Platelet-derived Endothelial Growth Factor Research Articles

Possible role of thymidine phosphorylase in gynecological tumors as an individualized treatment strategy

Thymidine phosphorylase (TP) is structurally similar to platelet-derived endothelial cell growth factor, and it activates 5-fluorouracil (5-FU) prodrugs and also promotes angiogenesis. In the present study, the possibility of using TP expression as a biomarker for 5-FU prodrugs, and the significance of TP as an angiogenic factor, were investigated in patients with gynecological tumors. The subjects enrolled in the study were 188 patients with gynecological tumors who provided informed consent and underwent tumor resection at the Department of Obstetrics and Gynecology of Tokai University Hospital between February 2002 and January 2010. Measurement of the enzymatic activity of TP and dihydropyrimidine dehydrogenase (DPD) was performed by enzyme-linked immunosorbent assay. In addition, immunohistochemistry (IHC) analysis of microvessels by monochrome imaging, western blotting and reverse transcription-polymerase chain reaction were performed. The mean TP activity and the TP/DPD ratio were increased in squamous cell carcinoma of the cervix (306.9 and 2.2 U/mg protein, respectively) and adenosquamous carcinoma (317.6 and 1.4 U/mg protein, respectively) compared with benign tumors and other malignancies, including endometrial (uterine) carcinoma, ovarian serous adenocarcinoma and ovarian mucinous adenocarcinoma. However, these parameters were also elevated in other histological types of cancer such as clear cell adenocarcinoma of the ovary (115.2 and 2.1 U/mg protein, respectively), in which the microvessel area was the largest of all the histological types analyzed. Since high TP expression and a high TP/DPD ratio were identified in other tumors besides cervical cancer, it is possible that patients for whom 5-FU prodrugs are indicated could be selected appropriately if their TP activity is determined and their TP expression is analyzed by IHC prior to initiation of the treatment.

Review on TAS-102 development and its use for metastatic colorectal cancer

TAS-102 is the combination of trifluridine (TFT) with tipiracil (TPI) in a 1:0.5 molar ratio. TFT is a fluoropyrimidine that retains cytotoxic activity in 5-fluorouracil resistant cell lines. Due to TFT short half-life, early clinical development was discouraging. Thereafter, TFT was shown to be promptly degraded by thymidine phosphorylase, also known as platelet-derived endothelial cell growth factor, a pro-angiogenic protein and a poor prognosis marker in colorectal cancer. TPI is a specific antagonist of thymidine phosphorylase and led to an increase in TFT serum levels when both agents are combined. Moreover, TPI is a potential anti-angiogenic molecule and could exert antitumor actions per se. TAS-102 was tested in several Phase I studies published in the early 21st century. The best regimen was settled as 70mg/m(2)/day, q12h, orally given at days 1-5 and days 8-13, each 28days. Recently, the first Phase III trial evaluating TAS-102 in refractory colorectal cancer patients was published. The RECOURSE trial demonstrated a survival advantage of the agent over supportive care, and definitely established TAS-102 as a novel strategy in the current armamentarium against colorectal cancer. Here we review the preclinical data regarding TFT and TPI that led to the development of TAS-102, and the set of clinical data that ultimately proved that TAS-102 improved outcomes in colorectal cancer patients.

Effects of Platelet-Derived Endothelial Cell Growth Factor and Doppler Perfusion Index in Patients with Colorectal Hepatic Metastases

Background: We aimed to find out if there is a correlation between Doppler perfusion index (DPI) and platelet- derived endothelial cell growth factor (PD-ECGF), which is an angiogenic factor with angiopoietic function, in patients with colorectal carcinoma. Methods: 50 colorectal carcinoma patients (22 cases with liver metastases, 28 cases without liver metastases) and 50 healthy controls were assessed with Doppler ultrasound as a preoperative evaluation. PD-ECGF expression in postoperative specimens of the 50 cases with colorectal carcinoma was assayed by immunohistochemistry and real-time polymerase chain reaction methods. Results: The mean DPI value was 0.29 ± 0.05 in patients suffering from colon cancer with hepatic metastases and 0.12 ± 0.03 in the healthy control group. The DPI value was significantly higher in patients with liver metastases (p < 0.05). PD-ECGF expression in patients with colorectal liver metastases was significantly higher than that in the group without liver metastases (p < 0.05). A positive correlation was found between DPI value and PD-ECGF expression in patients with liver metastases (p < 0.05). Conclusions: DPI and PD-ECGF may be valuable factors when screening hepatic metastases in patients with colorectal cancer and serve as practical measurements in postoperative follow-up.

Thymidine Phosphorylase in Cancer; Enemy or Friend?

Thymidine phosphorylase (TP) is a nucleoside metabolism enzyme that plays an important role in the pyrimidine pathway.TP catalyzes the conversion of thymidine to thymine and 2-deoxy-α-D-ribose-1-phosphate (dRib-1-P). Although this reaction is reversible, the main metabolic function of TP is catabolic. TP is identical to the angiogenic factor platelet-derived endothelial-cell growth factor (PD-ECGF). TP is overexpressed in several human cancers in response to cellular stressful conditions like hypoxia, acidosis, chemotherapy and radiotherapy. TP has been shown to promote tumor angiogenesis, invasion, metastasis, evasion of the immune-response and resistance to apoptosis. Some of the biological effects of TP are dependent on its enzymatic activity, while others are mediated through cytokines like interleukin 10 (IL-10), basic fibroblast growth factor (bFGF) and tumour necrosis factor α (TNFα). Interestingly, TP also plays a role in cancer treatment through its role in the conversion of the oral fluoropyrimidine capecitabine into its active form 5-FU. TP is a predictive marker for fluoropyrimidine response. Given its various biological functions in cancer progression, TP is a promising target in cancer treatment. Further translational research is required in this area.

