Honokiol, a small molecular weight natural product, inhibits angiogenesis in vitro and tumor growth in vivo.

Natural products comprise a major source of small molecular weight angiogenesis inhibitors. We have used the transformed endothelial cell line SVR as an effective screen of natural product extracts to isolate anti-angiogenesis and anti-tumor compounds. Aqueous extracts of Magnolia grandiflora exhibit potent activity in our SVR proliferation assays.

Cutaneous lesions of secondary syphilis are highly angiogenic.

Background: The role of angiogenesis in infectious processes is poorly studied. Some viruses have been linked to angiogenesis, but the role of bacteria and protozoa in inducing angiogenesis in chronic infections is poorly understood.

Objectives: We examined the role of angiogenesis in syphilis, a common and often difficult-to-treat infectious disease, especially in the setting of HIV/AIDS.

High-level expression of vascular endothelial growth factor and its receptors in an aphthous ulcer.

Background: Aphthous ulcers are an extremely common disorder of unknown etiology. These ulcers cause significant morbidity through pain and interference with eating. Thalidomide, an angiogenesis inhibitor, is efficacious for the treatment of aphthous ulcers.

Malignant transformation of melanocytes to melanoma by constitutive activation of mitogen-activated protein kinase kinase (MAPKK) signaling.

Malignant melanoma is the cancer with the most rapid increase in incidence in the United States. Ultraviolet light and deficiency of the p16ink4a gene are known factors that predispose one to the development of malignant melanoma. The signal transduction pathways that underlie the progression of melanoma from their precursors, atypical nevi, are not well understood.

Mitogen-actived protein kinase activation is an early event in melanoma progression.

Purpose: Melanoma is the most common cause of death from cutaneous malignancy, and is the cancer that is most rapidly rising in incidence. Because current therapeutic methods for metastatic melanoma are poorly efficacious, enhanced understanding of signal transduction in melanoma progression is warranted. Prior experimental studies in murine models and human tissues have shown a correlation among activation of mitogen activated protein kinase (MAPK) signaling, angiogenesis, and tumorigenesis.

Design, synthesis, and biological evaluation of angiogenesis inhibitors: aromatic enone and dienone analogues of curcumin.

The quest to find new antitumor compounds is an ongoing research endeavor in many laboratories around the world. The use of small-molecule angiogenesis inhibitors promises to be a potentially effective method for cancer treatment and possible prevention. Many antiangiogenic compounds are in various stages of laboratory evaluations and clinical trials.

SVR angiosarcomas can be rejected by CD4 costimulation dependent and CD8 costimulation independent pathways.

Purpose: We wished to determine whether virally- induced endothelial tumors are rejected by CD4 and CD8 lymphocytes, and whether there are differences in requirements for costimulation in the rejection of these tumors by lymphocyte subsets.

Experimental Design: We have developed a model of endothelial tumorigenesis through the sequential introduction of SV40 large T antigen and oncogenic H-ras into endothelial cells. These cells (SVR cells) form highly aggressive angiosarcomas in immunocompromised mice, but do not grow in syngeneic C57BL/6 mice.

Functional tyrosine kinase inhibitor profiling: a generally applicable method points to a novel role of platelet-derived growth factor receptor-beta in tuberous sclerosis.

Tumors often exhibit activation of specific tyrosine kinases, which may allow targeting of therapy through inhibition of tyrosine kinase signaling. This strategy has been used successfully in the development of STI571 (gleevec), an inhibitor of bcr-abl tyrosine kinase that has been used successfully in the treatment of chronic myelogenous leukemia. STI571 also shows activity against c-kit and platelet-derived growth factor receptor-beta (PDGFRbeta) tyrosine kinase signaling, thus potentially expanding the number of tumors that may respond to it.

Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force.

Purpose: Patients with neurofibromatosis 1 (NF1) are at increased risk for a variety of cardiovascular disorders, but the natural history and pathogenesis of these abnormalities are poorly understood.

Methods: The National Neurofibromatosis Foundation convened an expert task force to review current knowledge about cardiovascular manifestations of NF1 and to make recommendations regarding clinical management and research priorities related to these features of the disease.

Results: This report summarizes the NF1 Cardiovascular Task Force's current understanding of vasculopathy, hypertension, and congenital heart defects that occur in association with NF1.

Reactive oxygen-induced carcinogenesis causes hypermethylation of p16(Ink4a) and activation of MAP kinase.

Background: Implantation of foreign materials into mice and humans has been noted to result in the appearance of soft tissue sarcomas at the site of implantation. These materials include metal replacement joints and Dacron vascular grafts. In addition, occupational exposure to nickel has been shown to result in an increased risk of carcinogenesis.

Phosphorylation by mitogen-activated protein kinase mediates the hypoxia-induced turnover of the TAL1/SCL transcription factor in endothelial cells.

The basic helix-loop-helix transcription factor TAL1 (or SCL), originally identified from its involvement by a chromosomal rearrangement in T-cell acute lymphoblastic leukemia, is required for hematopoietic development. TAL1 also has a critical role in embryonic vascular remodeling and is expressed in endothelial cells postnatally, although little is known about its function or regulation in this cell type. We report here that the important proangiogenic stimulus hypoxia stimulates phosphorylation, ubiquitination, and proteasomal breakdown of TAL1 in endothelial cells.

Tuberous sclerosis-associated lesions of the kidney, brain, and skin are angiogenic neoplasms.

