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PubMed2003

New molecular pathways in angiogenesis.

Angiogenesis has developed into a major area of cancer research. Recently, several newly identified signalling pathways have been shown to play a role in both normal and pathological (including tumour) angiogenesis. Several of the molecules involved in these pathways have potential as novel anti-cancer therapeutic targets including members of the ephrin/Eph receptor, Notch/delta, sprouty, hedgehog and roundabout/slit families. These developments are reviewed.

Ephrins↗

PubMed2006

Trypsins and their role in carcinoma growth.

There are more than 100 distinct types of cancer, and subtypes can be found within specific organs. Cancer progression is a complex multi-step process. These steps reflect alterations that drive the progressive transformation of normal cells into highly malignant ones. One critical step in tumor growth and invasion is the proteolytic processing of the extracellular matrix environment. The degradation of the extracellular matrix not only enables cell migration, invasion, and metastasis formation, but also affects cell behavior in multiple ways; on one hand by cleaving extracellular matrix bound growth factors and on the other hand by inhibiting angiogenesis into the tumor by liberating cryptic endogenous inhibitors of angiogenesis. Serine proteases and matrix metalloproteases are families of proteolytic enzymes involved in physiological and pathological extracellular matrix and basement membrane processing. In this review, we will focus on the role and activation of trypsinogens, a family of serine proteases, in cancer progression.

Angiogenesis Inhibitors↗

PubMed1996

Pathology of malignant melanoma, including new markers and techniques in diagnosis and prognosis.

Although good prognostic markers are already available for patients with cutaneous melanoma, there still is a need for additional markers that are helpful to assess prognosis in individual patients. These so-called progression markers are likely to be found in molecules that play a role in the process of metastasis. Here, emphasis is put on the potential clinical implications of studies on the adhesion molecules from the integrin and CD44 families, proteases of the plasminogen activation system, and components involved in angiogenesis. Based on their differential expression in melanocytic tumor progression, several molecules of these categories appear promising for prognostic and diagnostic purposes. In this respect, the parallelism between key processes in the pathogenesis of metastasis and of angiogenesis is noteworthy. As technical developments in molecular pathology are relevant for diagnostic and prognostic purposes, some recent applications are discussed. An integrated molecular approach in a proper clinicopathologic context is advocated, including proper quality control measures.

Biomarkers, Tumor↗

PubMed1998

Angiogenesis and hypertension.

BACKGROUND: The formation of new blood vessels is an important process in embryonic development and in physiological repair processes. Abnormalities in blood vessel growth have been associated with various pathologies. HYPERTENSION AND IMPAIRED VASCULAR GROWTH: The basic observation underlying the hypothesis that essential hypertension is based on an impaired capacity for vascular growth is the nature of the structural alterations of microvascular beds in essential hypertension. Recent advances in understanding the molecular and cellular mechanisms of vascular growth suggest that the remodeling of individual vessels and vascular networks in hypertension may be a pathological variant of the formation of mature networks. PATHOGENESIS OF IMPAIRED VASCULAR GROWTH: Genetic and fetal influences appear to have significant effects in determining impaired vascular development as an early cause of essential hypertension.

Animals↗

PubMed2004

[The relationship between tumor angiogenesis and cellular proliferation activity in nasal inverted papilloma].

OBJECTIVE: To investigate the expression of CD34 and proliferating cell nuclear antigen (PCNA) and to study the relationship between tumor angiogenesis and cellular proliferation activity in nasal inverted papilloma (NIP). METHOD: The expression of CD34 protein and proliferating cell nuclear antigen were detected in 30 cases of NIP, 16 cases of nasal polyps (NP) and 11 cases of nasal squamous cell carcinoma (NSCC) with immunohistochemical S-P method and the tumor angiogenesis (as assessed by MVD) and cellular proliferation activity (as assessed by PCNA labeling index, PCNA-LI) was evaluated. RESULT: A significant difference in CD34 expression was found among the three diseases above mentioned. The MVD were 32.41 +/- 5.68; 53.22 +/- 9.31 and 80.37 +/- 10.21 in NP, NIP and NSCC. The expression rate of PCNA (PCNA-LI) was 28.67 +/- 9.29; 35.35 +/- 7.02 and 63.18 +/- 12.17 in NP, NIP and NSCC (P<0.01). There was a significant difference in PCNA expression among the three diseases (P<0.01). A significant positive correlation was found between MVD and PCNA-LI (r=0.56, P<0.01). Tumors with a low PCNA-LI was associated with low MVD and vice versa. CONCLUSION: With a significant relation between tumor angiogenesis, cellular proliferation activity and pathological types, MVD, PCNA-LI can be used as a strong independent indicator to judge tumor aggressive behavior, proliferative activity, development of local or regional metastases and prognosis in nasal inverted papilloma.

