Process Of Tumor Angiogenesis Research Articles

Current Trends and Future Directions in Clinical Trials for Malignant Melanoma Treatment Using Anti-Angiogenic Strategies

Melanoma is the most lethal skin cancer with a high propensity to metastasis and conventionally is poorly responsive to non-surgical treatments including chemotherapy and radiotherapy. Considerable advances have been made recently targeting BRAF mutations and immune regulation and, for the first time, credible options exist for patients with metastatic disease. Angiogenesis, the growth of new blood vessels, is an absolute prerequisite for tumour growth beyond a few millimetres in size. Melanoma neovascularisation is correlated with poor prognosis, reduced overall survival, ulceration and increased rate of relapse. Melanoma cells secrete several proangiogenic cytokines including Vascular Endothelial Growth Factor VEGF-A and raised levels of expression are associated with the switch from indolent radial, to invasive vertical and then metastatic growth phases. Understanding the processes underlying angiogenesis and how it relates to tumour growth broadly and to melanoma specifically is instrumental in the current drive to develop new treatments that target a range of tumour cell receptors and intracellular processes from receptor antagonism to monoclonal antibodies aimed at the disruption of the process of tumour angiogenesis. We discuss recent and current trials for metastatic melanoma therapy, and discuss potential directions of future treatment scheduling considering different treatment scheduling approaches beyond the parameters of standard drug trials.

The Molecular and Cellular Processes of Tumor Cell-Mediated Tumor Angiogenesis and Vasculogenesis,

Abstract 3267It is well known that tumors make blood vessels through endothelial cell-mediated angiogenesis; whereas, increasing data have shown that tumor cell-mediated vasculogenesis plays an important role in tumor neovascularization in a variety of high metastatic malignant tumors, but the mechanisms are largely unknown. We previously established new models for studying the mechanisms of tumor angiogenesis and vasculogenesis (Zhou Q. et al. Method 44(2):190–195, 2008; Zhou Q, et al. Nature: Structure and Molecular Biology 2010, 17:57–62). Using in vitro tube formation system and in vivo mouse tumor xenografts, we have recently tested the vasculogenic capability of 85 tumor cell lines and studied the molecular and cellular processes of tumor cell-mediated tumor neovascularization. Among 62 human tumor cell lines tested, 25 of them were able to directly form capillary-like tubes in vitro and tumor blood vessels in vivo tumor xenografts, while 10 out of 23 mouse tumor cell lines displayed tube-forming and vasculogenic capabilities. Notably, these vasculogenic tumor cells were mostly derived from high metastatic and aggressive tumors, including pre-cancerous stem cells, cancer stem cells, high metastatic tumor cells, and tumor endothelial cells.Utilizing DNA microarray, tumor tissue array, RT-PCR, western blotting, and immunofluorescient staining, we observed that 15 genes were highly expressed in vasculogenic cancer stem cells and various tumor cells; among them, 4 genes did not expressed in all of the 15 normal human tissues while other 11 genes were only expressed in the testis, but absent in other normal tissues. Additionally, many embryonic angiogenic and vasculogenic genes were overexpressed in the vasculogenic tumor cells, implying that these genes may play an important role in tumor vasculogenesis. Accordingly, we raise a hypothetic model that endogenous and exogenous factors induce tumor cells to express a variety of angiogenic and vasculogenic genes which drive the vasculogenic tumor cells to connect each other and to interact with endothelial cells and various blood cells, resulting in generation of tumor blood vessels.Furthermore, we explored the role and mechanism of human ovarian cancer Hey1B cell-mediated tumor neovascularization. Herein, for the first time we found that Hey1B cells directly formed capillary tubular structure in vitro independent of any growth factors and functional tumor blood vessels in vivo tumor xenografts. Moreover, we observed that more than 30 angiogenic and vasculogenic genes were overexpressed in the cells and the tumor tissues, including VE-cadherin, FGFR1, VEGFA, HIF1A, Sema4D, plexinB1, EphB2, NOTCH1, ROBO4, Ephrin B2, SFRP1, MAFB, SOX17, WIPF2, MAGEF1, MAGED1, New3, ZFP106, RUNX1, and other 16 poorly annotated genes, while Akt and ERK signaling pathways were found to be over activated in Hey1B cells and the tumor tissues. This valuable information gets new insight into the mechanisms of tumor cell-predominant neovascularization.Using Hey1B cells as tumor vasculogenic model, we screened anti-tumor vasculogenic small molecules in the traditional Chinese herbal medicinal library and found that lycorine hydrochloride (LH) effectively inhibited Hey1B cell-mediated tube formation in vitro, blood vessel generation and tumor growth in vivo. Molecular mechanism analysis showed that LH markedly inhibited the expression of VE-cadherin, Sema4D, FGFR1, VEGFA, NOTCH1 and SFRP1 genes, and it also blocked Akt and ERK signaling pathways.Taken together, a varieties of angiogenic and vasculogenic genes are overexpressed in angiogenic and vasculogenic tumor cells, meanwhile, Akt and ERK signaling pathways were activated in the vasculogenic tumor cells tested; and that LH effectively suppresses ovarian cancer neovascularization and tumor growth through inhibition of several key genes and signaling pathways. Therefore, angiogenic and vasculogenic genes and tumor cells are good targets for novel anti-tumor vasculogenesis and anti-tumor drug discovery. Disclosures:No relevant conflicts of interest to declare.

