Effects of Vascular-Endothelial Protein Tyrosine Phosphatase Inhibition on Breast Cancer Vasculature and Metastatic Progression (original) (raw)
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Normalizing tumoral vessels to treat cancer: an out-of-the-box strategy involving TIE2 pathway
Translational Cancer Research, 2017
The idea of targeting vessels for cancer therapy, termed antiangiogenesis, was coined by Folkman in his pioneer report in 1971 (1, 2). Folkman's seminal contribution to cancer biology was the early description of what we now understand as the tumor microenvironment (2). In this manuscript, he postulated that tumor growth depends on vessel recruitment and that the growth of vascular and tumor cells are interdependent. Per instance, he stated that the maintenance of the mitotic index of the two cell populations depends on each other, and that the secretion of diffusible factors from tumor cells influences the formation of tumor capillaries (1). Furthermore, he described that the blockade of proangiogenic signals resulted in the regression of the new blood vessels. In addition, he hypothesized that central tumor necrosis is the consequence of poor perfusion due to increased internal pressure and decreased of the blood flow at the tumor site (1, 2). This hypothesis was tested by Rakesh Jain who demonstrated that Folkman's assumption was correct, and further suggested that increased interstitial fluid pressure might impede the delivery of large anticancer agents to tumors (2, 3). Antiangiogenic Therapy The conceptual basis of antiangiogenic therapy was based on eradicating tumors by destroying their vascular structures and, subsequently, depriving cancer cells of nutrients and oxygen. Although the description of a blood vessel growth stimulator factor was dated in 1939 (4), the discovery of vascular endothelial growth factor, VEGF, was what constituted
Tumor Vascular Changes Mediated by Inhibition of Oncogenic Signaling
Cancer Research, 2009
Many inhibitors of the EGFR-RAS-PI3 kinase-AKT signaling pathway are in clinical use or under development for cancer therapy. Here we show that treatment of mice bearing human tumor xenografts with inhibitors that block EGFR, RAS, PI3 kinase or AKT resulted in prolonged and durable enhancement of tumor vascular flow, perfusion and decreased tumor hypoxia. The vessels in the treated tumors had decreased tortuosity and increased internodal length accounting for the functional alterations. Inhibition of tumor growth cannot account for these results as the drugs were given at doses that did not alter tumor growth. The tumor cell itself was an essential target as HT1080 tumors that lack EGFR did not respond to an EGFR inhibitor, but did respond with vascular alterations to RAS or PI3 Kinase inhibition. We extended these observations to spontaneously arising tumors in MMTV-neu mice. These tumors also responded to PI3 kinase inhibition with decreased tumor hypoxia, increased vascular flow and morphological alterations of their vessels including increased vascular maturity and acquisition of pericyte markers. These changes are similar to the vascular normalization that has been described after anti-angiogenic treatment of xenografts. One difficulty in the use of vascular normalization as a therapeutic strategy has been its limited duration. In contrast, blocking tumor cell RAS-PI3K-AKT signaling led to persistent vascular changes that might be incorporated into clinical strategies based on improvement of vascular flow or decreased hypoxia. These results indicate that vascular alterations must be considered as a consequence of signaling inhibition in cancer therapy.
