YKL-39 is an independent prognostic factor in gastric adenocarcinoma and is associated with tumor-associated macrophage infiltration and angiogenesis.

BACKGROUND: Gastric cancer has a high incidence and mortality rate. Angiogenesis is necessary for tumor infiltration and metastasis and affects patient prognosis. YKL-39 has monocyte chemotactic activity and pro-angiogenic activity in some tumors. In this study, we investigated the relationship between YKL-39 and tumor-associated macrophages and microangiogenesis in gastric cancer to determine its potential as a prognostic biomarker. MATERIALS AND METHODS: A total of 119 patients with gastric cancer who had undergone gastrectomy at the 940th Hospital of the Joint Security Force between 2014 and 2018 were included in this study. We assayed the protein expression of YKL-39, CD68, and CD34 by immunohistochemistry in tissues of 119 patients with gastric cancer, as well as the intracellular expression of YKL-39 and CD68 by immunofluorescence. Data were analyzed with SPSS Statistics 25.0 to explore the impact of expression of YKL-39, CD68, and CD34 in gastric cancer patients and the relationship among them. RESULTS: Our results show that YKL-39 was expressed in both the nucleus and cytoplasm of gastric cancer cells and tumor mesenchyme. YKL-39 protein expression was associated with the depth of tumor infiltration, lymph node metastasis, and TNM stage; CD68 protein expression was associated with lymph node metastasis and TNM stage; CD34 protein expression was not associated with clinicopathological characteristics. Expression of YKL-39 was positively correlated with CD68 and CD34 (p < 0.001), and high expression of YKL-39 was associated with poor prognosis (p < 0.05). CONCLUSION: In gastric cancer, YKL-39 expression is positively correlated with the degree of tumor-associated macrophage infiltration and angiogenesis, and is a potential prognostic marker for gastric cancer.

Anti-angiogenic effect of a chemically sulfated polysaccharide from Phellinus ribis by inhibiting VEGF/VEGFR pathway.

Previous studies have demonstrated that the sulfated polysaccharide named PRP-S16 could inhibit the proliferation, migration, and tube formation of endothelial cells in vitro. Here, its anti-angiogenic effect and mechanism in vivo were investigated by Lewis lung carcinoma (LLC) mice model. PRP-S16 significantly reduced the microvessel density (MVD) of tumor, exhibiting a high tumor growth inhibitory effect in LLC mice. All designed assays including quantitative real-time PCR, immunohistochemistry, enzyme-linked immunosorbent assay and western blotting showed that PRP-S16 reduced the mRNA and the protein expression of vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) in serum or tumor tissue of mice. Western blotting also detected decreased phosphorylated (p)-VEGFR-1, p-VEGFR-2, hypoxia-inducible factor-1α (HIF-1α), protein kinase B (Akt), and matrix metalloproteinases-9 (MMP-9). PRP-S16 had no adverse effects on angiogenesis in non-target organs. These findings suggested that the mechanism of anti-angiogenesis of PRP-S16 in vivo was due to inhibition of VEGF/VEGFR signaling pathway and it might be a promising candidate for tumor by anti-angiogenic therapy.

Tumor Angiogenic Inhibition Triggered Necrosis (TAITN) in Oral Cancer.

CXCR4 is a chemokine receptor crucial in tumor progression, although the angiogenic role of CXCR4 in oral squamous cell carcinoma (OSCC) has not been investigated. Here we show that CXCR4 is crucial for tumor angiogenesis, thereby supporting tumor survival in OSCC. Immunohistochemistry on human clinical specimens revealed that CXCR4 and a tumor vasculature marker CD34 were co-distributed in tumor vessels in human OSCC specimens. To uncover the effects of CXCR4 inhibition, we treated the OSCC-xenografted mice with AMD3100, so-called plerixafor, an antagonist of CXCR4. Notably, we found a unique pathophysiological structure defined as tumor angiogenic inhibition triggered necrosis (TAITN), which was induced by the CXCR4 antagonism. Treatment with AMD3100 increased necrotic areas with the induction of hypoxia-inducible factor-1α in the xenografted tumors, suggesting that AMD3100-induced TAITN was involved in hypoxia and ischemia. Taken together, we demonstrated that CXCR4 plays a crucial role in tumor angiogenesis required for OSCC progression, whereas TAITN induced by CXCR4 antagonism could be an effective anti-angiogenic therapeutic strategy in OSCC treatment.

A d-Peptide Ligand of Integrins for Simultaneously Targeting Angiogenic Blood Vasculature and Glioma Cells.

The current prognosis of glioma patients remains poor after intensive multimodal treatments, which is partially due to the existence of the blood-brain tumor barrier (BBTB). In the present study, a novel "bifunctional ligand" (termed DVS) was developed by retro-inverso isomerization. DVS is a ligand of integrins highly expressed on glioma cells and tumor neovasculature. DVS exhibited exceptional stability in serum and demonstrated significantly higher targeting efficiency for glioma and HUVEC cells compared with the parent L-peptide. As a result, DVS modified micelles (DVS-MS) exhibited high encapsulation efficiency of doxorubicin, ideal size distribution, and sustained release behavior of the payload. In vivo studies showed that DVS-MS could target and efficiently deliver fluorescence to tumor cells and tumor vasculature not only in the mice bearing subcutaneous tumors but also in those bearing intracranial tumors. Moreover, doxorubicin loaded DVS modified micelles exerted potent tumor growth inhibitory activity against subcutaneous and intracranial human glioma in comparison to drug loaded plain micelles and LVS modified micelles. Therefore, DVS appears to be a suitable targeting ligand with potential applications for glioma targeted drug delivery.