Angiotensin-(1-7) inhibits the migration and invasion of A549 human lung adenocarcinoma cells through inactivation of the PI3K/Akt and MAPK signaling pathways

The local renin-angiotensin system (RAS) is one of the crucial components in the tumor microenvironment. Recent evidence suggests that the local RAS plays an important role in tumor metabolism, survival, angiogenesis and invasion processes. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous peptide of the RAS with vasodilator and anti-proliferative properties. Previous studies have demonstrated that Ang-(1-7) inhibits both the growth of human lung cancer cells invitro and tumor angiogenesis invivo through activation of the MAS receptor. This study investigated the anti-metastatic effect of Ang-(1-7) in A549 human lung adenocarcinoma cells invitro. We found that Ang-(1-7) reduced the cell migratory and invasive abilities by reducing the expression and activity of MMP-2 and MMP-9. Furthermore, we demonstrated that the anti-migration and anti-invasion effect of Ang-(1-7) was mediated through inactivation of the PI3K/Akt, P38 and JNK signal pathways. Our results suggest that Ang-(1-7) may have therapeutic potential against advanced lung carcinoma as a new agent.

Numerical simulation of inhibiting effects on solid tumour cells in anti-angiogenic therapy: application of coupled mathematical model of angiogenesis with tumour growth

To investigate the inhibiting effects of the anti-angiogenic factor andostatin and the anti-angiogenic drug endostatin on tumour angiogenesis and tumour cells, a coupled mathematical model of tumor angiogenesis with tumour growth and blood perfusion is developed. Simulation results show that angiostatin and endostatin can improve the abnormal microenvironment inside the tumour tissue by effectively inhibiting the process of tumor angiogenesis and decreasing tumour cells. The present model can be used as a valid theoretical method in the investigation of the tumour anti-angiogenic therapy.

Tumor stem cells and tumor angiogenesis

The process of tumor angiogenesis is a complicated chain reaction which happens under the action of a series of positive feedback and negative feedback factors . Cancer stem cells are small part cell groups of self-renewal and multilineage differentiation potential in tumors. Many studies indicate that tumor stem cells participate in the process of tumor angiogenesis, and vascular endothelial growth factor can regulate endothelial proliferation and angiogenesis, thereby promoting tumor growth and metastasis. Key words: Neoplastic stem cells ; Neovascularization, pathologic; Vascular endothelial growth factors

Abstract 5288: Tumor-endothelial 3D spheroids for dynamic imaging of cancer progression

