This application focuses on the mechanisms of pathogenesis of hemangiomas and associated angiogenesis. Hemangiomas are the most common cutaneous vascular lesions of childhood, and are present in 5 percent of infants at 1 year of age. These hemangiomas may grow to large sizes and may result in compression of vital structures or high output cardiac failure. Treatment of large hemangiomas requires lengthy treatment with steroids or alpha interferon, and surgery. These treatments are associated with a high level of morbidity, including growth retardation, infection, and irreversible neuropathy. A significant number of these hemangiomas do not respond to treatment, resulting in death. Vascular malformations represent another skin lesion of childhood with considerable morbidity. Initially, vascular malformations may resemble hemangiomas, but unlike hemangiomas, vascular malformations do not spontaneously regress. Instead, they tend to enlarge with time, causing pain, deformity, and limb overgrowth. Unlike hemangiomas, there are no medical treatments for vascular malformations. Studies performed during the last funding period have suggested that hemangiomas and vascular malformations can be distinguished by signaling pathways. We have found that model hemangioma cells require a combination of reactive oxygen and akt activation, while model vascular malformation cells use akt activation alone. In addition, we have found that the developmentally important gene Wilms tumor 1 (WT-1) is present in hemangiomas, but not in vascular malformations. We plan to investigate whether WT-1 is necessary for physiologic endothelial regression. Hypothesis: Differences in signal transduction can predict the behavior of endothelial neoplasms in vivo.
Specific Aim 1. To determine the presence of Notch ligands and receptors in human vascular lesions and functional role of Notch ligands in murine bend3 hemangiomas.
Specific Aim 2. To determine the downstream signaling events of nox4 and reactive oxygen in vascular lesions.
Specific Aim 3. To determine the role of the Wilms tumor 1 gene in endothelial remodeling and formation of vascular malformations. The studies outlined in this application will contribute to our basic understanding of cutaneous angiogenesis. In addition, insights gained from the studies described in this application may lead to novel therapeutic approaches to cutaneous disease through signal transduction modulation. Indeed, discoveries made during the prior funding cycle include small molecule angiogenesis inhibitors such as honokiol, solenopsin, carbazole, and triphenylmethanes.
Hemangiomas and vascular malformations are the most common vascular lesions of children, and cause a considerable deal of morbidity because of functional impairment of vital structures and deformity. The biology of these lesions is not fully understood, and the treatment of these lesions causes side effects due to medicines and extensive surgery. The studies in this application have the potential of developing new treatments for these disorders that do not have the side effects of current therapy and given that the same processes may be occurring in other disorders, such as skin inflammation and tumors, advances from these studies may lead to better treatments for skin inflammation and tumors.
|Arbiser, Jack L (2014) PHIPing out: a genetic basis for tumor ulceration. J Invest Dermatol 134:600-2|
|Wang, Xu; Beitler, Jonathan J; Wang, Hong et al. (2014) Honokiol enhances paclitaxel efficacy in multi-drug resistant human cancer model through the induction of apoptosis. PLoS One 9:e86369|
|Hahm, Eun-Ryeong; Karlsson, A Isabella; Bonner, Michael Y et al. (2014) Honokiol inhibits androgen receptor activity in prostate cancer cells. Prostate 74:408-20|
|Bonner, Michael Y; Arbiser, Jack L (2014) The antioxidant paradox: what are antioxidants and how should they be used in a therapeutic context for cancer. Future Med Chem 6:1413-22|
|Avtanski, Dimiter B; Nagalingam, Arumugam; Bonner, Michael Y et al. (2014) Honokiol inhibits epithelial-mesenchymal transition in breast cancer cells by targeting signal transducer and activator of transcription 3/Zeb1/E-cadherin axis. Mol Oncol 8:565-80|
|Garufi, Alessia; D'Orazi, Valerio; Arbiser, Jack L et al. (2014) Gentian violet induces wtp53 transactivation in cancer cells. Int J Oncol 44:1084-90|
|Banerjee, Pallavi; Basu, Aninda; Arbiser, Jack L et al. (2013) The natural product honokiol inhibits calcineurin inhibitor-induced and Ras-mediated tumor promoting pathways. Cancer Lett 338:292-9|
|Martin, S; Lamb, H K; Brady, C et al. (2013) Inducing apoptosis of cancer cells using small-molecule plant compounds that bind to GRP78. Br J Cancer 109:433-43|
|Spence-Shishido, Allyson; Carr, Christopher; Bonner, Michael Y et al. (2013) In vivo Gram staining of tinea versicolor. JAMA Dermatol 149:991-2|
|Maley, Alexander M; Arbiser, Jack L (2013) Gentian violet: a 19th century drug re-emerges in the 21st century. Exp Dermatol 22:775-80|
Showing the most recent 10 out of 64 publications