Modelling Tumor-induced Angiogenesis: Combination of Stochastic Sprout Spacing and Sprout Progression.

BACKGROUND: Angiogenesis initiated by cancerous cells is the process by which new blood vessels are formed to enhance oxygenation and growth of tumor. OBJECTIVE: In this paper, we present a new multiscale mathematical model for the formation of a vascular network in tumor angiogenesis process. METHODS: Our model couples an improved sprout spacing model as a stochastic mathematical model of sprouting along an existing parent blood vessel, with a mathematical model of sprout progression in the extracellular matrix (ECM) in response to some tumor angiogenic factors (TAFs). We perform simulations of the siting of capillary sprouts on an existing blood vessel using finite difference approximation of the dynamic equations of some angiogenesis activators and inhibitors. Angiogenesis activators are chemicals secreted by hypoxic tumor cells for initiating angiogenesis, and inhibitors of the angiogenesis are chemicals that are produced around every new sprout during tumor angiogenesis to inhibit the formation of further sprouts as a feedback of sprouting in angiogenesis. Moreover, for modelling sprout progression in ECM, we use three equations for the motility of endothelial cells at the tip of the activated sprouts, the consumption of TAF and the production and uptake of Fibronectin by endothelial cells. RESULTS: Coupling these two basic models not only does provide a better time estimation of angiogenesis process, but also it is more compatible with reality. CONCLUSION: This model can be used to provide basic information for angiogenesis in the related studies. Related simulations can estimate the position and number of sprouts along parent blood vessel during the initial steps of angiogenesis and models the process of sprout progression in ECM until they vascularize a tumor.

Optical imaging of head and neck squamous cell carcinoma in vivo using arginine-glycine-aspartic acid peptide conjugated near-infrared quantum dots.

Molecular imaging plays a key role in personalized medicine and tumor diagnosis. Quantum dots with near-infrared emission spectra demonstrate excellent tissue penetration and photostability, and have recently emerged as important tools for in vivo tumor imaging. Integrin αvß3 has been shown to be highly and specifically expressed in endothelial cells of tumor angiogenic vessels in almost all types of tumors, and specifically binds to the peptide containing arginine-glycine-aspartic acid (RGD). In this study, we conjugated RGD with quantum dots with emission wavelength of 800 nm (QD800) to generate QD800-RGD, and used it via intravenous injection as a probe to image tumors in nude mice bearing head and neck squamous cell carcinoma (HNSCC). Twelve hours after the injection, the mice were still alive and were sacrificed to isolate tumors and ten major organs for ex vivo analysis to localize the probe in these tissues. The results showed that QD800-RGD was specifically targeted to integrin αvß3 in vitro and in vivo, producing clear tumor fluorescence images after the intravenous injection. The tumor-to-background ratio and size of tumor image were highest within 6 hours of the injection and declined significantly at 9 hours after the injection, but there was still a clearly visible tumor image at 12 hours. The greatest amount of QD800-RGD was found in liver and spleen, followed by tumor and lung, and a weak fluorescence signal was seen in tibia. No detectable signal of QD800-RGD was found in brain, heart, kidney, testis, stomach, or intestine. Our study demonstrated that using integrin αvß3 as target, it is possible to use intravenously injected QD800-RGD to generate high quality images of HNSCC, and the technique offers great potential in the diagnosis and personalized therapy for HNSCC.

An Immunohistochemical Study of Tumor Angiogenesity and EMA Reactivity in Papillary Thyroid Carcinoma / 대한암학회지

PURPOSE: This study was carried out to investigate the correlation among tumor angiogenetic activity, epithelial membrane antigen (EMA) reactivity and various clinicopathologic parameters. We also evaluated the validity of both as an independent prognostic factor in patients with papillary thyroid carcinoma. MATERIALS & METHODS: We studied 120 patients out of 727 patients with papillary thyroid casrcinoma who underwent thyroidectomy at our institute from January 1986 to December 1994. The age of the patients ranged from 14 to 80 years with a mean of 48.2 years. There were 24 males and 96 females (M:F=1:4). The paraffin embedded tissues of these patients were stained with the monoclonal antibodies against factor VIII related antigen, antigen CD34 to highlight microvessels and against EMA to show immunoreactivity. We measured microvessel density (MVD) in the area of highest vascular density at 200 times of magnification (0.785 mm2 per field). The positive cells for EMA were counted as percentages of the whole cell population and the degree of reaction was rated on a five-point scale. RESULTS: Mean MVDs and EMA reactivities by location of tissue per field were 64.8+/-18.9, 1.97+/-0.74, in the center of the tumor; 41.3+/-15.3, 1.55+/-0.68 in the periphery of tumor; and 22.1+/-14.4, 1.09+/-0.75 in normal thyroid tissue, respectively. In relation to TNM stage, only the MVDs of patients with stage IV disease were higher than those of other disease stages with statistical significance (p<.05). In relation to DeGroot stage, the MVDs of patients with stage IV disease was also higher than others with statistical significance (p<.005). There were no significant differences in MVD and EMA reactivity between the two groups of low risk (n=77) and high risk (n=43) by AMES scale. The MVDs and EMA reactivities of patients with local recurrence (n=23) and death (n=7) during the follow-up period had no statistical significance against those patients without recurrence and living patients. CONCLUSION: Tumor angiogenic activity and EMA reactivity in papillary thyroid carcinoma did not correlate with TNM stage, DeGroot stage, AMES score, local recurrence, and patient death. However, MVD was significantly higher in patients with distant metastasis and may be useful in predicting the distant metastasis in papillary thyroid carcinoma.