeutic goal in systemic sclerosis (SSc) is the formation of new vessels rather than the inhibition of angiogenesis. Surprisingly, several proangiogenic factors such as VEGF or MCP-1 (CCL-2) are overexpressed in the skin of patients with SSc despite the reduction in the capillary density. The role of these findings for the defective angiogenesis in SSc is currently investigated in our laboratory.

Angiostatic Proteins↗
PubMed2005

Prognostic significance of VEGF immunohistochemical expression and tumor angiogenesis in head and neck squamous cell carcinoma.

PURPOSE: Tumor angiogenesis is crucial for both the growth of the primary tumor and the development of metastases. Among the factors causing tumor angiogenesis, vascular endothelial growth factor (VEGF) is considered as a leading candidate. We aimed to assess the prognostic significance of VEGF and tumor angiogenesis in head and neck squamous cell carcinoma (HNSCC). METHODS: We performed a retrospective study of 69 patients with HNSCC, in order to investigate whether VEGF immunohistochemical expression and tumor angiogenesis correlate with clinicopathological parameters and outcome. Tumor angiogenesis was estimated by determining microvessel density (MVD), and VEGF expression was assessed quantitatively. RESULTS: Vascular endothelial growth factor and MVD correlated statistically significant with the clinical stage, but not with the presence of lymph node metastasis at the time of diagnosis. Tumors located in the oral cavity and larynx more often expressed high VEGF immunostaining compared with tumors located in the lower lip. High VEGF expression was associated with higher clinical stage and worse overall survival in this cohort of patients. CONCLUSIONS: Vascular endothelial growth factor expression may have prognostic significance for patients with HNSCC.

Adult↗
PubMed1998

Human lymphoblastoid cells produce extracellular matrix-degrading enzymes and induce endothelial cell proliferation, migration, morphogenesis, and angiogenesis.

Human lymphoproliferative diseases can be hypothesized to invade locally and to metastatize via mechanisms similar to those developed by a variety of solid tumors, i.e., the secretion of extracellular matrix-degrading enzymes and stimulation of angiogenesis. To assess this hypothesis, Namalwa, Raji, and Daudi cell lines (Burkitt's lymphoma), LIK and SB cell lines (B-cell lymphoblastic leukemia), CEM and Jurkat cell lines (T-cell lymphoblastic leukemia), and U266 cell line (multiple myeloma) were evaluated for their capacity to produce matrix metalloproteinase-2 and -9, and urokinase-type plasminogen activator. These cell lines were also assessed for their ability: (1) to produce the angiogenic basic fibroblast growth factor and vascular endothelial growth factor; (2) to induce an angiogenic phenotype in cultured endothelial cells, represented by cell proliferation, chemotaxis, and morphogenesis; (3) to stimulate angiogenesis in different in vivo experimental models. All cell lines expressed the mRNA for one or both metalloproteinases. Namalwa, Raji, LIK, SB, and U266 cells secreted the active form of both metalloproteinases, while Daudi, CEM, and Jurkat cells produced metalloproteinase-2 but not-9. In contrast, urokinase-type plasminogen activator was secreted only by SB cells. While Raji, LIK, SB, CEM, and Jurkat cells secreted both basic fibroblast growth factor and vascular endothelial growth factor, Daudi and U266 cells produced only the former, and Namalwa cells only the latter. Accordingly, the conditioned medium of all cell lines stimulated cell proliferation and/or chemotaxis in cultured endothelial cells, with the exception of that of Namalwa cells which was ineffective. The conditioned medium of CEM and Jurkat cells induced morphogenesis in cultured endothelial cells grown on a reconstituted basement membrane (Matrigel). Lastly, Namalwa, Raji, LIK, SB, U266, CEM, and Jurkat cells induced angiogenesis and mononuclear cell recruitment in the murine Matrigel sponge model and in a chick embryo chorioallantoic membrane assay. The extent of angiogenesis in both models was strictly correlated with the density of the mononuclear cell infiltrate. The results indicate that human lymphoproliferative disease cells possess both local and remote invasive ability via the secretion of matrix-degrading enzymes and the induction of angiogenesis which is fostered by host inflammatory cells and by an intervening ensemble of angiogenic factors.

Animals↗