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Results for “Neovascularization, Pathologic”

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PubMed1995

Clinical importance of the determination of tumor angiogenesis in breast carcinoma: much more than a new prognostic tool.

PURPOSE: To review prognostic and therapeutic applications of angiogenesis research in breast carcinoma. METHODS: We reviewed the (1) biologic role of angiogenesis, particularly in transformation, progression, and metastasis of breast cancer; (2) methods to detect angiogenic activity in human pathology; (3) clinical studies relating clinical outcome of patients with breast cancer to the assessment of angiogenesis; (4) predictive value of angiogenesis for response to anticancer therapies; and (5) pharmacologic characteristics of current antiangiogenic drugs. RESULTS: There is mounting evidence that angiogenesis plays a relevant role in the biologic aggressiveness of breast cancer. Using either immunohistochemical or biochemical methods, several studies have shown a worse prognosis for those patients with tumors with high angiogenic activity. In some studies angiogenesis has an independent prognostic value. The most promising angiogenic inhibitors are under early-phase clinical evaluation in patients with tumors resistant to conventional therapies. Novel therapeutic strategies for breast cancer patients are presented and discussed. CONCLUSION: The majority of the retrospective studies show that angiogenesis is an important new prognostic indicator in early-stage breast carcinoma. This marker should be evaluated in prospective controlled clinical trials to demonstrate whether adjuvant therapies may improve the prognosis of those patients at high risk, eg, those with highly vascularized tumors. Since invasive breast carcinoma has a well defined stromal vascular component and produces angiogenic factors, it seems reasonable to postulate that this tumor may be one of the most responsive to angiogenesis inhibitors given alone or in combination with conventional anticancer treatments.

Breast Neoplasms↗

PubMed1993

Pathology of warm ischaemia and reperfusion injury in adipomusculocutaneous flaps.

In-vivo assessment and histological analysis after 168 hours of reperfusion were used to determine the normothermic (37 degrees C) ischaemic tolerance of adipomusculocutaneous, free flap, isotransplants in inbred AS rats. Flaps stored for up to 2 hours under normothermic conditions survived; flaps stored for 4 hours partially survived but those which had been stored for more than 6 hours became totally necrotic. Neither treatment with the iron chelator desferrioxamine (DFX) nor hypertonic citrate (HCA) flush increased the ischaemic tolerance of flaps which had been stored for 4 hours since neither diminished the amount of necrosis. Treated and untreated flaps stored for 4 hours were also assessed 0, 0.5, 24, 48, 96 and 168 hours after isotransplantation. They were compared to control flaps which had not been stored prior to reperfusion and negative control flaps which were not stored but isotransplanted without a blood supply. Oedema reached a peak at 24 hours and there was progressive increase in general severe necrosis, reaching a plateau by 48 hours. Suture line epidermalization and thickening was established by 48 hours. Among flaps stored for 4 hours, those treated with DFX had the most necrosis. Adipose tissue and striated muscle proved the least tolerant to warm ischaemic stress. These experiments suggest reperfusion injury contributes to eventual flap necrosis, but the role of free radicals has not been established. The 4-hour stored flap is a useful model to study the effects of ischaemia both in flap tissue and at the suture line.

Adipose Tissue↗

PubMed1994

Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model.

Vascular endothelial growth factor (VEGF) is a heparin-binding, endothelial cell-specific mitogen. Previous studies have suggested that VEGF is a regulator of naturally occurring physiologic and pathologic angiogenesis. In this study we investigated the hypothesis that the angiogenic potential of VEGF is sufficient to constitute a therapeutic effect. The soluble 165-amino acid isoform of VEGF was administered as a single intra-arterial bolus to the internal iliac artery of rabbits in which the ipsilateral femoral artery was excised to induce severe, unilateral hind limb ischemia. Doses of 500-1,000 micrograms of VEGF produced statistically significant augmentation of collateral vessel development by angiography as well as the number of capillaries by histology; consequent amelioration of the hemodynamic deficit in the ischemic limb was significantly greater in animals receiving VEGF than in nontreated controls (calf blood pressure ratio, 0.75 +/- 0.14 vs. 0.48 +/- 0.19, P < 0.05). Serial angiograms disclosed progressive linear extension of the collateral artery of origin (stem artery) to the distal point of parent vessel (reentry artery) reconstitution in seven of nine VEGF-treated animals. These findings establish proof of principle for the concept that the angiogenic activity of VEGF is sufficiently potent to achieve therapeutic benefit. Such a strategy might ultimately be applicable to patients with severe limb ischemia secondary to arterial occlusive disease.

