Tumor Neovascularization and Developments in Therapeutics

Katayama, Yuki; Uchino, Junichi; Chihara, Yusuke; Tamiya, Nanako; Kaneko, Yoshiko; Yamada, Tadaaki; Takayama, K.

doi:10.3390/cancers11030316

Cited by 96 publications

(83 citation statements)

References 127 publications

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“…Therapeutic approaches that target the TME are important for the prevention of recurrence and metastasis 27 . The veterinary literature increasingly has recognized the importance of various aspects of the TME, including angiogenic activity, intratumoral hypoxia, and tumor‐infiltrating Tregs.…”

Section: Discussionmentioning

confidence: 99%

Assessment of postoperative adjuvant treatment using toceranib phosphate against adenocarcinoma in dogs

Yamazaki

Tanaka

Mie

et al. 2020

Veterinary Internal Medicne

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Background: Toceranib phosphate (TOC) could be made widely available for treating tumors in dogs if evidence shows that TOC inhibits recurrence after surgery.Objectives: To investigate how postoperative adjuvant treatment with TOC modulates the tumor microenvironment (TME), by assessing effects on angiogenic activity, tumorinfiltrating regulatory T cells (Tregs), and intratumoral hypoxia.Animals: Ninety-two client-owned dogs were included: 28 with apocrine gland anal sac adenocarcinoma, 24 with small intestinal adenocarcinoma, 22 with lung adenocarcinoma, and 18 with renal cell carcinoma.Methods: Retrospective, multicenter study comparing time to progression (TTP) between 42 dogs treated by surgery and TOC and 50 dogs treated by surgery alone.Differences were analyzed in the expression of vascular endothelial growth factor receptor-2 (VEGFR2) and the number of Foxp3 + Tregs and hypoxia-inducible factor (HIF)-1α + cells in tumor tissues sampled at the first and second (recurrence) surgeries.Results: Median TTP for dogs treated by surgery and TOC (360 days) was higher than that for dogs treated by surgery alone (298 days; hazard ratio, 0.82; 95% confidence interval [CI], 0.65-0.96; P = .02). In dogs treated by surgery and TOC, VEGFR2 expression and the number of Tregs and HIF-1α + cells were significantly lower in tissues sampled at the second surgery than in those sampled after the first surgery. In dogs treated by surgery alone, significant differences were found between samples from the 2 surgeries.Conclusions and Clinical Importance: Toceranib phosphate could prove to be a useful postoperative adjuvant treatment because of its modulation of the TME. K E Y W O R D S adenocarcinoma, postoperative adjuvant treatment, toceranib phosphate, tumor microenvironment

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Section: Discussionmentioning

confidence: 99%

Assessment of postoperative adjuvant treatment using toceranib phosphate against adenocarcinoma in dogs

Yamazaki

Tanaka

Mie

et al. 2020

Veterinary Internal Medicne

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“…For tumors with very small volume (1-2 mm 3 ), the supply of oxygen and nutrients from neighboring capillaries via vascular cooption 16 is sufficient because the diffusion distance of oxygen is 100-200 mm. 19 To grow beyond this size, generation of new blood vessels toward the tumor, i.e., neovascularization, is required. 9,15 Mathivet et al 23 observed a progres- in an orthotopic mouse model.…”