Antigens, CD34↗

PubMed1998

The angiographic diagnosis of colonic carcinoma.

Carcinoma of the colon is a common cause of chronic iron deficiency anaemia in elderly patients and is conventionally diagnosed by either barium enema or colonoscopy. Occasionally these studies are inconclusive and individuals may proceed to further imaging, including angiography. Between December 1991 and October 1996, 337 patients were referred for visceral angiography to determine the cause of chronic gastrointestinal bleeding. In seven of these individuals (two males and five females with an age range of 65-74 years), all of whom had been investigated by barium enema and colonoscopy, both reported as showing no cause for bleeding, an arteriographic diagnosis of colonic carcinoma was made. Four of these demonstrated patchy areas of increased vascularity whilst three were predominantly hypovascular. Early venous drainage was seen in five. Marked irregularity and truncation of vasa rectae was present in six; more subtle irregularity was visible in one. The mural veins were irregular with or without truncation in five of the six patients in whom they were visualized. The marginal artery was angiographically involved in only two cases and in one of these the tumour was irresectable. It is important to recognize that a previous 'normal' colonoscopy and barium enema does not exclude a colonic neoplasm, even if advanced, and that this diagnosis may be made angiographically. Confusion with other pathologies, such as angiodysplasia, should be prevented by close scrutiny of vasa rectae at the site of arteriographic abnormality, which will usually demonstrate vascular irregularity and truncation highly suggestive of malignancy.

Aged↗

PubMed1996

In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease.

Expression of tissue factor (TF) in the endothelium has been observed only rarely in human disease and has been thought to be elaborated on the surface of vascular endothelial cells (VECs) in vitro as an artifact of tissue culture. Using monoclonal antibodies and a novel probe for functional TF, we have localized TF to the VECs (and tumor cells) within the tumors of seven patients with invasive breast cancer but not in the VECs (or tumor cells) of benign tumors from ten patients with fibrocystic disease of the breast. The potent procoagulant TF was shown to be a marker of the initiation of angiogenesis in human breast cancer. Further evidence that the TF was the demonstration of a similar distribution of cross-linked fibrin only in the VECs of the malignant tumors. We interpret these data as further support for the concept that tumor cells can activate nearby VECs and regulate blood vessel growth in vivo. Large clinical pathologic studies will be necessary to determine whether TF is a useful marker for the "switch" to the angiogenic phenotype" in human breast disease and/or correlates with the thromboembolic complications of breast cancer.

Breast Neoplasms↗

PubMed2006

Mechanisms of angiogenesis in gliomas.

Gliomas are the most frequent primary tumors of the central nervous system in adults. Glioblastoma multiforme, the most aggressive form of astrocytic tumors, displays a rapid progression that is accompanied by particular poor prognosis of patients. Intense angiogenesis is a distinguishing pathologic characteristic of these tumors and in fact, glioblastomas are of the most highly vascularized malignant tumors. For this reason, research and therapy strategies have focused on understanding the mechanisms leading to the origin of tumor angiogenic blood vessels in order to develop new approaches that effectively block angiogenesis and cause tumor regression. We discuss here some important features of glioma angiogenesis and we present molecules and factors and their possible functions and interactions that play a role in neovascularization. In spite of the great progress that molecular biology has achieved on investigating tumor angiogenesis, many aspects remain obscure and the complexity of the angiogenic process stands for an obstacle in identifying the exact and complete molecular pathways orchestrating new blood vessels formation, which are necessary for the survival and expansion of these tumors.

Central Nervous System Neoplasms↗

PubMed1993

Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture.

