Normalizing tumoral vessels to treat cancer: an out-of-the-box strategy involving TIE2 pathway

Fueyo, Juan; Hossain, Mohammad B.; Nguyen, Teresa T.; Gomez-Manzano, Candelaria

doi:10.21037/tcr.2017.03.64

Cited by 3 publications

(3 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The tyrosine-protein kinase receptor, Tie2, expressed primarily in endothelial cells, has recently been identified as a crucial target for vascular normalization in cancer [21,36]. Tie2 activation has been implicated in noncanonical PAR-3 activation-mediated stabilization of vascular integrity [37].…”

Section: Activation Of Endothelial Tie2 Is Crucial For Tfmg-induced Vmentioning

confidence: 99%

Tie2-mediated vascular remodeling by ferritin-based protein C nanoparticles confers antitumor and anti-metastatic activities

et al. 2020

View full text Add to dashboard Cite

Background Conventional therapeutic approaches for tumor angiogenesis, which are primarily focused on the inhibition of active angiogenesis to starve cancerous cells, target the vascular endothelial growth factor signaling pathway. This aggravates hypoxia within the tumor core and ultimately leads to increased tumor proliferation and metastasis. To overcome this limitation, we developed nanoparticles with antiseptic activity that target tumor vascular abnormalities. Methods Ferritin-based protein C nanoparticles (PCNs), known as TFG and TFMG, were generated and tested in Lewis lung carcinoma (LLC) allograft and MMTV-PyMT spontaneous breast cancer models. Immunohistochemical analysis was performed on tumor samples to evaluate the tumor vasculature. Western blot and permeability assays were used to explore the role and mechanism of the antitumor effects of PCNs in vivo. For knocking down proteins of interest, endothelial cells were transfected with siRNAs. Statistical analysis was performed using one-way ANOVA followed by post hoc Dunnett’s multiple comparison test. Results PCNs significantly inhibited hypoxia and increased pericyte coverage, leading to the inhibition of tumor growth and metastasis, while increasing survival in LLC allograft and MMTV-PyMT spontaneous breast cancer models. The coadministration of cisplatin with PCNs induced a synergistic suppression of tumor growth by improving drug delivery as evidenced by increased blood prefusion and decreased vascular permeability. Moreover, PCNs altered the immune cell profiles within the tumor by increasing cytotoxic T cells and M1-like macrophages with antitumor activity. PCNs induced PAR-1/PAR-3 heterodimerization through EPCR occupation and PAR-1 activation, which resulted in Gα13-RhoA-mediated-Tie2 activation and stabilized vascular tight junctions via the Akt-FoxO3a signaling pathway. Conclusions Cancer treatment targeting the tumor vasculature by inducing antitumor immune responses and enhancing the delivery of a chemotherapeutic agent with PCNs resulted in tumor regression and may provide an effective therapeutic strategy.

show abstract

Section: Activation Of Endothelial Tie2 Is Crucial For Tfmg-induced Vmentioning

confidence: 99%

Tie2-mediated vascular remodeling by ferritin-based protein C nanoparticles confers antitumor and anti-metastatic activities

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Angiopoietin-1/2 (Ang1/2) plays a dynamic role in vessel formation, permeability, maturation, and maintenance. 98 Serum Ang2 is emerging as an endothelium activation marker in certain diseases, such as acute lung injury, hypertension-related myocardial infarction, sepsis, and many cancers, 99 and it has been reported to be overexpressed in tumors after anti-angiogenic therapies; 98 however, cediranib treatment induced transient decreases in Ang2 in plasma. 100 In tumor tissue, the Ang1/Ang2 ratio correlated with the degree of vascular normalization and with the survival of patients with glioblastoma.…”

Section: Plasma or Serum Markermentioning

confidence: 99%

Monitoring of tumor vascular normalization: the key points from basic research to clinical application

Quan

et al. 2018

CMAR

View full text Add to dashboard Cite

Tumor vascular normalization alleviates hypoxia in the tumor microenvironment, reduces the degree of malignancy, and increases the efficacy of traditional therapy. However, the time window for vascular normalization is narrow; therefore, how to determine the initial and final points of the time window accurately is a key factor in combination therapy. At present, the gold standard for detecting the normalization of tumor blood vessels is histological staining, including tumor perfusion, microvessel density (MVD), vascular morphology, and permeability. However, this detection method is almost unrepeatable in the same individual and does not dynamically monitor the trend of the time window; therefore, finding a relatively simple and specific monitoring index has important clinical significance. Imaging has long been used to assess changes in tumor blood vessels and tumor changes caused by the oxygen environment in clinical practice; some preclinical and clinical research studies demonstrate the feasibility to assess vascular changes, and some new methods were in preclinical research. In this review, we update the most recent insights of evaluating tumor vascular normalization.

show abstract

“…Tumor vessels are tortuous, with increased permeability and functional abnormalities. Therefore, vessel normalization is considered an alternative to simple anti-angiogenesis in cancer therapy [18,19]. Angiopoietins (Ang1 and Ang2) and their Tie2 receptor tyrosine kinase have wide-ranging effects in tumors, including angiogenesis, inflammation, tumor vessel normalization, and neovasculogenesis [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Novel Oncolytic Virus Armed with Cancer Suicide Gene and Normal Vasculogenic Gene for Improved Anti-Tumor Activity

Jeong

Yoo

2020

Cancers

View full text Add to dashboard Cite

Here, we developed a novel oncolytic vaccinia virus (NOV) with the dual advantages of cancer selectivity and normal vessel reconstructive activity by replacing the viral thymidine kinase (vTk) and vaccinia growth factor (VGF) genes with genes encoding TNF-related apoptosis-inducing ligand (TRAIL) and angiopoietin 1 (Ang1), respectively. The pan-cancer-specific oncolytic potency of NOV was confirmed in various human and mouse cancer cell lines (colon, liver, pancreas, cholangiocarcinoma, cervical cancer, osteosarcoma, and melanoma). Vaccinia virus (VV) treatment directly induced early apoptosis in tumors within 24 h, and this effect was enhanced with further engineering; VGF and Tk deletion with Ang1 and TRAIL insertion. Meanwhile, treatment with the conventional anti-cancer drug cisplatin did not induce apoptosis. A virus-treated CT26 mouse colon cancer syngeneic model showed attenuated tumor growth, which was in accordance with the results of percent survival measurement, CD8 expression analysis, and TUNEL staining with advanced genetic engineering (vAng1 < vTRAIL < NOV). Taken together, our results indicate that NOV induces cancer tissue apoptosis and anti-tumor immunity and may constitute a highly advantageous therapeutic agent for next-generation solid tumor virotherapy with pan-cancer-specific oncolytic activity and high biosafety.

show abstract

Normalizing tumoral vessels to treat cancer: an out-of-the-box strategy involving TIE2 pathway

Cited by 3 publications

References 28 publications

Tie2-mediated vascular remodeling by ferritin-based protein C nanoparticles confers antitumor and anti-metastatic activities

Tie2-mediated vascular remodeling by ferritin-based protein C nanoparticles confers antitumor and anti-metastatic activities

Monitoring of tumor vascular normalization: the key points from basic research to clinical application

Novel Oncolytic Virus Armed with Cancer Suicide Gene and Normal Vasculogenic Gene for Improved Anti-Tumor Activity

Contact Info

Product

Resources

About