Angiography↗

PubMed1992

Capillary growth: a two-cell system.

Angiogenesis is central to a number of normal and pathologic processes, including tumor growth. The identification of several angiogenic factors and the isolation and culture of capillary endothelial cells (EC) have led to a greater understanding of the cellular and biochemical bases of new vessel growth. Until recently EC have been the focus of most studies of microvascular growth. However, capillaries are not simply tubes of EC but have also a second cellular component, the mural cell or pericyte. Little is known about the later stages of vessel growth, including the addition of the pericyte to the capillary and its influence on EC growth and function. Historically the pericyte was defined by its abluminal association with the EC in the capillary. Though the pericyte's function was largely unknown, ultrastructural studies led to speculation regarding a role for the pericyte in contraction, as a stem cell and in the control of microvascular growth. Establishment of methods for the isolation, culture and identification of pericytes has permitted investigation into the role of the pericyte. EC and pericytes make frequent contact in vivo and co-culture studies of EC and pericytes reveal that the two cell types interact in a variety of ways including diffusible growth regulators, heterotypic contacts, and gap junctions. This intercellular communication is likely to be an important component of the complex mechanism(s) controlling microvascular growth and function.

Animals↗

PubMed1994

Prognostic significance of proteolytic enzymes in human brain tumors.

Proteases and their inhibitors have been shown to play roles in tumor invasion and metastasis in a number of experimental models. Recently, relative increases in the amounts of urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor samples have been correlated with poorer, pathological grade, shorter disease-free interval, and shorter survival. To date, all studies investigating the prognostic significance of proteases and their inhibitors have been limited to extracranial cancer. In this article, we review the literature and present our data on the prognostic significance of proteases in human brain tumors. High levels of uPA were seen in malignant glioma and metastatic tumors (n = 82), whereas normal levels of uPA were found in low-grade gliomas. Analysis with magnetic resonance imaging (MRI) demonstrated a significant correlation between high levels of uPA and necrosis and edema (n = 50; P < 0.05). Similarly, patients with high levels of uPA had shorter survival than did patients with low levels of uPA. Tissue-type plasminogen activator (tPA), which was virtually absent in glioblastoma multiforme (GBM), colon lung, and breast metastasis, was found in normal quantities in anaplastic astrocytoma (AA), low-grade glioma (LGG), and meningioma. Melanoma had significantly more tPA activity than normal brain did. A reverse correlation was found between tPA and MRI findings of necrosis, enhancement, and edema. Similarly, patients with no detectable tPA activity had shorter survival than did patients with detectable tPA activity. We conclude that high levels of uPA and absent tPA activity correlate with histologically malignant brain tumors, aggressive characteristics, and shorter survival.

Brain↗

PubMed1992

Prediction by postrevascularization biopsies of cadaveric kidney allografts of rejection, graft loss, and preservation nephropathy.