Abstract The increasing use of anti-angiogenic drugs for the treatment of cancer has emerged from the explosion of knowledge about the process of tumor angiogenesis. However, the clinical results of using such drugs have been relatively modest and new agents are likely needed. A robust pre-clinical model of cellular mechanisms governing tumor angiogenesis may improve our ability to develop strategies for tumor specific drug delivery with superior pharmacokinetics, controlled biodistribution, efficacy, and safety profiles. We have developed a system to grow 3D-cultures of tumor and endothelial cells in hanging drops of medium. Subsequently, we transplant these spheroidal cultures into the dorsal skin fold window chamber of mice for intravital multiphoton imaging of neovasculature and disease progression. Our initial observation was that there was a marked difference in neovascularization from the GFP-tumor-endothelial spheroids in comparison to GFP-tumor spheroids in the window chamber mouse model. Molecular analysis using an antibody array showed a pronounced upregulation of angiogenic factors in the tumor tissue derived from the tumor-endothelial spheroid compared to the spheroid grown with tumor cells alone. Interleukin-1α, FGF-1α, CCN3/NOV, PIGF-2, MMP-3, MMP-8 and MMP-9 were seven identified proteins that showed distinct differences in expression between the two spheroid types. Further, the relative increase in tumor growth of tumor-endothelial spheroids implanted on the rear hind limb was much faster than the tumor cell alone spheroid and resulted in evidence of greater metastasis to the lung. We thus strongly believe that the 3D tumor-endothelial spheroid implanted in the dorsal fold window chamber of mice is a more realistic and informative model for dynamic imaging of critical aspects of tumor angiogenesis and the study of metastasis. Efforts are underway to monitor molecular and cellular events related to radiation exposure combined with anti-angiogenic agents of varying mechanisms of action to determine prudent new avenues for therapeutic success. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5288. doi:10.1158/1538-7445.AM2011-5288

Coupled modelling of tumour angiogenesis, tumour growth and blood perfusion

We propose a mathematical modelling system to investigate the dynamic process of tumour cell proliferation, death and tumour angiogenesis by fully coupling the vessel growth, tumour growth and blood perfusion. Tumour growth and angiogenesis are coupled by the chemical microenvironment and the cell–matrix interaction. The haemodynamic calculation is carried out on the updated vasculature. The domains of intravascular, transcapillary and interstitial fluid flow were coupled in the model to provide a comprehensive solution of blood perfusion variables. An estimation of vessel collapse is made according to the wall shear stress criterion to provide feedback on vasculature remodelling. The simulation can show the process of tumour angiogenesis and the spatial distribution of tumour cells for periods of up to 24 days. It can show the major features of tumour and tumour microvasculature during the period such as the formation of a large necrotic core in the tumour centre with few functional vessels passing through, and a well circulated tumour periphery regions in which the microvascular density is high and associated with more aggressive proliferating cells of the growing tumour which are all consistent with physiological observations. The study also demonstrated that the simulation results are not dependent on the initial tumour and networks, which further confirms the application of the coupled model feedback mechanisms. The model enables us to examine the interactions between angiogenesis and tumour growth, and to study the dynamic response of a solid tumour to the changes in the microenvironment. This simulation framework can be a foundation for further applications such as drug delivery and anti-angiogenic therapies.

Coupled modeling of tumour angiogenesis, tumour growth, and blood perfusion

This paper proposes a more realistic mathematical simulation method to investigate the dynamic process of tumour angio-genesis by fully coupling the vessel growth, tumour growth and associated blood perfusion. The tumour growth and angiogenesis are coupled by the chemical microenvironment and the cell-matrix interaction. The haemodynamic calculation is carried out on the new vasculature, and an estimation of vessel collapse is made according to the wall shear stress criterion. The results are consistent with physiological observations, and further confirm the application of the coupled model feedback mechanism. The model is available to examine the interactions between angiogenesis and tumour growth, to study the change in the dynamic process of chemical environment and the vessel remodeling.