BACKGROUND: Delineation of the morphologic aspects of age-related macular degeneration (ARMD) is helpful in correlation with the clinical features and may contribute to understanding the pathogenesis. METHODS: All eyes on file in the Eye Pathology Laboratory, Wilmer Institute, with the known features of ARMD were analyzed according to age, sex, and race. Methods included routine sections in the macula, stepped-serial and serial sections, and electron microscopy and two-dimensional reconstruction in selected cases. RESULTS: There were 760 eyes with ARMD from 450 patients. Only 5.3% of these patients were black. Nodular drusen were observed in 6.2% of eyes (n = 47), basal laminar deposits in 54.7%, basal linear deposits in 27.6%, neovascularization in 38.2%, and disciform scars in 40.8%. Three types of soft drusen were identified and were observed in 28.0%. The mean diameter of the disciform scar was 3.73 mm, and mean thickness was 0.27 mm. In disciform scars greater than 0.2 mm in thickness, only approximately 25% of the surface of the scar had some remaining photoreceptor cells. Serous or hemorrhagic detachments were observed in 10.4% of eyes. Retinal pigment epithelial (RPE) atrophy without disciform scars was observed in 24.6% of eyes. Areolar atrophy was the most common feature observed in eyes of black patients. CONCLUSION: This comprehensive histopathologic evaluation provides the tabulation of the various morphologic features of ARMD. Basal laminar deposit and basal linear deposit, but not nodular drusen, are important positive associations with choroidal neovascularization, disciform scarring, and visual loss. Preservation of photoreceptor cells was seen only over disciform scars 0.2 mm thickness or less.

Adult↗

PubMed2001

Neuropathology of occipital horn syndrome.

Occipital horn syndrome, formerly known as Ehlers-Danlos syndrome type IX or X-linked cutis laxa, is an allelic variant of Menkes' syndrome. Although the clinical symptomatology and systemic pathology findings have been well described in occipital horn syndrome, the neuropathology has not previously been reported. A kindred affected by the X-linked occipital horn syndrome is followed at the University of Alabama at Birmingham. A severely mentally retarded dysmorphic man, who died at the age of 26 years, never gained the ability to walk or talk. Among other findings at autopsy, the patient had the skeletal anomalies previously described with occipital horn syndrome. Neuropathologic findings included neovascularization and extreme reduplication of the cerebral arteries, in conjunction with cystic medial degeneration; bilateral cerebellar hypoplasia; focal cortical dysplasia, and cerebellar heterotopias. These findings are similar to those seen in the brains of patients with Menkes' syndrome, which is not surprising, given the known phenotypic overlap and the proven allelism of occipital horn syndrome with classic Menkes' syndrome.

Adolescent↗

PubMed1999

Suppression of coronary vasculitis in a murine model of Kawasaki disease using an angiogenesis inhibitor.

Coronary arteritis can be induced in C57BL/6 mice with a single intraperitoneal (ip) injection of Lactobacillus casei cell fragments. Histologic sections resemble the vasculitis and aneurysms observed in the medium-sized coronary arteries of children with Kawasaki disease. Since endothelial cells could play an important role in the development of vasculitis, a recently described angiogenesis inhibitor that is not an immunosuppressive agent, AGM-1470 (derived from Aspergillus fumigatus), was used to evaluate its therapeutic potential in this model. A total of 32 mice were administered 0.5 mg of sterile L. casei preparation ip on day 0 and randomized to either a treatment (AGM-1470, 27mg/kg sc alternate days) or a control (vehicle only) protocol. Hearts were harvested on day 14 (early disease) or at the end of the study on day 28 (established disease). Histologic sections were scored blindly for vasculitis. Day 14 sections from both protocols manifested only minimal disease, indicating that the vasculitis had not yet matured. By day 28, the AGM-1470 group had significantly less coronary vasculitis than the control group (0.7 vs 2.6, p < 0.005, respectively). These studies suggest that endothelial cells may play an active role in this pathologic process and that angiogenesis inhibitors, such as AGM-1470, could be useful tools for the treatment and understanding of vasculitis.