Section: Early Gb Recurrence Detection With Vammentioning

confidence: 99%

Vascular architecture mapping for early detection of glioblastoma recurrence

Stadlbauer

Eyüpoglu²,

Buchfelder³

et al. 2019

Neurosurgical Focus

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OBJECTIVETreatment failure and inevitable tumor recurrence are the main reasons for the poor prognosis of glioblastoma (GB). Gross-total resection at repeat craniotomy for GB recurrence improves patient overall survival but requires early and reliable detection. It is known, however, that even advanced MRI approaches have limited diagnostic performance for distinguishing tumor progression from pseudoprogression. The novel MRI technique of vascular architectural mapping (VAM) provides deeper insight into tumor microvascularity and neovascularization. In this study the authors evaluated the usefulness of VAM for the monitoring of GB patients and quantitatively analyzed the features of neovascularization of early- and progressed-stage GB recurrence.METHODSIn total, a group of 115 GB patients who received overall 374 follow-up MRI examinations after standard treatment were retrospectively evaluated in this study. The clinical routine MRI (cMRI) protocol at 3 Tesla was extended with the authors’ experimental VAM approach, requiring 2 minutes of extra time for data acquisition. Custom-made MATLAB software was used for calculation of imaging biomarker maps of macrovascular perfusion from perfusion cMRI as well as of microvascular perfusion and architecture from VAM data. Additionally, cMRI data were analyzed by two board-certified radiologists in consensus. Statistical procedures included receiver operating characteristic (ROC) analysis to determine diagnostic performances for GB recurrence detection.RESULTSOverall, cMRI showed GB recurrence in 89 patients, and in 28 of these patients recurrence was detected earlier with VAM data, by 1 (20 patients) or 2 (8 patients) follow-up examinations, than with cMRI data. The mean time difference between recurrence detection with VAM and cMRI data was 147 days. During this time period the mean tumor volume increased significantly (p < 0.001) from 9.7 to 26.8 cm3. Quantitative analysis of imaging biomarkers demonstrated microvascular but no macrovascular hyperperfusion in early GB recurrence. Therefore, ROC analysis revealed superior diagnostic performance for VAM compared with cMRI.CONCLUSIONSThis study demonstrated that the targeted assessment of microvascular features using the VAM technique provided valuable information about early neovascularization activity in recurrent GB that is complementary to perfusion cMRI and may be helpful for earlier and more precise monitoring of patients suffering from GB. This VAM approach is compatible with existing cMRI protocols. Prospective clinical trials are necessary to investigate the clinical usefulness and potential benefit of increased overall survival with the use of VAM in patients with recurrent GB.

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“…Thus suggesting that oncogene-induced senescence represents a genuine protective physiological process [53]. On the contrary, the tendency of the tumor group expressing high levels of B-raf V600E towards neovascularization is indicative of rapid cancer cell proliferation, tumor invasion and cancer progression in general [54].…”

Section: Discussionmentioning

confidence: 99%

The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma – Association with Clinical Outcome and Tumor Phenotypes

Betancourt¹,

Szász²,

Kuras³

et al. 2019

Preprint

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In comparison to other human cancer types, malignant melanoma exhibits the greatest amount of heterogeneity. After DNA-based detection of the BRAF V600E mutation in melanoma patients, targeted inhibitor treatment is the current recommendation. This approach, however, does not take the abundance of the therapeutic target, i.e., the B-raf V600E protein, into consideration. As shown by immunohistochemistry, the protein expression profiles of metastatic melanomas do clearly reveal the existence of inter- and intra-tumor variability. Nevertheless, the technique is only semi-quantitative. To quantitate the mutant protein there is a fundamental need for more precise techniques that are aimed at defining the currently non-existent link between the levels of the target protein and subsequent drug efficacy. Using cutting-edge mass spectrometry combined with DNA and mRNA sequencing, the mutated B-raf protein within metastatic tumors was quantitated for the first time. B-raf V600E protein analysis revealed a subjacent layer of heterogeneity for mutation-positive metastatic melanomas. These were characterized into two distinct groups with different tumor morphologies, protein profiles and patient clinical outcomes. This study provides evidence that a higher level of expression for the mutated protein is associated with a more aggressive tumor progression. Our study design that is comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis may enable the eventual delineation of patient responders/non-responders and the subsequent therapy of malignant melanoma.

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Tumor Neovascularization and Developments in Therapeutics

Cited by 96 publications

References 127 publications

Assessment of postoperative adjuvant treatment using toceranib phosphate against adenocarcinoma in dogs

Assessment of postoperative adjuvant treatment using toceranib phosphate against adenocarcinoma in dogs

Vascular architecture mapping for early detection of glioblastoma recurrence

The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma – Association with Clinical Outcome and Tumor Phenotypes

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Tumor Neovascularization and Developments in Therapeutics

Cited by 96 publications

References 127 publications

Assessment of postoperative adjuvant treatment using toceranib phosphate against adenocarcinoma in dogs

Assessment of postoperative adjuvant treatment using toceranib phosphate against adenocarcinoma in dogs

Vascular architecture mapping for early detection of glioblastoma recurrence

The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma &ndash; Association with Clinical Outcome and Tumor Phenotypes

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The Hidden Story on Heterogeneous B-raf V600E Mutation Quantitative Protein Expression in Metastatic Melanoma – Association with Clinical Outcome and Tumor Phenotypes