Tumor cell-derived PDGF-B potentiates mouse mesenchymal stem cells-pericytes transition and recruitment through an interaction with NRP-1

BackgroundNew blood vessel formation, or angiogenic switch, is an essential event in the development of solid tumors and their metastatic growth. Tumor blood vessel formation and remodeling is a complex and multi-step processes. The differentiation and recruitment of mural cells including vascular smooth muscle cells and pericytes are essential steps in tumor angiogenesis. However, the role of tumor cells in differentiation and recruitment of mural cells has not yet been fully elucidated. This study focuses on the role of human tumor cells in governing the differentiation of mouse mesenchymal stem cells (MSCs) to pericytes and their recruitment in the tumor angiogenesis process.ResultsWe show that C3H/10T1/2 mouse embryonic mesenchymal stem cells, under the influence of different tumor cell-derived conditioned media, differentiate into mature pericytes. These differentiated pericytes, in turn, are recruited to bind with capillary-like networks formed by endothelial cells on the matrigel under in vitro conditions and recruited to bind with blood vessels on gel-foam under in vivo conditions. The degree of recruitment of pericytes into in vitro neo-angiogenesis is tumor cell phenotype specific. Interestingly, invasive cells recruit less pericytes as compared to non-invasive cells. We identified tumor cell-secreted platelet-derived growth factor-B (PDGF-B) as a crucial factor controlling the differentiation and recruitment processes through an interaction with neuropilin-1 (NRP-1) in mesenchymal stem cells.ConclusionThese new insights into the roles of tumor cell-secreted PDGF-B-NRP-1 signaling in MSCs-fate determination may help to develop new antiangiogenic strategies to prevent the tumor growth and metastasis and result in more effective cancer therapies.

Novel Metals and Metal Complexes as Platforms for Cancer Therapy

Metals are essential cellular components selected by nature to function in several indispensable biochemical processes for living organisms. Metals are endowed with unique characteristics that include redox activity, variable coordination modes, and reactivity towards organic substrates. Due to their reactivity, metals are tightly regulated under normal conditions and aberrant metal ion concentrations are associated with various pathological disorders, including cancer. For these reasons, coordination complexes, either as drugs or prodrugs, become very attractive probes as potential anticancer agents. The use of metals and their salts for medicinal purposes, from iatrochemistry to modern day, has been present throughout human history. The discovery of cisplatin, cis-[Pt(II) (NH(3))(2)Cl(2)], was a defining moment which triggered the interest in platinum(II)- and other metal-containing complexes as potential novel anticancer drugs. Other interests in this field address concerns for uptake, toxicity, and resistance to metallodrugs. This review article highlights selected metals that have gained considerable interest in both the development and the treatment of cancer. For example, copper is enriched in various human cancer tissues and is a co-factor essential for tumor angiogenesis processes. However the use of copper-binding ligands to target tumor copper could provide a novel strategy for cancer selective treatment. The use of nonessential metals as probes to target molecular pathways as anticancer agents is also emphasized. Finally, based on the interface between molecular biology and bioinorganic chemistry the design of coordination complexes for cancer treatment is reviewed and design strategies and mechanisms of action are discussed.

Molecular study on copper-mediated tumor proteasome inhibition and cell death

The metal ion copper is a cofactor essential for maintaining normal biological and physical functions in human beings. High copper levels have been found in variety of tumor tissues and are involved in tumor angiogenesis processes. The ubiquitin-proteasome system plays an important role in cell growth and apoptosis and has been shown as a novel target for cancer therapy. We previously reported that some organic copper complexes can inhibit the proteasomal chymotrypsin-like activity and induce apoptosis in human cancer cells and xenograft models. In the current study, we investigated the effect of oxidation status of copper, Cu(I) or Cu(II), on inhibition of proteasome activity, induction of apoptosis, and induction of reactive oxygen species (ROS) in human cancer cells. We report four major findings here: i) both Cu(I) and Cu(II) could inhibit the chymotrypsin-like activity of purified 20S proteasome, but Cu(I) was more potent than Cu(II), ii) purified 20S proteasome protein was able to reduce Cu(II) to Cu(I), suggesting that Cu(I) is the oxidation status of copper that directly reacts with the proteasome, iii) when complexed with the copper ligand neocuproine, Cu(I) showed higher ability to induce ROS production in cancer cells, compared with Cu(II), iv) addition of a ROS scavenger in the cancer cell culture-blocked copper-induced ROS generation, but did not overcome copper-mediated proteasome-inhibitory and cell death-inducing events, demonstrating the ROS-independent proteasome-inhibitory property of copper complexes.

