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PubMed2005

VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis.

Vascular endothelial growth factor receptor-2 (VEGFR-2) activation by VEGF-A is essential in vasculogenesis and angiogenesis. We have generated a pan-phosphorylation site map of VEGFR-2 and identified one major tyrosine phosphorylation site in the kinase insert (Y951), in addition to two major sites in the C-terminal tail (Y1175 and Y1214). In developing vessels, phosphorylation of Y1175 and Y1214 was detected in all VEGFR-2-expressing endothelial cells, whereas phosphorylation of Y951 was identified in a subset of vessels. Phosphorylated Y951 bound the T-cell-specific adapter (TSAd), which was expressed in tumor vessels. Mutation of Y951 to F and introduction of phosphorylated Y951 peptide or TSAd siRNA into endothelial cells blocked VEGF-A-induced actin stress fibers and migration, but not mitogenesis. Tumor vascularization and growth was reduced in TSAd-deficient mice, indicating a critical role of Y951-TSAd signaling in pathological angiogenesis.

Actins↗

PubMedDate not supplied

[Angiogenesis of gynecologic tumors studied with color Doppler].

Angiogenesis is obligatory event in solid tumors growth. Weak muscular layer in the newly formed tumoral vessels results in decreased resistance to blood flow and characteristic Doppler signal. The number and arrangement of the blood vessels differ between benign and malignant lesions as well. Parameters mentioned above enable a precise ultrasound differential diagnosis between benign and malignant tumors. Malignant uterine tumors are better perfused and have lower resistance to blood flow than benign ones. Benign lesions with secondary changes (necrosis) may have lowered resistance indices. The finding of pathological perfusion makes the diagnosis of endometrial carcinoma also very accurate. High sensitivity of the transvaginal color Doppler in detecting newly formed blood vessels in an early stages of ovarian cancer may establish this technique as a screening method for this still very high lethality disease.

Female↗

PubMed2004

Advances in the biology of astrocytomas.

PURPOSE OF REVIEW: Conventional surgery, radio- and chemotherapy have failed to significantly improve the prognosis of patients with malignant astrocytomas--hence the need for understanding their molecular biology. Harvesting this understanding to yield novel biological targeted therapies has approached the clinical doorstep. Therapeutic efficacy will likely require combinatorial therapy involving biologicals and conventional therapies, with small incremental efficacy in selected sub-groups. This review highlights some of the findings over the past year (June 2003-2004) that have contributed to this slow but essential journey towards our understanding of the biology of astrocytomas. RECENT FINDINGS: The accumulation of loss and/or gain of function molecular alterations underlying astrocytoma formation, progression and key growth parameters including proliferation, angiogenesis, apoptosis, invasion and resistance are emerging. These alterations involve those regulating the growth factor/receptor and downstream signaling networks, cell cycle, immune modulators and other key biological processes. The advances are facilitated by interactions amongst clinician and basic scientists, in both academia and industry. They have incorporated high-throughput bioinformatics analysis of genomic and expression array data, the emerging field of proteomics and development of various genetically engineered models of astrocytomas. SUMMARY: Astrocytomas, like other cancers, are a result of several molecular alterations, some of which strongly correlate to their pathological grade. However, molecular heterogeneity exists between astrocytomas of similar grades and likely between varying micro-environmental regions of a single tumor. Characterization of the molecular signature of an astrocytoma and linking with the appropriate 'tailored' therapie(s) is the hope of the future.

Animals↗

PubMed2004

Angiogenesis in osteoarthritis and spondylosis: successful repair with undesirable outcomes.