This prospective study of postrevascularization biopsies was undertaken to determine if pathological changes might be correlated with subsequent allograft rejection and loss. Such a relationship, if identified, could be used to predict graft outcome, thus permitting earlier intervention for individuals at an increased risk for rejection or graft loss. Fifty-seven biopsies were obtained, and the number of polymorphonuclear leukocytes marginating in the glomerular loops and peritubular capillaries was documented along with risk factors associated with the recipients' immunological status and with risk factors associated with ischemic preservation injury. The presence of seven PMN leukocytes in the peritubular capillaries is related to the subsequent occurrence of cellular rejection and accurately predicted in 82% of the patients studied whether or not rejection would occur. Mean glomerular PMN leukocyte count was related to cold ischemia time and subsequent graft loss, while an elevated mean glomerular PMN leukocyte count in conjunction with an elevated peritubular PMN leukocyte count was always associated with hyperacute rejection. Focal glomerular thrombosis (less than 50%) and tubular cast formation are manifestations of preservation nephropathy and had no effect on graft outcome. These findings suggest that the peritubular capillaries are a more sensitive target for immune changes and that minor donor/recipient disparities can be detected in the peritubular capillaries while preexisting sensitization to the donor is reflected by concurrent changes in the glomerular and peritubular capillaries.

Adolescent↗

PubMed1995

Blood vessel morphometry in human colorectal lesions.

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). All 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 microns semithin sections from five patients per group were stained with toluidine blue. A multistage systematic sampling procedure was adopted. The inner outlines of all blood vessels in the lamina propria (LP) were digitised using a Zeiss VIDAS Image Analyzer at a final magnification of x1,050. The 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 (Vv), numerical density (NA), length density (LV) and mean transverse sectional area (A). Statistically significant differences in Vv and A were detected between all 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 all parameters were the highest in ADCA.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗

PubMedDate not supplied

Significance of angiogenesis in tumour progression and metastasis.

Angiogenesis is defined as a vascular neoformation usually of capillary origin. This phenomenon is important during development and under several physiological and or pathological conditions. In recent years, progress has been made to understand this phenomenon at the molecular level. This includes the identification of potent angiogenic factors, the appreciation of the role of proteases, the importance of the extracellular matrix, and the emerging characterisation of signal transduction pathways in endothelial cells. Two important participants in angiogenesis are molecules from the fibroblast growth factor (FGF) and the transforming growth factor-beta (TGF-beta) family. In our laboratory, we have extensively studied the roles and mechanisms of action of the major FGF prototype, FGF-2 and of the TGF-beta member, TGF-beta 1. Different isoforms of FGF-2 have been previously described, a high molecular weight (HMW) form associated with the nucleus and 18 kDa bFGF that is cytoplasmic. These two forms of FGF-2 also exhibit different functions when expressed endogenously. TGF-beta is formed from a latent complex by plasmin-dependent and plasmin-independent pathways. With the exception of macrophages, the plasmin-dependent pathway requires coculture conditions, urokinase, and the concentration of TGF-beta on the cell surface by the mannose-6-phosphate receptor and transglutaminase. Other important angiogenic modulators include vascular endothelial growth factor (VEGF) and angiostatin. The nature of the tumour angiogenesis factor is not yet known with certainty, but several identified and not yet identified angiogenic factors may act in concert. It is hoped that an angiostatic treatment for cancer will be derived from these molecular studies.

Disease Progression↗

PubMed1993

Radicicol, a microbial cell differentiation modulator, inhibits in vivo angiogenesis.

Angiogenesis plays a significant role in various pathological states, including the progressive growth of solid tumors, rheumatoid arthritis, psoriasis, and diabetic retinopathy, in addition to its crucial role in embryonic development. Recent studies have revealed that an angiogenesis inhibitor is efficacious for these so-called angiogenic diseases. In the previous studies, we found that retinoids and vitamin D3 analogs, which are known to exhibit cell differentiation-modulating activity, effectively inhibit angiogenesis in vivo, thus forming the basis of our working hypothesis that a modulator of cell differentiation is capable of affecting angiogenesis. In this study, to verify this hypothesis further, radicicol (syn. monorden; 5-chloro-6-(7,8-epoxy-10-hydoxy-2-oxo-3,5-undecadienyl)-beta -resorcylic acid mu-lactone), a microbial cell differentiation modulator from a fungus, a strain of Neocosmospora tenuicristata, was examined for its anti-angiogenic activity in a bioassay system involving chorioallantoic membranes of growing chick embryos. The microbial cell differentiation modulator dose dependently inhibited embryonic angiogenesis, the ID50 value being 200 ng/egg. Radicicol also inhibited both the proliferation of and plasminogen activator production by vascular endothelial cells in the nM concentration range in a concentration-dependent manner, suggesting the possible involvement of these inhibitory effects in the anti-angiogenic action of the microbial product. These results indicate that radicicol might be a potential drug for treating different angiogenesis-dependent diseases, such as solid tumors, psoriasis, rheumatoid arthritis, and diabetic retinopathy.