3D-CTA and 4D-CE-MRA for dynamic monitoring tumor angiogenesis in a rabbit VX2 tumor

To study possibility of dynamic monitoring tumor angiogenesis in vivo by 3D-CTA on a 64-row multidetector CT and 4D-CE-MRA on a 3T MR scanner; compare the advantages and faults of these two methods; and analyze the relationship between tumor angiogenesis and tumor growth. This study had been approved by the institutional animal care and use committee. Thirty New Zealand white rabbits with implanted VX2 tumors in the right thigh muscle were randomly divided into five groups according to survive time (n = 6). The rabbits were scanned by a 64-row multidetector CT and a 3T MR at 4, 7, 10, 13, 16 days after tumor implantation respectively, and then sacrificed to extract the tumor. The tumors' long diameters, short diameters and volume measurements derived from CT and MR imaging were compared with pathological data. The minimum tumor diameter and the number of new tumor blood vessels detectable by 3D-CTA and 4D-CE-MRA were also compared. The morphologic process of tumor angiogenesis was monitored and described. (1) The volume of tumors measured by CT imaging, MR imaging and pathological data had no significant difference (P > 0.05). (2) The minimum diameter of tumor vessels displayed on 3D-CTA and 4D-CE-MRA images was 0.68 mm +/- 0.07 mm and 0.85 mm +/- 0.12 mm respectively. The minimum diameter of tumor vessels displayed on 3D-CTA imaging was significantly smaller than 4D-CE-MRA imaging (t = -6.5075, P = 0.005). (3) The number of tumor vessels on 3D-CTA imaging and 4D-CE-MRA imaging had no significant difference at 4, 7, 10 days after tumor implantation. The number of tumor vessels on 3D-CTA images were significantly more than that on 4D-CE-MRA images at 13, 16 days after tumor implantation (all P < 0.01). (4) The morphologic process of tumor angiogenesis was demonstrated as sprouting from pre-existing blood vessel, forming lots of new vessels around tumor, and forming the immature vessels web with lots of tortuous, dilated, irregular vessels penetrating into the tumor at last. Volume CT and high magnet field MR can monitor tumor growth in vivo. 3D-CTA and 4D-CE-MRA can dynamicly monitor morphological changes of tumor angiogenesis in vivo. Of the two methods, 3D-CTA has better spatial resolution, but 4D-CE-MRA allows better temporal resolution of tumor angiogenesis monitoring.

A comparison of 3D-CTA and 4D-CE-MRA for the dynamic monitoring of angiogenesis in a rabbit VX2 tumor

To compare three-dimensional computed tomography angiography (3D-CTA) and four-dimensional contrast-enhanced magnetic resonance angiography (4D-CE-MRA) for the in vivo monitoring of tumor angiogenesis. VX2 tumors were implanted into the right thigh muscle of 30 New Zealand white rabbits. The animals were randomly assigned to 5 groups, which, respectively, were scanned by 3D-CTA and 4D-CE-MRA on day 4, 7, 10, 13, or 16 after tumor implantation. After scanning, tumors were resected and processed for conventional histology and CD-31 immunohistochemistry. Tumor volume measurements derived from CT and MR imaging were compared with histopathological data. The minimum tumor diameter and the number of new tumor blood vessels detectable by 3D-CTA and 4D-CE-MRA were also compared. There were no significant differences in the tumor volume measurements derived from CT, MR, and histological analysis. The minimum diameter of tumor vessels detectable by 3D-CTA (0.68 ± 0.07 mm) was significantly less than that by 4D-CE-MRA (0.85 ± 0.12 mm) (P=0.005). The number of tumor vessels detected by each imaging method was not significantly different until day 13 after implantation, when 3D-CTA detected a greater number (P<0.001). The morphologic process of tumor angiogenesis was demonstrated dynamically by 3D-CTA and 4D-CE-MRA in vivo. Tumor angiogenesis can be dynamically monitored in vivo by 3D-CTA and 4D-CE-MRA. Of the two methods, 3D-CTA has better spatial resolution, but 4D-CE-MRA allows temporal resolution of tumor angiogenesis.