PURPOSE OF REVIEW: Osteoarthritis and spondylosis are frequently described as "wear-and-tear" arthritis, apparently contradicting modern management, which focuses on continuing and progressive exercise. Laboratory findings, including the growth of new blood vessels, encourage comparisons with repair processes. This review aims to place recent evidence in the context of previous work emphasizing the dynamic nature of tissues in these conditions. RECENT FINDINGS: Synovitis has now become recognized as a common and important feature of osteoarthritis, and vascular growth is enhanced in osteoarthritic synovia when infiltrating macrophages generate angiogenic factors. As the molecular balance between angiogenic and antiangiogenic factors is disturbed, new blood vessels are permitted to grow into normally avascular structures, such as the articular cartilage and intervertebral disc. Angiogenesis is a key factor in new bone formation in osteophytes and at the osteochondral junction, thereby contributing to radiologic disease progression. Innervation of new blood vessels may contribute importantly to chronic pain. SUMMARY: Reconceptualizing osteoarthritis and spondylosis as reparative processes provides a pathologic model consistent with current advice to exercise, when exercise facilitates repair. Repair does not, however, lead to normal tissue, and understanding the mechanisms by which changes in joint innervation may occur as a consequence of angiogenesis should lead to novel therapies that alleviate the common symptoms of these highly prevalent conditions.

Cartilage, Articular↗

PubMed2002

Cytokines in dementias.

Knowledge regarding putative inflammatory component(s) participating in Alzheimer's disease (AD) and in vascular dementia (VAD) remains scarce. Recently, we have demonstrated the presence of inflammatory components, such as cytokines, in the CSF of demented patients. Although the initial events triggering the neurodegenerative processes in AD versus VAD may be different and thus lead to different neuropathological outcome, they may initiate a similar cascade of cytokine production in response to neuronal injury. The cytokines released in the CNS may in turn, act in a similar manner in both diseases, amplifying certain pathological changes such as amyloidogenesis and amyloid accumulation in the blood vessels, white matter lesions and angiogenesis. This hypothesis is supported by clinical studies demonstrating the presence of white matter infarcts and cerebrovascular pathology in patients with AD as well as the presence of senile plaques in patients with VAD. This review will focus on the production of pro-inflammatory and anti-inflammatory cytokines in dementia, and their putative role for glia cell activation, amyloidogenesis, vascular changes, white matter damage and neurodegeneration.

Adjuvants, Immunologic↗

PubMed1987

Vascular response of the cornea to contact lens wear.

The subject of contact lens-induced corneal vascularization has attracted considerable interest in recent times in view of the relatively high prevalence of this condition with the use of extended wear soft lenses. This paper reviews clinical features and underlying mechanisms of the vascular response to lens wear. The concept of a "normal" vascular response to contact lens wear is proposed; the limits of this response are defined and incorporated into a simple grading system. The clinical presentation of vessel growth in the cornea is described together with appropriate methods of slit lamp evaluation. Current theories of the pathology and etiology of lens-induced vascularization are reviewed, and a dual-etiology model of stromal vessel formation is described. It is concluded that the prognosis for halting the progression of vascularization is excellent; however, little information is available concerning the long-term regression of "ghost" vessels.

Contact Lenses, Extended-Wear↗

PubMed2005

Angiogenesis: the major abnormality of the keratin-14 IL-4 transgenic mouse model of atopic dermatitis.

OBJECTIVE: Angiogenesis plays an important role in psoriasis, but its role in atopic dermatitis is unknown. The authors examined the dermal microvasculature of an IL-4 transgenic mouse model of atopic dermatitis to determine whether angiogenesis was present. METHODS: Transmission and scanning electron microscopy and confocal microscopy studies were performed. RESULTS: Transmission electron microscopy showed sprouting, transcapillary pillars of intussusception, thickened endothelial cells with large nuclei, and increased interendothelial junctional cleft number and length. Compared to nontransgenic littermates, there was a significant increase in the lengths and numbers of the interendothelial junctional clefts, along with a decrease in the length ratios of tight junction to interendothelial junctional clefts in both the early and late disease stages. In the early and late skin lesions, scanning electron microscopy of vascular corrosion casts showed disorganization of the capillary network hierarchy with increased density of capillary sprouts. Confocal microscopy of the animals with early and late skin lesions showed significant reduction in tight junction protein claudin-5. CONCLUSIONS: Angiogenesis is the major pathologic feature in this model of atopic dermatitis. The chronic skin inflammation is intertwined with and may cause the angiogenesis, but the angiogenesis itself is likely to be important in this disease process.

Animals↗

PubMed2000

Thrombospondin-1/HIV-1 tat protein interaction: modulation of the biological activity of extracellular Tat.