Journal of Clinical Investigation, 1997
Tie2 is a novel receptor tyrosine kinase that is expressed almost exclusively by vascular endothelium. Disruption of Tie2 function in transgenic mice resulted in embryonic lethality secondary to characteristic vascular defects; similar defects occurred after disruption of the Tie2 ligand. These findings indicate that the Tie2/Tie2 ligand pathway plays important roles during development of the embryonic vasculature. To determine whether the Tie2 pathway was involved in pathologic angiogenesis in adult tissues, a soluble form of the extracellular domain of murine Tie2 (ExTek.6His) was developed and used as a Tie2 inhibitor. After a single application of the ExTek.6His protein into a rat cutaneous window chamber, growth of a mammary tumor inside the chamber was reduced by Ͼ 75% ( P Ͻ 0.005), and tumor vascular length density was reduced by 40% when compared with control-treated tumors ( P Ͻ 0.01). In the rat cornea, Ex-Tek.6His blocked angiogenesis stimulated by tumor cell conditioned media. ExTek.6His protein did not affect the viability of cultured tumor cells, indicating that the antitumor effect of ExTek.6His was due to the inhibition of tumor angiogenesis. These data demonstrate a role for the Tie2 pathway in pathologic angiogenesis, suggesting that targeting this pathway may yield effective antiangiogenic agents for treatment of cancer and other angiogenic diseases. ( J. Clin. Invest. 1997. 100:2072-2078.) Key words: endothelium • receptor tyrosine kinase • angiogenesis • Tie2 • cancer
Endothelial Dysfunction in Breast Cancer In-Vivo Model
Proceedings
Although the endothelial dysfunction is related with tumor development, there is no consensus on the suppressive or supportive effect on tumor growth. The goal of the present study was to evaluate endothelial dysfunction related factors in animal breast cancer model that was developed by administrating endothelial nitric oxide synthase blocking agent, Nitro-L-arginine methyl ester hydrochloride (L-NAME). Endothelial dysfunction related main factors such as nitric oxide synthase, interleukin-6, vascular endothelial growth factor receptor-2 and vascular endothelial cadherin were investigated by immunohistochemically in tumor and carotid artery tissues. In tumor tissues apoptosis was determined by TUNEL assay. The level of endothelin-1 in blood was measured by ELISA. İntima-media thickness of carotid artery was evaluated with Doppler-USG measurements. As a result, in this study it was shown that vascular endothelial growth factor receptor-2, endothelin-1, endothelial nitric oxide synth...
Neoplasia
Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)-targeted therapies predominantly affect nascent, immature tumor vessels. Since platelet-derived growth factor receptor (PDGFR) blockade inhibits vessel maturation and thus increases the amount of immature tumor vessels, we evaluated whether the combined PDGFR inhibition by nilotinib and VEGFR2 blockade by DC101 has synergistic therapy effects in a desmoplastic breast cancer xenograft model. In this context, besides immunohistological evaluation, molecular ultrasound imaging with BR55, the clinically used VEGFR2-targeted microbubbles, was applied to monitor VEGFR2-positive vessels noninvasively and to assess the therapy effects on tumor angiogenesis. DC101 treatment alone inhibited tumor angiogenesis, resulting in lower tumor growth and in significantly lower vessel density than in the control group after 14 days of therapy. In contrast, nilotinib inhibited vessel maturation but enhanced VEGFR2 expression, leading to markedly increased tumor volumes and a significantly higher vessel density. The combination of both drugs led to an almost similar tumor growth as in the DC101 treatment group, but VEGFR2 expression and microvessel density were higher and comparable to the controls. Further analyses revealed significantly higher levels of tumor cell-derived VEGF in nilotinib-treated tumors. In line with this, nilotinib, especially in low doses, induced an upregulation of VEGF and IL-6 mRNA in the tumor cells in vitro, thus providing an explanation for the enhanced angiogenesis observed in nilotinib-treated tumors in vivo. These findings suggest that nilotinib inhibits vessel maturation but counteracts the effects of antiangiogenic co-therapy by enhancing VEGF expression by the tumor cells and stimulating tumor angiogenesis.
Switching of vascular phenotypes within a murine breast cancer model induced by angiopoietin-2
The Journal of Pathology, 2009
Sustained growth of solid tumours can rely on both the formation of new and the co-option of existing blood vessels. Current models suggest that binding of angiopoietin-2 (Ang-2) to its endothelial Tie2 receptor prevents receptor phosphorylation, destabilizes blood vessels, and promotes vascular permeability. In contrast, binding of angiopoietin-1 (Ang-1) induces Tie2 receptor activation and supports the formation of mature blood vessels covered by pericytes.
Inhibition of Angiogenesis in the treatment of breast cancer
International Journal of Advanced Biochemistry Research, 2022
Worldwide every year more than 2million women suffer from breast cancer. The food habit and the current lifestyle, lead to an increase in obesity. Obesity is one of the chief causes of breast cancer. Angiogenesis is highly crucial for tumor growth. The tumor development and metastasis are fully dependent on angiogenesis or the newly formed blood vessels, which supply nutrients for the tumor development. Several early diagnosis methods for detection of breast cancer are there like, mammography which is an X-ray technique to visualize inside the breast. This technique is used for the early detection of breast cancer. Antiangiogenic treatment plays a major role in treating breast cancer, as it inhibits the supply of nutrients which is essential for tumor growth. Our review will be focusing on the anti-angiogenic drugs which inhibit the formation of new blood vessels. Inhibiting angiogenesis is an effective way to treat breast cancer as it is a safe and effective method.