Abstract 5160: Tumor cells potentiate mesenchymal stem cells-pericytes transition and requirement through PDGF-BB-NRP-1 axis

Abstract New blood vessel formation or angiogenic switch is an essential event in the development of solid tumors and their metastatic growth. Tumor blood vessel formation and remodeling is a complex and multi-step processes. The differentiation and recruitment of mural cells including vascular smooth muscle cells and pericytes are essential steps in tumor angiogenesis. However, the role of tumor cells in differentiation and recruitment of mural cells is unknown. In this study we focus on the role of tumor cells in governing the differentiation of mesenchymal stem cells (MSCs) to pericytes and their recruitment in tumor angiogenesis process. We show that C3H/10T1/2 mouse embryonic mesenchymal stem cells, under the influence of different tumor cells-derived conditioned media, differentiate into mature pericytes. These differentiated pericytes, in turn, are recruited to bind with capillary-like networks formed by endothelial cells on the matrigel under in vitro condition. The degree of recruitment of pericytes into in vitro neo-angiogenesis is tumor cell phenotype specific. Interestingly, the invasive cells recruit less pericytes as compared to non-invasive cells. We identify tumor cell-secreted platelet derived growth factor (PDGF-BB) as a crucial factor controlling differentiation and recruitment processes through a cross-talk with NRP-1. These new insights into the roles of tumor cell-secreted PDGF in MSCs-fate determination may help in developing new antiangiogenic strategies to prevent the tumor growth and metastasis and also to treat cancers more effectively. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5160.

Aquaporins in tumor growth and angiogenesis

The aquaporins (AQPs) are a family of transmembrane water channel proteins widely distributed and play a major role in transcellular and transepithelial water movement. Moreover, recent evidence indicates that AQPs may be involved in cell migration and angiogenesis. This review article summarizes literature data concerning the involvement of AQPs in tumor growth, angiogenesis and metastatic process and suggest a potential therapeutic approach by antagonizing their biological activity.

Signaling Mechanism(S) of Reactive Oxygen Species in Epithelial-Mesenchymal Transition Reminiscent of Cancer Stem Cells in Tumor Progression

Reactive oxygen species (ROS) are known to serve as a second messenger in the intracellular signal transduction pathway for a variety of cellular processes, including inflammation, cell cycle progression, apoptosis, aging and cancer. Recently, ROS have been found to be associated with tumor metastasis involving the processes of tumor cell migration, invasion and angiogenesis. Emerging evidence also suggests that Epithelial-Mesenchymal Transition (EMT), a process that is reminiscent of cancer stem cells, is an important step toward tumor invasion and metastasis, and intimately involved in de novo and acquired drug resistance. In light of recent advances, we are summarizing the role of ROS in EMT by cataloging how its deregulation is involved in EMT and tumor aggressiveness. Further attempts have been made to summarize the role of several chemopreventive agents that could be useful for targeted inactivation of ROS, suggesting that many natural agents could be useful for the reversal of EMT, which would become a novel approach for the prevention of tumor progression and/or treatment of human malignancies especially by killing EMT-type cells that shares similar characteristics with cancer stem cells.

Expression of Vascular Endothelial Growth Factor and Presence of Angiovascular Cells in Tissues from Different Thyroid Disorders