Tat protein, a trans-activating factor of the human immunodeficiency virus type 1, acts also as an extracellular molecule modulating gene expression, cell survival, growth, transformation, and angiogenesis. Here we demonstrate that human thrombospondin-1 (TSP), a plasma glycoprotein and constituent of the extracellular matrix, binds to glutathione-S-transferase (GST)-Tat protein but not to GST. Scatchard plot analysis of the binding of free GST-Tat to immobilized TSP reveals a high-affinity interaction (Kd equal to 25 nM). Accordingly, TSP inhibits cell internalization and HIV-1 LTR trans-activating activity of extracellular Tat in HL3T1 cells with ID50 equal to 10-30 nM. Also, TSP inhibits cell interaction and mitogenic activity of extracellular Tat in T53 Tat-less cells. TSP is instead ineffective when administered after the interaction of Tat with cell surface heparan-sulfate proteoglycans has occurred, in keeping with its ability to prevent but not disrupt Tat/heparin interaction in vitro. Finally, TSP inhibits the autocrine loop of stimulation exerted by endogenous Tat in parental T53 cells. Accordingly, TSP overexpression inhibits cell proliferation, angiogenic activity, and tumorigenic capacity of stable T53 transfectants. Our data demonstrate the ability of TSP to bind to Tat protein and to affect its LTR trans-activating, mitogenic, angiogenic, and tumorigenic activity. These findings suggest that TSP may be implicated in the progression of AIDS and in AIDS-associated pathologies by modulating the bioavailability and biological activity of extracellular Tat.

Adenocarcinoma↗

PubMed2002

Recent developments in antiangiogenic therapy.

The use of antiangiogenic therapy is gaining momentum as a novel treatment for a number of conditions, ranging from cancer to psoriasis. This has stemmed from research in the early 1970s showing that the formation of new blood vessels by pre-existing endothelial cells is essential in tumour growth and progression. However, although antiangiogenic therapy was hailed as a new avenue of treatment for cancer, initial clinical data have been disappointing. This has led to the reassessment of antiangiogenic therapy for cancer, and new strategies have been proposed to increase the efficacy of these agents in this setting. Angiogenesis has also been implicated in other conditions that are notoriously difficult to treat, such as arteriosclerosis, arthritis, psoriasis and diabetic retinopathy. Increased understanding of the angiogenic process, the diversity of its inducers and mediators, appropriate drug schedules and the use of these agents with other modalities may lead to radically new treatment regimens for many of these conditions. The role of angiogenesis in different pathological settings, and emerging antiangiogenic agents currently in preclinical and clinical studies are discussed in this review. However, while potential benefits are profound, limitations of antiangiogenic therapy have also been identified, suggesting that there is also a need for caution in applying these compounds to the clinical setting.

Angiogenesis Inhibitors↗

PubMed2005

Processing of VEGF-A by matrix metalloproteinases regulates bioavailability and vascular patterning in tumors.

Vascular endothelial growth factor (VEGF) is a critical mediator of blood vessel formation during development and in pathological conditions. In this study, we demonstrate that VEGF bioavailability is regulated extracellularly by matrix metalloproteinases (MMPs) through intramolecular processing. Specifically, we show that a subset of MMPs can cleave matrix-bound isoforms of VEGF, releasing soluble fragments. We have mapped the region of MMP processing, have generated recombinant forms that mimic MMP-cleaved and MMP-resistant VEGF, and have explored their biological impact in tumors. Although all forms induced similar VEGF receptor 2 phosphorylation levels, the angiogenic outcomes were distinct. MMP-cleaved VEGF promoted the capillary dilation of existent vessels but mediated a marginal neovascular response within the tumor. In contrast, MMP-resistant VEGF supported extensive growth of thin vessels with multiple and frequent branch points. Our findings support the view that matrix-bound VEGF and nontethered VEGF provide different signaling outcomes. These findings reveal a novel aspect in the regulation of extracellular VEGF that holds significance for vascular patterning.

Animals↗

PubMed2002

Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis.

Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF, VEGF-A) is a multifunctional cytokine with important roles in pathological angiogenesis. Using an adenoviral vector engineered to express murine VEGF-A(164), we previously investigated the steps and mechanisms by which this cytokine induced the formation of new blood vessels in adult immunodeficient mice and demonstrated that the newly formed blood vessels closely resembled those found in VEGF-A-expressing tumors. We now report that, in addition to inducing angiogenesis, VEGF-A(164) also induces a strong lymphangiogenic response. This finding was unanticipated because lymphangiogenesis has been thought to be mediated by other members of the VPF/VEGF family, namely, VEGF-C and VEGF-D. The new "giant" lymphatics generated by VEGF-A(164) were structurally and functionally abnormal: greatly enlarged with incompetent valves, sluggish flow, and delayed lymph clearance. They closely resembled the large lymphatics found in lymphangiomas/lymphatic malformations, perhaps implicating VEGF-A in the pathogenesis of these lesions. Whereas the angiogenic response was maintained only as long as VEGF-A was expressed, giant lymphatics, once formed, became VEGF-A independent and persisted indefinitely, long after VEGF-A expression ceased. These findings raise the possibility that similar, abnormal lymphatics develop in other pathologies in which VEGF-A is overexpressed, e.g., malignant tumors and chronic inflammation.

Adenoviridae↗

PubMed1994

Clinical prognostic significance of tumour angiogenesis.

BACKGROUND: The importance of tumour angiogenesis in the process of tumour growth and metastasis has recently gained wide acceptance. This has lead to intense investigation into the biology of tumour angiogenesis and its clinical significance. An understanding of angiogenesis may allow therapeutic modulation in order to interrupt the progression from tumourigenesis to metastatic disease and control growth of distant metastases. DESIGN: A review was undertaken of studies relating clinical outcome to the assessment of tumour angiogenesis in patients with cancer. RESULTS: Studies have been recently reported in a variety of tumours, particularly early breast cancer and melanoma. Quantitative pathology, using microvessel counting, has been the main method applied. However assessment of angiogenic growth factors may provide an alternative. In early breast cancer many studies have shown a worse prognosis for those patients with highly vascular tumours. The prognostic influence of tumour angiogenesis is independent of conventional prognostic indicators. Similar, although more varied results, have been obtained in studies of melanoma and other tumour types. CONCLUSION: Tumour angiogenesis, as assessed with quantitative pathology, is an important prognostic indicator in early breast cancer and possibly in other tumour types. Further confirmatory studies are required before this indicator is routinely used to guide treatment selection. Assessment of tumour angiogenesis will be increasingly important in the investigation of new therapies aimed at inhibiting angiogenesis or targeting tumour vasculature.

Breast Neoplasms↗

PubMed2003

The non-classical export routes: FGF1 and IL-1alpha point the way.

Non-classical protein release independent of the ER-Golgi pathway has been reported for an increasing number of proteins lacking an N-terminal signal sequence. The export of FGF1 and IL-1alpha, two pro-angiogenic polypeptides, provides two such examples. In both cases, export is based on the Cu2+-dependent formation of multiprotein complexes containing the S100A13 protein and might involve translocation of the protein across the membrane as a 'molten globule'. FGF1 and IL-1alpha are involved in pathological processes such as restenosis and tumor formation. Inhibition of their export by Cu2+ chelators is thus an effective strategy for treatment of several diseases.

Animals↗

PubMed1991

Pathology and molecular mechanisms of multistage human hepatocarcinogenesis.

Recent fundamental research has disclosed the presence of multiple genetic alterations including activation of oncogenes and inactivation of tumor suppressor genes in various human cancers. These multiple genetic alterations are thought to be correlated with multiple stages of carcinogenesis and further progression. Hepatocellular carcinoma (HCC) is a typical example. The majority of HCCs are associated with infection by hepatitis virus B or C. In the damaged liver, small nodular lesions develop due to clonal expansion of hepatocytes. Some of these nodules are diagnosed as early HCC of the well differentiated type and correspond to in situ or microinvasive carcinoma. Within these nodules, moderately or poorly differentiated HCCs often emerge as nodule-in-nodule lesions when the diameter of the nodules exceeds 1.5 cm. Ordinary HCCs formed by progression show highly increased cell proliferation, neovascularization, production of high-molecular-mass forms of basic fibroblast growth factor and aneuploidy in some tumors. Corresponding to this stage of malignant progression, HCCs show loss of heterozygosity for multiple chromosomes including chromosomes 4, 16q and 17p. Tumor suppressor gene p53, located on 17p, is frequently mutated in high-grade, but not in early, HCCs. Thus, it is strongly suggested that inactivation of multiple tumor suppressor genes plays an important role in progression, and probably directly or indirectly causes chromosome instability, enhanced cell proliferation and neovascularization.