Allantois↗

PubMed1993

Phenotype changes in tumor vessels associated with the progression of hepatocellular carcinoma.

Human hepatocellular carcinoma (HCC) is characterized by hypervascularity and tumor staining in angiograms, and tumor angiogenesis is considered indispensable for tumor growth. HCC is also characterized by an obvious multistage process of tumor progression. To find out in which stage of human hepatocarcinogenesis angiogenesis occurs, we have carried out a pathological study, of the phenotypic changes in tumor vessels taken from surgically resected liver tumors showing each step of the progression. Eleven early advanced HCCs (advanced HCC component in early HCC nodule, eAd HCC), seven early HCCs (eHCC) and six adenomatous hyperplasias (AH), the non-tumorous liver surrounding each and five normal livers were studied by lectin histochemistry and immunohistochemistry. The sinusoidal endothelial cells from the non-tumorous liver were shown to be negative for UEA-I (Ulex europaeus I), but the endothelial cells from the sinusoidal tumor vessels in advanced HCC components were strongly positive. In AH and eHCC, half the tumors were negative and the other half focally positive. In the early HCC lesion of eAdHCC, the rate of positivity for UEA-I was a little higher than in AH and eHCC but lower than in advanced HCC lesions in eAdHCC. Immunohistochemically, laminin was not detected in the sinusoids in the non-tumorous liver or in the sinusoidal tumor vessels in AH and eHCC. In eAdHCC, however, two early HCC lesions and four advanced HCC lesions were positive. An immunohistochemical examination for muscle actin revealed an increase in arterial tumor vessels in six advanced HCC lesions and one early HCC lesion of eAdHCC. The results indicate the emergence of UEA-I-positive sinusoidal tumor vessels to be most pronounced during the progression from eHCC to advanced HCC, and laminin-positive sinusoidal tumor vessels or actin-positive arterial tumor vessels to emerge mainly in advanced HCC.

Actins↗

PubMed1992

Angiogenesis, assessed by platelet/endothelial cell adhesion molecule antibodies, as indicator of node metastases and survival in breast cancer.

Animal models suggest a role for new vessel formation (angiogenesis) in tumours with metastatic potential, and there is some evidence that this is true for human tumours. What is needed is a sensitive and specific label for endothelial cells, and one candidate would be a monoclonal antibody to platelet/endothelial cell adhesion molecule (PECAM). We have counted microvessels in 103 primary breast cancers using the JC70 antibody to PECAM (or CD31). We compared our findings with various pathological indicators (lymph node status and tumour grade, size, and type and markers (oestrogen receptor, and c-erbB-2 expression and detection of mutant p53). Tumours showed significantly higher vascularisation than normal breast tissue and the number of blood vessels/mm2 was significantly associated with node metastasis. Only 2 out of 50 tumours with 99 vessel/mm2 or less were node positive whereas 31 out of 39 tumours with counts above 140/mm2 were positive (p < 0.0001). Tumour size and grade also correlated with node metastasis and vascularisation also increased with the size of the primary and with poor differentiation. However, within each subgroup of size or differentiation tumours without node involvement had much lower vascular counts, and multivariate analysis showed that vascular count alone explains the association of size and grade with node metastasis. Other markers, conventional or novel, did not correlate with vascularisation. Even with the short follow-up in this series, vascular counts correlated with early death. These results suggest that angiogenesis is closely linked to metastasis, that it is acquired at a critical density of vessels, and that this process occurs as tumours enlarge or become more poorly differentiated. Counting of newly formed microvessels stained with endothelium-specific antibodies may prove to be a useful tool in the early detection of metastatic potential and in the selection of patients for whom anti-angiogenesis drugs might be beneficial.

