Shear Stress Mediates Angiogenic Gene Expression in a Microfluidic Tumor Vascular Model

2012 ◽  
Author(s):  
Cara F. Buchanan ◽  
Elizabeth Voigt ◽  
Christopher S. Szot ◽  
Joseph W. Freeman ◽  
Pavlos P. Vlachos ◽  
...  
Keyword(s):  
Breast Cancer Cells ◽  
Culture Conditions ◽  
Treatment Modalities ◽  
Vascular Endothelial ◽  
Fluid Shear ◽  
Static Conditions ◽  
Angiopoietin 2 ◽  
Endothelial Growth Factor ◽  
Insight Into

While research has shown that the fluid mechanics of the tumor vasculature reduce transport and uptake of therapeutics, the underlying role of these stresses in regulating tumor-endothelial cell signaling and neovascularization are not well understood. Understanding the reciprocal interaction between endothelial and tumor cells to mediate angiogenesis, and the effect of fluid shear on this process, may offer insight into the development of improved treatment modalities to control highly vascularized tumors. We have previously shown that breast cancer cells cultured under 2D, static conditions with endothelial cells significantly increase expression of pro-angiogenic factors vascular endothelial growth factor (VEGF) and angiopoietin 2 (ANG2) [1]. These preliminary results motivated the investigation of tumor-endothelial cross-talk under 3D, dynamic co-culture conditions.

scholarly journals Insight into the Role of Angiopoietins in Ageing-Associated Diseases

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2636
Author(s):  
Shin-ichiro Hayashi ◽  
Hiromi Rakugi ◽  
Ryuichi Morishita
Keyword(s):  
Signaling Pathway ◽  
Clinical Applications ◽  
Vascular Endothelial ◽  
Major Pathway ◽  
Associated Diseases ◽  
Antiangiogenic Therapies ◽  
Endothelial Growth Factor ◽  
Insight Into

Angiopoietin (Ang) and its receptor, TIE signaling, contribute to the development and maturation of embryonic vasculature as well as vascular remodeling and permeability in adult tissues. Targeting both this signaling pathway and the major pathway with vascular endothelial growth factor (VEGF) is expected to permit clinical applications, especially in antiangiogenic therapies against tumors. Several drugs targeting the Ang-TIE signaling pathway in cancer patients are under clinical development. Similar to how cancer increases with age, unsuitable angiogenesis or endothelial dysfunction is often seen in other ageing-associated diseases (AADs) such as atherosclerosis, Alzheimer’s disease, type 2 diabetes, chronic kidney disease and cardiovascular diseases. Thus, the Ang-TIE pathway is a possible molecular target for AAD therapy. In this review, we focus on the potential role of the Ang-TIE signaling pathway in AADs, especially non-cancer-related AADs. We also suggest translational insights and future clinical applications of this pathway in those AADs.

scholarly journals Vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 are highly expressed in ovarian granulosa cell tumors

2011 ◽  
Vol 164 (1) ◽  
pp. 115-122 ◽  
Author(s):  
Anniina Färkkilä ◽  
Mikko Anttonen ◽  
Jurate Pociuviene ◽  
Arto Leminen ◽  
Ralf Butzow ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Granulosa Cell ◽  
Biologically Active ◽  
Treatment Modalities ◽  
Vascular Endothelial ◽  
Granulosa Cell Tumors ◽  
Ovarian Granulosa Cell ◽  
Endothelial Growth Factor

ObjectiveOvarian granulosa cell tumors (GCTs) are hormonally active sex cord stromal tumors accounting for 3–5% of all ovarian cancers. These tumors are generally diagnosed at an early stage but there is a high risk of recurrence, associated with high mortality. Treatment of recurrent GCTs is difficult, and biologically targeted treatment modalities are lacking. GCTs are highly vascularized, and angiogenic factors most probably play a role in their pathology. Vascular endothelial growth factor (VEGF) is a key regulator of tumor angiogenesis, but in GCTs, the role of VEGF and its receptors VEGFR-1 (FLT1) and VEGFR-2 (KDR) remains largely unknown. Our objective is to study the expression of VEGF and its receptors in human GCTs.MethodsWe analyzed GCTs from 106 patients for the expressions of VEGF and its receptors utilizing tumor tissue microarray, tumor mRNA, and patient serum samples.ResultsWe found that VEGF and its main biologically active receptor VEGFR-2 were highly expressed in primary and recurrent GCTs, when compared with normal granulosa-lutein cells. The expression of VEGF correlated positively to tumor microvessel density and to VEGFR-2 expression at the protein (P<0.05) and mRNA (P<0.05) levels. In contrast to VEGFR-2, the expression of VEGFR-1 was weak. Tumor VEGF protein expression was not prognostic for recurrence, however, we found high levels of circulating VEGF in the serum of patients with primary GCT.ConclusionsThe results suggest an important role of VEGF and VEGFR-2 in GCT pathology and support the possibility of applying novel VEGF- or VEGFR-2-targeted treatments to patients with GCT.

