Current Angiogenesis (Discontinued) - Volume 1, Issue 4, 2012

Endothelium, the tissue that lines the lumen of the myriad blood vessels and capillaries of the body, was long thought to be passive and virtually inert. Over time it has come to be recognized as exceedingly diverse as well as highly interactive with its surroundings. We trace back this concept of diversity within the broad definition of endothelial cells to its earliest recognition and review some of the work that has led to the current explosion of studies documenting endothelial cell heterogeneity.

Background:It has been shown that angiogenesis is an essential component of tumor growth, proliferation and metastasis, with increased angiogenic marker expression correlating with poor prognosis in patients with epithelial ovarian cancer. Interest in anti-angiogenic therapies has evolved, with development of targeted agents against vascular endothelial growth factor (VEFG), platelet derived growth factor (PDGF), and fibroblast growth factor (FGF), as well as novel tyrosine kinase inhibitors (TKIs), and vascular disrupting agents (VDAs). We sought to review the use of anti-angiogenic agents in the treatment of ovarian cancer. Methods: A PubMed search of articles in the English language discussing the use and efficacy of anti-angiogenic agents in ovarian cancer was performed using the key words: “ ovarian cancer,” “VEGF,” “PDGF,” “FGF,” “TKIs,” and “VDAs” alone or in combination. The search was also guided through a review of the reference lists of identified articles. Lastly, abstracts presented at recent national oncology meetings were queried for applicable papers. Results: The best-studied anti-angiogenic agent to date, bevacizumab, has shown significant improvements in progression free survival (PFS) in patients with advanced stage ovarian cancer in 2 large phase III clinical trials. In addition, inhibitors of parallel pathways that may contribute to tumor growth via angiogenesis, including PDGF and FGF mediated signaling, have shown modest single agent activity in phase II trials. Lastly, novel angiopoietin inhibitors as well as vascular disrupting agents are being investigated for use in patients with ovarian cancer. These agents, as a class, have a unique adverse event profile that is likely attributable to their mode of action. Conclusions: Targeted anti-angiogenic therapies may provide clinic benefit in the treatment of women with primary or recurrent epithelial ovarian cancer. It is unclear if combination therapy will result in greater effect than single agent treatment. Importantly, identification of women most likely to benefit from these novel targeted therapies is an area of great interest, in an effort to improve outcome and control cost.

Prostate cancer is the most common solid tumor affecting men in the United States and Western Europe. Currently, therapeutic options remain limited and novel therapies are needed that can provide low toxicity and high therapeutic index. One promising new agent is a potent inhibitor of angiogenesis with anti-metastatic activities, the pigment epithelium- derived factor (PEDF). Some additional functions of PEDF that augment its promise as a new therapeutic include its pro-apoptosis (tumor cells and tumor-associated endothelial cells) and potential pro-immunogenic (cytotoxic macrophages) activities. We will discuss findings by several groups using PEDF as an efficient therapeutic following many delivery strategies including gene, protein, peptide, or cell-based therapy. PEDF also has potential to serve as a proteomics biomarker for prostate cancer progression, as downregulated levels could help predict metastatic potential of tumors. We will provide an overview of the potential and promise for achieving translation of PEDF therapeutics for the treatment of advanced prostate cancer.

Angiogenesis, the process by which new blood vessels are formed, is a critical phenomenon that is activated during various stages of mammalian development. MicroRNAs (miRNAs), a class of short, single stranded, non-coding RNAs, are recognized as important regulators of angiogenesis, and the role of intracellular miRNAs in modulating angiogenesis signaling has been identified. The recent discovery of extracellular and circulating miRNAs has sparked new questions regarding their potential in modulating angiogenesis signaling not only within cells but also between cells. In this review, we discuss the characteristics of intracellular and extracellular miRNAs and decipher the potential functional roles for these molecules in regard to the angiogenic process. We summarize what is currently known about circulating miRNAs in distinct clinical populations and discuss evidence that implicates extracellular miRNAs as novel mediators of angiogenesis-associated intercellular signaling. Lastly, we offer a new perspective on the functional role of vesicleencapsulated circulating miRNA in modulating angiogenesis signaling pathways.