Antigens, Differentiation, Myelomonocytic↗

PubMed1990

Chemotaxis of human microvessel endothelial cells in response to acidic fibroblast growth factor.

Migration of microvessel endothelial cells (MEC) in response to angiogenic stimuli is a key aspect of angiogenesis, whether in physiologic or pathologic situations. In this work, we provide a rigorous quantitative assessment of the chemokinetic and chemotactic responses of human MEC to acidic fibroblast growth factor (aFGF). A uniform concentration of 1 micrograms/ml of heparin was included in most experiments to exploit heparin's potentiating effect on aFGF activity. The migration is measured in an under-agarose assay with a linear geometry, and evaluated in terms of the random motility and chemotaxis coefficients, mu and chi, which are defined in a mathematical model. The change in value of mu with changes in aFGF concentration provides a quantitative description of the stimulated random motility response, a process known as chemokinesis. This allows the true directional response in gradients to be quantified by the chemotaxis coefficient, chi, and its variation with attractant concentration. The effect of aFGF on MEC random motility is relatively small, with the random motility coefficient ranging from 4.6 +/- 0.4 x 10(-9) to 9.9 +/- 0.3 x 10(-9) cm2/second (mean +/- SE) over four orders of magnitude of aFGF concentration (10(-11) to 10(-8) M). On the other hand, the magnitude of the chemotaxis coefficient at optimal concentrations is quite large (2600 +/- 750 cm2/second-M around 10(-10) M aFGF), demonstrating a significant degree of MEC directional sensitivity to aFGF gradients. The chemotaxis coefficient shows a biphasic dependence on aFGF concentration, suggestive of a receptor-mediated response in which apparent differences in receptor occupancy govern directional bias. These results provide support for the hypothesis that MEC chemotaxis accounts for the directed microvessel growth observed in angiogenesis.

Cell Movement↗

PubMed1992

The vascular endothelial growth factor proteins: identification of biologically relevant regions by neutralizing monoclonal antibodies.

Angiogenesis plays critical roles in organ development during embryonic and fetal life, wound healing and in a variety of pathological conditions. Vascular endothelial growth factor (VEGF) is a secreted growth factor specific for vascular endothelial cells which induces angiogenesis in vivo. To gain a better understanding of the physiological role of VEGF, we have generated and characterized four murine monoclonal antibodies (mAbs) using the 165 amino acid species of recombinant human VEGF as immunogen. These mAbs (A3.13.1, A4.6.1, B4.3.1 and B2.6.2) belong to IgG1 isotype and have high affinities for VEGF (dissociation constants range from 2.2 x 10(-9) to 4 x 10(-10) M). Two different epitopes were detected with these mAbs. One epitope is recognized by mAbs A3.13.1 and B2.6.2, and the other recognized by mAbs A4.6.1 and B4.3.1. The epitope recognized by mAb A4.6.1 appears to be continuous while mAb B2.6.2 recognizes a discontinuous epitope. MAb A4.6.1 recognized three species of VEGF generated by alternative splicing, VEGF121, VEGF165 and VEGF189 while mAb B2.6.2 binds only VEGF165 and VEGF189. Results using an in vitro bovine adrenal cortex endothelial cell proliferation assay, in in vivo vascular permeability assay and an in vivo embryonic chicken angiogenesis assay showed that mAb A4.6.1 has potent VEGF neutralizing activities. MAb A4.6.1 was shown to block the binding of VEGF to its receptor(s) suggesting the inhibitory mechanism for VEGF activities. These well-defined mAbs should be very powerful tools to understand the structure-function relationship of various domains of VEGF and may have therapeutic potential.