Carcinoma, Hepatocellular↗

PubMed1998

Natural products as angiogenesis inhibitors.

Angiogenesis is a strictly controlled process in the healthy, adult human body. It is regulated by a variety of endogenous angiogenic and angiostatic factors. It is only switched on, e.g., during wound healing. Pathological angiogenesis occurs, for example, in cancer, chronic inflammation, or atherosclerosis. Angiogenesis inhibitors are able to interfere with various steps of angiogenesis, like basement destruction of blood vessels, proliferation and migration of endothelial cells, or the lumen formation. Among the known angiogenesis inhibitors compounds derived from natural sources, like flavonoids, sulphated carbohydrates, or triterpenoids are playing a prominent role.

Adult↗

PubMed2001

Vascular morphogenesis and remodeling in a human tumor xenograft: blood vessel formation and growth after ovariectomy and tumor implantation.

To determine mechanisms of blood vessel formation and growth in solid tumors, we used a model in which LS174T human colon adenocarcinomas are grown in the isolated ovarian pedicle of nude mice. Reconstruction of 3500 histological serial sections demonstrated that a new vascular network composed of venous-venous loops of varying sizes grows inside the tumor from the wall of the adjacent main vein. Loops elongate and remodel to establish complex loop systems. The mechanisms of loop formation and remodeling correspond to intussusceptive microvascular growth (IMG). In the tissue surrounding the tumor segmentation, another mechanism of IMG is prevalent in venous vessels. Comparison to vascular morphogenesis in the ovariectomized pedicle not only confirms the existence of corresponding mechanisms in both systems, but also reveals numerous sprouts that are superimposed onto loop systems and pathological deviations of loop formation, remodeling, and segmentation in the tumor. These pathological mechanisms interfere with vessel patency that likely cause heterogenous perfusion and hypoxia thus perpetuating angiogenesis. Blood vessel formation based on IMG was also detected in a large thrombus that completely occluded a part of an ovarian artery branch.

Adenocarcinoma↗

PubMedDate not supplied

Tumor-associated macrophages: foe or accomplice of tumors?

Macrophages are predominantly involved in the immune and inflammatory processes of solid tumors. Macrophages infiltrated into a tumor have an ambivalent relationship with the tumor, because they are innately very flexible and adaptable depending on the microenvironment of the tissue and the tissue-derived factors. The relationship between tumor-associated macrophages (TAMs) and a tumor is extremely complicated and has not yet been clearly elucidated. Now, the reintegration of biological knowledge including immunology, pathology and oncology is indispensable for the clinical application of TAMs to cancer therapy. In this review, we focus on the range of pro- and anti-tumor functions performed by TAMs and outline a new class of cancer therapies that aims at controlling the complex functions of TAMs.

Animals↗

PubMed1998

Microvessel density in prostate cancer: prognostic and therapeutic utility.

Microvessel density is a promising prognostic factor in management of patients with prostate cancer. Unlike cancer cell-based factors, microvessel density is a host stromal factor that has apparently limited heterogeneity within a cancer. Its predictive value for pathological stage has been demonstrated in most but not all reports. Further, recent studies reveal that microvessel density may be predictive of cancer recurrence and perhaps survival in some patients. Inhibition of angiogenesis may be an effective chemopreventive approach, particularly for men at high risk of prostate cancer. The patient described in the case study may benefit from microvessel density determination. Manual or computer-assisted counting of microvessels in the diagnostic needle biopsy specimen would provide a value that could be compared with published findings to predict pathological stage and outcome, particularly in combination with Gleason score and serum prostate-specific antigen concentration. The probability of extraprostatic extension may be sufficiently high that a urologist may choose not to operate on the patient. Similarly, the probability of recurrence after surgery or radiation may be sufficiently high to warrant adjuvant therapy.

Antineoplastic Agents↗