scholarly journals Hypoxia-inducible factors 1 and 2 are important transcriptional effectors in primary macrophages experiencing hypoxia

Blood ◽  
2009 ◽  
Vol 114 (4) ◽  
pp. 844-859 ◽  
Author(s):  
Hsin-Yu Fang ◽  
Russell Hughes ◽  
Craig Murdoch ◽  
Seth B. Coffelt ◽  
Subhra K. Biswas ◽  
...  
Keyword(s):  
Malignant Tumors ◽  
Nuclear Factor Κb ◽  
Atherosclerotic Plaques ◽  
Vascular Endothelial ◽  
Surface Receptors ◽  
Experimental Mouse ◽  
Angiopoietin 2 ◽  
Endothelial Growth Factor ◽  
Arthritic Joints

Abstract Ischemia exists in many diseased tissues, including arthritic joints, atherosclerotic plaques, and malignant tumors. Macrophages accumulate in these sites and up-regulate hypoxia-inducible transcription factors (HIFs) 1 and 2 in response to the hypoxia present. Here we show that the gene expression profile in primary human and murine macrophages changes markedly when they are exposed to hypoxia for 18 hours. For example, they were seen to up-regulate the cell surface receptors, CXCR4 and GLUT1, and the potent, tumor-promoting cytokines, vascular endothelial growth factor A, interleukin (IL)-1β and IL-8, adrenomedullin, CXCR4, and angiopoietin-2. Hypoxia also stimulated their expression and/or phosphorylation of various proteins in the nuclear factor-κB (NF-κB) signaling pathway. We then used both genetic and pharmacologic methods to manipulate the levels of HIFs-1α and 2α or NF-κB in primary macrophages to elucidate their role in the hypoxic induction of many of these key genes. These studies showed that both HIF-1 and -2, but not NF-κB, are important transcriptional effectors regulating the responses of macrophages to such a period of hypoxia. Further studies using experimental mouse models are now warranted to investigate the role of such macrophage responses in the progression of various diseased tissues, such as malignant tumors.

scholarly journals Manipulation of Quercetin and Melatonin in the Down-Regulation of HIF-1α, HSP-70 and VEGF Pathways in Rat’s Kidneys Induced by Hypoxic Stress

Dose-Response ◽  
2020 ◽  
Vol 18 (3) ◽  
pp. 155932582094979
Author(s):  
Aliah R. Alshanwani ◽  
Sameerah Shaheen ◽  
Laila M. Faddah ◽  
Ahlam M. Alhusaini ◽  
Hanaa M. Ali ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Histopathological Examination ◽  
Hemoglobin Concentration ◽  
Vascular Endothelial ◽  
Hsp 70 ◽  
Reactive Protein ◽  
Defensive Role ◽  
Factor Α ◽  
Endothelial Growth Factor

Hypoxia may lead to inflammatory responses by numerous signaling pathways. This investigation intended to inspect the defensive role of Quercetin (Quer) and/ or Melatonin (Mel) against reno toxicity induced by Sodium nitrite (Sod ntr). Sod ntr injection significantly decreased blood hemoglobin concentration (Hb) with a concurrent increase in serum tumor necrosis factor- α, interleukin-6, C-reactive protein, creatinine, and urea levels. Over protein-expression of vascular endothelial growth factor and heat shock, protein-70 and mRNA of HIF-1α were also observed. Pretreatment of the Sod ntr- injected rats with the aforementioned antioxidants; either alone or together significantly improved such parameters. Histopathological examination reinforced the previous results. It was concluded that the combined administration of Quer and Mel may be useful as a potential therapy against renal injury induced by Sod ntr. HIF-1α and HSP-70 are implicated in the induction of hypoxia and its treatment.

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