Adrenal Cortex↗

PubMed1991

Analysis of the roles of microvessel endothelial cell random motility and chemotaxis in angiogenesis.

The growth of new capillary blood vessels, or angiogenesis, is a prominent component of numerous physiological and pathological conditions. An understanding of the co-ordination of underlying cellular behaviors would be helpful for therapeutic manipulation of the process. A probabilistic mathematical model of angiogenesis is developed based upon specific microvessel endothelial cell (MEC) functions involved in vessel growth. The model focuses on the roles of MEC random motility and chemotaxis, to test the hypothesis that these MEC behaviors are of critical importance in determining capillary growth rate and network structure. Model predictions are computer simulations of microvessel networks, from which questions of interest are examined both qualitatively and quantitatively. Results indicate that a moderate MEC chemotactic response toward an angiogenic stimulus, similar to that measured in vitro in response to acidic fibroblast growth factor, is necessary to provide directed vascular network growth. Persistent random motility alone, with initial budding biased toward the stimulus, does not adequately provide directed network growth. A significant degree of randomness in cell migration direction, however, is required for vessel anastomosis and capillary loop formation, as simulations with an overly strong chemotactic response produce network structures largely absent of these features. The predicted vessel extension rate and network structure in the simulations are quantitatively consistent with experimental observations of angiogenesis in vivo. This suggests that the rate of vessel outgrowth is primarily determined by MEC migration rate, and consequently that quantitative in vitro migration assays might be useful tools for the prescreening of possible angiogenesis activators and inhibitors. Finally, reduction of MEC speed results in substantial inhibition of simulated angiogenesis. Together, these results predict that both random motility and chemotaxis are MEC functions critically involved in determining the rate and morphology of new microvessel network growth.

Cell Division↗

PubMed2025

The Involvement of PI3K-Akt Signaling in the Clinical and Pathological Findings of Idiopathic Multicentric Castleman Disease-Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, and Organomegaly and Not Otherwise Specified Subtypes.

Idiopathic multicentric Castleman disease is a rare lymphoproliferative disorder that is clinically classified into idiopathic plasmacytic lymphadenopathy (IPL); thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO); and not otherwise specified (NOS). Although each subtype shows varying degrees of hypervascularity, no statistical data on the degree of vascularization have been reported. Additionally, the mechanisms underlying vascularization in each clinical subtype are poorly understood. Here, we aimed to clarify these mechanisms by evaluating the histopathological characteristics of each clinical subtype across 37 patients and performing a whole-transcriptome analysis focusing on angiogenesis-related gene expression. Histologically, TAFRO and NOS exhibited a significantly higher degree of vascularization than IPL (IPL vs TAFRO, P < .001; IPL vs NOS, P = .002). In addition, the germinal centers (GCs) were significantly more atrophic in TAFRO than in IPL. In TAFRO and NOS, "whirlpool vessels" in GCs were seen in most cases (TAFRO, 9/9, 100%; NOS, 6/8, 75%) but not in IPL (IPL vs TAFRO, P < .001; IPL vs NOS, P = .007). Likewise, immunostaining for Ets-related gene revealed higher levels in endothelial cells of GCs in TAFRO than in IPL (P = .014), and TAFRO and NOS were associated with a significantly higher number of endothelial cells in interfollicular areas compared with that in IPL (TAFRO vs IPL, P < .001; NOS vs IPL, P = .002). Gene expression analysis revealed that the PI3K-Akt signaling pathway was significantly enriched in the TAFRO and NOS (TAFRO/NOS) groups. This pathway, which may be activated by vascular endothelial growth factor A and some integrins, is known to affect angiogenesis by increasing vascular permeability, which may explain the clinical manifestations of anasarca and/or fluid retention in TAFRO/NOS. These results suggest that the PI3K-Akt pathway plays an important role in the pathogenesis of TAFRO/NOS.

Humans↗

PubMed1995

Microvessel count predicts metastatic disease and survival in non-small cell lung cancer.