Vascular endothelial growth factor (VEGF) is involved in tumor angiogenesis and other pathophysiological processes. We studied the localization of VEGF in human thyroid tissues to clarify its involvement in proliferative processes in a variety of thyroid disorders. Immunohistochemical analysis using purified rabbit polyclonal anti-human VEGF or anti-human CD34 antibody and a streptavidin-biotin peroxidase complex detection system was performed on 58 tissue specimens from 53 patients with different thyroid disorders and 5 normal thyroid glands. Vascular endothelial growth factor was not detected in normal thyroid follicular cells. However, some thyroid tumor cells expressed VEGF in the cytoplasm (papillary carcinoma, 10/18; follicular carcinoma, 1/3; medullary carcinoma, 2/2; follicular adenoma, 3/11; adenomatous goiter, 2/4). In benign follicular adenoma and adenomatous goiter, weak expression of VEGF was found in small areas of the tumor, whereas in malignant thyroid tumors, it was strongly expressed in many cells. However, VEGF was not expressed in anaplastic carcinoma, malignant lymphoma, or Graves' disease. Angiovascular cells stained with CD34 antibody in tissues from different thyroid disorders reflected statistically significant differences in papillary carcinoma, follicular adenoma, and Graves' disease compared with normal thyroids, and such cells showed a trend toward increases in medullary carcinoma and adenomatous goiter. In contrast, low vascularity was observed in anaplastic carcinoma, malignant lymphoma, and follicular carcinoma. Because VEGF probably functions as a hypoxia-inducible angiogenic factor, overexpression of this mediator, concomitant with hypervascularity, may be induced more strongly in malignant thyroid tumors, which need more oxygen to proliferate, than in benign follicular tumors. However, neither VEGF nor CD34 was expressed in anaplastic thyroid carcinoma, which is an extremely poorly differentiated malignant tumor. CD34 but not VEGF was expressed in the hyperplastic thyroid tissues of Graves' disease composed of nontransformed cells. Thus, the expression of VEGF concomitant with CD34 is suggested to reflect both the transformation and differentiation state of malignant tumors.

Numerical simulation of solid tumor angiogenesis with Endostatin treatment: a combined analysis of inhibiting effect of anti-angiogenic factor and micro mechanical environment of extracellular matrix

To investigate the influence of anti-angiogenesis drug Endostatin on solid tumor angiogenesis, a mathematical model of tumor angiogenesis was developed with combined influences of local extra-cellular matrix mechanical environment, and the inhibiting effects of Angiostatin and Endostatin. Simulation results show that Angiostatin and Endostatin can effectively inhibit the process of tumor angiogenesis, and decrease the number of blood vessels in the tumor. The present model could be used as a valid theoretical method in the investigation of anti-angiogenic therapy of tumors.

KDR Activating Mutations in Human Angiosarcomas Are Sensitive to Specific Kinase Inhibitors

Angiosarcomas (AS) represent a heterogeneous group of malignant vascular tumors occurring not only in different anatomic locations but also in distinct clinical settings, such as radiation or associated chronic lymphedema. Although representing only 1% to 2% of soft tissue sarcomas, vascular sarcomas provide unique insight into the general process of tumor angiogenesis. However, no molecular candidates have been identified to guide a specific therapeutic intervention. By expression profiling, AS show distinct up-regulation of vascular-specific receptor tyrosine kinases, including TIE1, KDR, SNRK, TEK, and FLT1. Full sequencing of these five candidate genes identified 10% of patients harboring KDR mutations. A KDR-positive genotype was associated with strong KDR protein expression and was restricted to the breast anatomic site with or without prior exposure to radiation. Transient transfection of KDR mutants into COS-7 cells showed ligand-independent activation of the kinase, which was inhibited by specific KDR inhibitors. These data provide a basis for the activity of vascular endothelial growth factor receptor-directed therapy in the treatment of primary and radiation-induced AS.

Antiangiogenic drugs in ovarian cancer

Background: There is a critical need to develop effective new strategies for the management of patients with advanced epithelial ovarian cancer. Objective: The purpose of this manuscript is to discuss the rationale for, and initial clinical results of, attempts to interfere with the process of tumor angiogenesis as a novel treatment paradigm in ovarian cancer. Results/ conclusion: Phase II clinical trial data provide strong support for the suggestion that antiangiogenic agents have the potential to play a major therapeutic role in this difficult malignancy. It is reasonable to acknowledge that the pending results of several ongoing evidence-based randomized Phase III trials that directly explore the clinical utility of this strategy may substantially alter the current standard management approaches in advanced ovarian cancer.