Background: Tuberous sclerosis is an autosomal dominant condition characterized by the development of benign neoplasms of the brain, kidney, and skin. Progressive growth and malignant transformation of brain and kidney lesions constitute the major cause of morbidity and mortality in adults with tuberous sclerosis. In addition, growth of skin lesions may be disfiguring to patients.

Reactive oxygen generated by Nox1 triggers the angiogenic switch.

The reactive oxygen-generating enzyme Nox1 transforms NIH 3T3 cells, rendering them highly tumorigenic and, as shown herein, also increases tumorigenicity of DU-145 prostate epithelial cells. Although Nox1 modestly stimulates cell division in both fibroblasts and epithelial cells, an increased mitogenic rate alone did not account fully for the marked tumorigenicity. Herein, we show that Nox1 is a potent trigger of the angiogenic switch, increasing the vascularity of tumors and inducing molecular markers of angiogenesis.

Neuroendocrine lung tumors: grade correlates with proliferation but not angiogenesis.

Angiogenesis has been implicated in the progression of human neoplasia from benign precursor to invasive and metastatic phenotypes. The acquisition of dominant oncogenes in preneoplastic cells in vitro and in vivo has been associated with the increased ability of tumor cells to secrete angiogenic mediators and recruit blood vessels. However, in a subset of benign lesions, high levels of angiogenesis have been found before the conversion to invasive and metastatic phenotypes.

Are keloids really "gli-loids"?: High-level expression of gli-1 oncogene in keloids.

Background: Keloids are a common lesion arising from sites of previous trauma and are a considerable source of morbidity because of continued growth of lesions, pruritus, and physical appearance. They consist of mesenchymal cells embedded in a stroma of disordered collagen matrix. Clinically, keloids are distinguished from scars in that keloids demonstrate continued growth over the borders of the original injury.

Diffuse dermal angiomatosis of the breast: response to isotretinoin.

Dermal angiomatosis of the breast is an extremely rare disorder of unknown origin characterized by increased angiomatosis and ulceration. We report a case of a young woman whose disorder responded to isotretinoin. Our findings have potential relevance to the treatment of skin disorders in which ulceration is a prominent feature.

Microphthalmia transcription factor immunohistochemistry: a useful diagnostic marker in the diagnosis and detection of cutaneous melanoma, sentinel lymph node metastases, and extracutaneous melanocytic neoplasms.

Background: Melanoma is the most lethal form of skin cancer. Diagnosis of amelanotic melanoma and detection of micrometastases in sentinel lymph nodes pose diagnostic and therapeutic dilemmas for the dermatopathologist and clinician.

Objective: The purpose of this article is to determine the utility of immunohistochemistry using antibodies specific for microphthalmia in the identification of melanocytic lesions in the skin, eye, central nervous system, and sentinel lymph nodes.

The generation and characterization of a cell line derived from a sporadic renal angiomyolipoma: use of telomerase to obtain stable populations of cells from benign neoplasms.

Angiomyolipomas are benign tumors of the kidney derived from putative perivascular epithelioid cells, that may undergo differentiation into cells with features of melanocytes, smooth muscle, and fat. To gain further insight into angiomyolipomas, we have generated the first human angiomyolipoma cell line by sequential introduction of SV40 large T antigen and human telomerase into human angiomyolipoma cells. These cells show phenotypic characteristics of angiomyolipomas, namely differentiation markers of smooth muscle (smooth muscle actin), adipose tissue (peroxisome proliferator-activator receptor gamma, PPARgamma), and melanocytes (microophthalmia, MITF), thus demonstrating that a single cell type can exhibit all of these phenotypes.

Differential expression of active mitogen-activated protein kinase in cutaneous endothelial neoplasms: implications for biologic behavior and response to therapy.

Background: Tumors of endothelium range from benign hemangiomas of infancy to highly malignant angiosarcomas of the elderly. Hemangiomas are the most common tumors in infants and may affect up to 10% of all children. The biologic behavior of these lesions ranges from self-resolving, in the case of hemangiomas and pyogenic granulomas, to lethal metastatic neoplasms in the case of angiosarcoma.

Regulation of angiogenesis and tumorigenesis by signal transduction cascades: lessons from benign and malignant endothelial tumors.

Oncogenes and tumor suppressor genes are implicated in the regulation of the angiogenic switch. Much of the data accumulated to date uses NIH 3T3 cells, which are deficient in the tumor suppressor gene p16, as models for these studies. We have used a novel system, derived by sequential introduction of a temperature-sensitive SV40 large T antigen and oncogenic H-ras, to study the angiogenic switch.

Inhibition of MAP kinase kinase causes morphological reversion and dissociation between soft agar growth and in vivo tumorigenesis in angiosarcoma cells.

Activated ras causes increased activity of several signal transduction systems, including the mitogen-activated protein kinase kinase (MAPKK) pathway and the phosphoinositol-3-kinase (PI-3-K) pathway. We have previously shown that the PI-3-K pathway plays a major role in regulation of ras-mediated tumor angiogenesis in angiosarcoma cells. However, the contribution of the MAPKK pathway to tumorigenesis and angiogenesis is not fully understood.

Immortalized human adult articular chondrocytes maintain cartilage-specific phenotype and responses to interleukin-1beta.

Objective: To develop a reproducible immortalized human chondrocyte culture model for studying the regulation of chondrocyte functions relevant to arthritic diseases in adult humans.

Methods: Primary adult articular chondrocytes were immortalized with a retrovirus expressing a temperature-sensitive mutant of SV40-large T antigen (tsTAg). The established tsT/AC62 chondrocyte cell line was examined in monolayer and alginate culture systems.