TLR4 is important in P. aeruginosa keratitis, yet whether it regulates angiogenesis, contributing to disparate disease outcome in murine models, remains unknown. When tested in susceptible (C57BL/6, B6) and resistant (BALB/c) mice, TLR4 mRNA levels were increased in B6 over BALB/c mice after infection. Protein levels of VEGF-A, and VEGFR1 also were increased, while VEGF-R2 was unchanged. To test the significance of higher corneal levels of VEGF-R1 in B6 mice, blood vessel ingrowth from the limbus was documented and quantitated after infection, and showed decreased ingrowth in B6 vs BALB/c mice. To further determine whether changes in TLR4 levels modulated angiogenesis, TLR4 was knocked down in B6 mice. VEGF-R1, VEGF-A and VEGFR-2 protein levels were slightly reduced, (significant only for VEGF-R1). In contrast, similar knockdown in BALB/c mice increased VEGF-A and VEGF-R1, with no difference in VEGFR-2 between groups. Immunohistochemistry using dual staining for VEGF-R1 and macrophages from TLR4 knockdown or TLR4 LPS deficient (TLR4lps-d) BALB/c mice showed increased VEGF-R1 staining in both groups over controls. ELISA confirmed that TLR4lps-d infected BALB/c mice also had increased corneal protein levels of VEGF-R1 and VEGF-A, with no difference in VEGF-R2. The studies provide evidence that TLR4 disparately regulates angiogenic molecules in the infected cornea of susceptible and resistant mice and that higher levels of VEGF-A and VEGF-R1 correlate with decreased vascularity and poor outcome.

Exudative age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the western world. Recent developments in the field yielded vascular endothelial growth factor (VEGF) targeted strategies that caused a revolution in the treatment of AMD. Although the therapy of the disease has dramatically improved, the treatment depends on repetitive and invasive intravitreal injections of neutralizing antibodies or antibody-based constructs that have the risk of side effects and are still a major burden for the patient. Learning from the field of oncology, it is clear that new therapeutic opportunities for AMD are finding their way into the clinic. The rapidly developing market of new angiostatic agents will allow better treatments for exudative AMD in the near future. This review summarizes the opportunities and challenges of this field of research.

Angiogenesis plays a critical role in tissue development, reproduction and repair in both health and disease. Pathologically, tumorigenesis relies heavily on angiogenesis for vascularization to extract necessary nutrients and oxygen from the local microenvironment to support tumor growth. The development of anti-angiogenic agents has become an attractive drug discovery strategy for anti-cancer therapy. Targeting signal transduction pathway components currently serves as one of the most validated therapeutic development approaches among all of the other druggable factors in the complicated tumor microenvironment. In this respect, kinase inhibitors interfering with critical regulators of angiogenesis such as VEGFR and PDGFR have provided valuable information from preclinical and clinical perspectives. Herein, we summarize the recent efforts towards the development of kinase inhibitors that target a variety of signaling pathway nodes in the angiogenesis process from both drug discovery and pharmacological points of view in order to provide an overview of their current applications and future development.

Objective: Oral submucous fibrosis (OSF) is a precancerous condition characterized by extensive fibrosis of the submucosa, leading to limitation in the mouth opening. Despite its precancerous nature, role of angiogenesis in the malignant transformation of the epithelium in the background of fibrosis has not been studied in detail for OSF. Immunohistochemial expression of vascular endothelial growth factor (VEGF), a potent angiogenic cytokine, implicated in tumor angiogenesis of several types, was analyzed in OSF. Materials and Methods: Immunohistochemical expression of VEGF was evaluated on thirty (30) paraffin-embedded tissue sections of diagnosed cases of OSF and ten (10) control samples of healthy volunteers. Results: Out of 30 cases, 18 (60%) cases showed cytoplasmic expression of VEGF in the basal epithelial cells and fibroblasts, of which 17(94%) were of mild and one (6%) of moderate intensity respectively. Remaining 12 (40%) cases of OSF and 10 controls showed no immunoreactivity for VEGF. There was no statistically significant difference observed between the disease stages and staining intensity of VEGF. Conclusion: VEGF immunoreactivity was found to be statistically increased in OSF compared to normal healthy controls suggesting that upregulation of VEGF may play an important role in tumor progression during malignant transformation of atrophic epithelium in OSF.