Animals↗

PubMed2004

Vascular endothelial growth factor- and thrombin-induced termination factor, Down syndrome critical region-1, attenuates endothelial cell proliferation and angiogenesis.

Activation and dysfunction of the endothelium underlie many vascular disorders including atherosclerosis, tumor growth, and inflammation. Endothelial cell activation is mediated by many different extra-cellular signals, which result in overlapping yet distinct patterns of gene expression. Here we show, in DNA microarray analyses, that vascular endothelial growth factor (VEGF) and thrombin result in dramatic and rapid upregulation of Down syndrome critical region (DSCR)-1 gene encoding exons 4-7, a negative feedback regulator of calcium-calcineurin-NF-AT signaling. VEGF- and thrombin-mediated induction of DSCR-1 involves the cooperative binding of NF-ATc and GATA-2/3 to neighboring consensus motifs in the upstream promoter. Constitutive expression of DSCR-1 in endothelial cells markedly impaired NF-ATc nuclear localization, proliferation, and tube formation. Under in vivo conditions, overexpression of DSCR-1 reduced vascular density in matrigel plugs and melanoma tumor growth in mice. Taken together, these findings support a model in which VEGF- and thrombin-mediated induction of endothelial cell proliferation triggers a negative feedback loop consisting of DSCR-1 gene induction and secondary inhibition of NF-AT signaling. As a natural brake in the angiogenic process, this negative pathway may lend itself to therapeutic manipulation in pathological states.

Animals↗

PubMed2004

[Significance of leukocytes in the regulation of retinal edema, ischemia, and angiogenesis].

BACKGROUND: Involvement of leukocytes in three major pathologic conditions in the retina, i.e., edema, ischemia, and angiogenesis, has recently been thoroughly investigated. The accumulated evidence will lead to an integrated understanding of the relationship between leukocytes and retinal disorders, which is required for clinical applications of new medical treatment. METHOD: Leukocyte roles in the retinal vascular pathology were assessed by reviewing the related literature. RESULTS: Vascular endothelial growth factor(VEGF)-induced leukocyte adhesion to the retinal vessels was shown to result in blood-retinal barrier breakdown, and the leukocyte-mediated pathogenesis was also seen in a model of diabetic retinopathy. A possible mechanism by which retinal angiogenesis develops intraviteral proliferation instead of compensating the avascular retina is that VEGF-producing monocytes/macrophages infiltrate the vitreous with subsequent migration of retinal vascular endothelial cells. On the other hand, cytotoxic T lymphocyte-mediated apoptosis of endothelial cells appears to cause the suppression of pathological retinal angiogenesis and the formation of ischemic retina secondary to vascular regression. CONCLUSION: Leukocytes are considered to regulate retinal edema, ischemia, and angiogenesis.

Animals↗

PubMed2003

Wilms' tumor growth is suppressed by antiangiogenic pigment epithelium-derived factor in a xenograft model.

BACKGROUND/PURPOSE: Pigment epithelium-derived factor (PEDF), a potent endogenous inhibitor of angiogenesis, is highly expressed in the kidney. The authors postulated that systemic administration of PEDF would decrease Wilms' tumor growth in a xenograft model, and increased renal vascularity would result in a mouse null for PEDF. METHODS: Tumors were induced in athymic mice using human anaplastic Wilms' tumor cells. Purified PEDF protein or vehicle was administered for 7 days beginning 2 to 3 weeks after inoculation. Tumors were stained with anti-PEDF and anti-Factor VIII antibodies. Mitoses and microvascular density (MVD) were counted per high-power field (hpf). PEDF-null mice were generated on a SV129/C57Bl6 background. Wild-type and null kidneys were assessed for MVD. RESULTS: Mean tumor weight in the 2-week group was 60% less than controls (P <.05). The MVD and mitotic count in treated tumors were significantly less than controls (P <.05). PEDF stained strongly in normal kidneys but was minimal to absent in Wilms' tumor. PEDF-null kidneys had increased MVD compared with wild-type (P <.05). CONCLUSIONS: PEDF is expressed strongly in normal murine kidney, and loss of its angioinhibitory activity may contribute to pathologic angiogenesis in Wilms' tumor. Systemic PEDF suppresses WT growth by targeting both the tumor cells and its associated vasculature.