The growth of newly formed vessels, or neoangiogenesis, represents an important step in both physiological and pathological situations: in particular, tumour growth and metastasis require angiogenesis. Microvessel count (MC), which represents a measure of tumour angiogenesis, has been associated with metastatic spread in cutaneous, mammary, prostatic, head and neck, and early-stage lung cancer. In this study, the role of tumour angiogenesis as a prognostic indicator was examined in 253 primary non-small lung cancer (NSCLC) patients. Microvessels were counted by highlighting endothelial cells with anti-Factor VIII monoclonal antibody (Mab) in methacarn-fixed tumour samples. In univariat analysis, MC (P< 0.000001), sex (P=0.0036), histotype (P < 0.014), tumour status (P <0.007), and vessel invasion (P < 0.019) were significantly related to hilar and/or mediastinal nodal involvement. However, in the stepwise logistic regression analysis, MC (P<0.000003) retained the most important influence on nodal metastasis. The overall survival analysis calculated by the Kaplan-Meier method revealed that tumours with high MC ( > 25 vessels/field) were significantly associated with increased death risk (log-rank test P = 0.00067; Cox's test P = 0.00046; Gehan's Wilcoxon test P = 0.00108). In 94 patients, the development of metastatic disease during follow-up was significantly related to MC. Indeed, patients who developed metastasis during follow-up showed a higher MC, either as a dichotomous (P = 0.01) or as a continuous (P = 0.003) variable, than patients who had developed no metastasis at the time of the analysis. Moreover, in the stepwise logistic regression analysis, MC retained the most important influence on distant metastases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.

VPF/VEGF is a multifunctional cytokine that contributes to angiogenesis by both direct and indirect mechanisms. On the one hand, VPF/VEGF stimulates the ECs lining nearby microvessels to proliferate, to migrate, and to alter their pattern of gene expression. On the other hand, VPF/VEGF renders these same microvascular ECs hyperpermeable so that they spill plasma proteins into the extravascular space, leading to the clotting of extravasated fibrinogen with deposition of a fibrin gel. Extravascular fibrin serves as a provisional matrix that favors and supports the ingrowth of new blood vessels and other mesenchymal cells that generate mature, vascularized stroma. These same principles apply in tumors, in several examples of non-neoplastic pathology, and in physiological processes that involve angiogenesis and new stroma generation. In all of these examples, microvascular hyperpermeability and the introduction of a provisional, plasma-derived matrix precede and accompany the onset of EC division and new blood vessel formation. It would seem, therefore, that tumors have "borrowed" fundamental mechanisms that developed in multicellular organisms for purposes of tissue defense, renewal, and repair. VPF/VEGF, therefore has taught us something new about angiogenesis; namely, that vascular hyperpermeability and consequent plasma protein extravasation are important, perhaps essential, elements in its generation. However, this finding raises a paradox. While VPF/VEGF induces vascular hyperpermeability, other potent angiogenic factors apparently do not, at least in subtoxic concentrations that are more than sufficient to induce angiogenesis. Nonetheless, wherever angiogenesis has been studied, the newly generated vessels have been found to be hyperpermeable. How, therefore, do angiogenic factors other than VPF/VEGF lead to the formation of new and leaky blood vessels? We do not as yet have a complete answer to this question. One possibility is that at least some angiogenic factors mediate their effect by inducing or stimulating the expression of VPF/VEGF. In fact, there is already one clear example of this. TGF-alpha is a potent angiogenic factor but does not itself increase microvascular permeability. However, TGF-alpha strikingly upregulates VPF/VEGF expression in cultured keratinocytes and is thought to be responsible, at least in part, for the overexpression of VPF/VEGF in psoriasis. Moreover, overexpression of TGF-alpha, along with that of the EGF receptor with which it interacts, is characteristic of many malignant tumors, raising the possibility that TGF-alpha acts to stimulate VPF/VEGF expression in other types of epithelial cells and in this manner induces angiogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

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↗