Angiogenesis Inhibitors↗

PubMedDate not supplied

The role of diffuse optical spectroscopy in the clinical management of breast cancer.

Diffuse optical spectroscopy (DOS) of breast tissue provides quantitative, functional information based on optical absorption and scattering properties that cannot be obtained with other radiographic methods. DOS-measured absorption spectra are used to determine the tissue concentrations of deoxyhemoglobin (Hb-R), oxyhemoglobin (Hb-O2), lipid, and water (H2O), as well as to provide an index of tissue hemoglobin oxygen saturation (StO2). Tissue-scattering spectra provide insight into epithelial, collagen, and lipid contributions to breast density. Clinical studies of women with malignant tumors show that DOS is sensitive to processes such as increased tissue vascularization, hypoxia, and edema. In studies of healthy women, DOS detects variations in breast physiology associated with menopausal status, menstrual cycle changes, and hormone replacement. Current research involves using DOS to monitor tumor response to therapy and the co-registration of DOS with magnetic resonance imaging. By correlating DOS-derived parameters with lesion pathology and specific molecular markers, we anticipate that composite "tissue optical indices" can be developed that non-invasively characterize both tumor and normal breast-tissue function.

Biophysical Phenomena↗

PubMed1997

[Giant fibrovascular polyp of the esophagus].

Fibrovascular polyps of the oesophagus are rare tumor-like lesions characterized by development of the peduncolated intraluminal masses that can reach gigantic size and may have spectacular clinical presentation including regurgitation of a fleshy mass into the mouth and can lead to sudden death for occlusion of the larynx. Starting from a case observed and successfully treated by transoral resection we review the clinical radiographic and pathological findings of benign oesophageal tumor that requires surgical removal because of the progressive nature of the symptoms and the small, just known, risk of sudden death. The approach depends on the pedicule site.

Aged↗

PubMedDate not supplied

The role of chemokines in the immunopathology of pulmonary disease.

During the last decade, our understanding of the mechanisms involved in the initiation and maintenance of pulmonary disease has been greatly aided by advances in the field of chemokine biology. Chemokines comprise four supergene families, two of these families (the CC and CXC chemokine groups) are quite large and contain over 50 identified ligands and at least 14 individual receptors. Two additional chemokine families (C, CXXXC chemokines) are small and contain lymphotactin and fractalkine, respectively, as their members. In addition to their originally identified chemotactic activity, chemokines possess a variety of biological activities, ranging from immunomodulating leukocyte activation to suppressing HIV infection. The latter effect is due to the ability of specific chemokine receptors to serve as co-receptor for HIV entry into specific leukocyte sub-populations. A number of in vitro and in vivo studies have underscored the importance of chemokine biology in the progression of both acute and chronic lung diseases. These investigations have demonstrated the importance of targeting chemokines for new therapeutic approaches to treat pulmonary disease. A variety of acute and chronic lung diseases have been shown to possess a chemokine component and contribute to the initiation and maintenance of lung pathology, thus, there is little doubt that a further understanding of the mechanisms of pulmonary diseases will rely upon advances in the field of chemokine biology.

Acute Disease↗

PubMed2005

[Expression and significance of angiopoietins in oral squamous cell carcinoma].

OBJECTIVE: To observe the expression of angiopoietins in oral squamous cell carcinoma and relationship between the expression of angiopoietins and pathologic classification. METHODS: The expression of Ang-1 and Ang-2 protein in samples from 42 oral squamous cell carcinoma and 16 oral normal mucosa were detected by immunohistochemical technique. RESULTS: The expression of Ang-1 and Ang-2 was found in both oral squamous cell carcinoma and normal control. It was found Ang-1 expression alike in oral squamous cell carcinoma and control (P > 0.05). Ang-2 expressed at low level in control while strongly positive in oral squamous cell caroinoma and the level of Ang-2 expression in oral squamous cell caroinoma was related to pathologic classification (P < 0.05). CONCLUSION: Ang-2 expression in oral squamous cell carcinoma is related to angiogenesis and pathological classification, which is probably involved in angiogenesis regulation, promotes the development and metastasis of oral squamous cell carcinoma.

Angiopoietin-1↗