Thymidine phosphorylase gene variant, platelet counts and survival in gastrointestinal cancer patients treated by fluoropyrimidines.

The predictive value of thymidine phosphorylase gene variants (TP, also called platelet-derived endothelial cell growth factor) and thrombocytosis were controversial and worthy of further study in gastrointestinal cancer (GIC) patients. We screened all of the common missense single nucleotide polymorphisms (MAF ≥ 0.1) in fluoropyrimidines (FU) pathway genes (including TP, TS, ENOSF1 and DPD). Three of them were selected and genotyped using Sequenom MassARRAY in 141 GIC patients. TP expression was assessed by immunohistochemistry. Our aim was to evaluate the prognostic significance of studied genes and platelet counts in GIC patients. Multivariate analyses indicated in rs11479-T allele carriers, platelet counts negatively correlated to overall survival. In addition, T allele of TP: rs11479 was associated with higher TP expression in cancer tissues. We suggest TP: rs11479 variant combined with platelet counts may be useful prognostic makers in GIC patients receiving first-line FU chemotherapy and thrombopoietin factor should be used with caution in the rs11479 T allele bearing patients.

Expression of platelet-derived growth factor in esophageal squamous cell carcinoma and its relationship with clinicopathologic indexes

Objective To explore the expression of platelet-derived endothelial growth factor (PDGF) in esophageal squamous cell carcinoma (ESCC) and its relationship with clinicopathologic indexes.Methods Forty-three patients who had ESCC radical excision were selected.The esophago diseased regions of the patients which had been ablated in exairesis were collected as ESCC group.Normal esophago epithelia from the broken ends of excisional pecimen (the distance to tumor border ＞ 5 cm) in 25 patients were collected as control group.The expression of PDGF in the two groups was detected by immunohistochemistry and the correlation between the chnical pathology parameter of esophageal squamous cell carcinoma and PDGF expression was analyzed.Results The absorbance (A) value of PDGF expression in ESCC group (0.091 ±0.002) was significantly higher than that in control group (0.074 ±0.008) and the difference was significant (P ＜ 0.05).The expression of PDGF was associated with lymph nodes metastasis and tumour node metastases staging (r =0.673,0.525,P ＜ 0.05),but had no correlation with volume and differentiation degree of neoplasms (r =0.379,0.453,P ＞ 0.05).Conclusion PDGF plays an important role in the genesis' and development of ESCC,and it has important reference value for the diagnosis,prognosis judgment and therapy of ESCC. Key words: Esophageal squamous cell carcinoma; Platelet-derived endothelial growth factor; Pathology

Prognostic factors and status of hormone receptors and angiogenic factors in uterine carcinosarcoma

To determine novel prognostic factors and treatment modalities for uterine carcinosarcoma (UCS). We performed immunohistochemical staining of estrogen receptor (ER)-α, ER-β, progesterone receptor, gonadotropin-releasing hormone receptor, vascular endothelial growth factor (VEGF), platelet-derived endothelial cell growth factor (PD-ECGF) and platelet-derived growth factor receptor (PDGFR)-β in a clinicopathological study of 15 UCS patients. No significant differences were found between the sarcomatous and carcinomatous components with respect to expression of ER-α, ER-β and progesterone receptor. However, VEGF was significantly more frequently expressed in the carcinomatous component, while PD-ECGF and PDGFR-β were significantly more frequently expressed in the sarcomatous component. Only one patient showed gonadotropin-releasing hormone receptor expression in the sarcomatous component. Moreover, ER-β expression in resected specimens, increased serum levels of carbohydrate antigen (CA)-125 and C-reactive protein (CRP), and thrombocytosis were determined as significant UCS prognostic factors. Combination of anti-VEGF therapy and anti-PD-ECGF or anti-PDGFR-β therapy would be expected in advanced or recurrent UCS. Furthermore, careful monitoring for early detection of recurrence should be performed when UCS patients showed preoperative increase in serum CA-125 levels, CRP and platelet counts, and ER-β expression in biopsied or surgically resected specimens.

Adverse reactions to targeted and non-targeted chemotherapeutic drugs with emphasis on hypersensitivity responses and the invasive metastatic switch

More than 100 drugs are used to treat the many different cancers. They can be divided into agents with relatively broad, non-targeted specificity and targeted drugs developed on the basis of a more refined understanding of individual cancers and directed at specific molecular targets on different cancer cells. Individual drugs in both groups have been classified on the basis of their mechanism of action in killing cancer cells. The targeted drugs include proteasome inhibitors, toxic chimeric proteins and signal transduction inhibitors such as tyrosine kinase (non-receptor and receptor), serine/threonine kinase, histone deacetylase and mammalian target of rapamycin inhibitors. Increasingly used targeted vascular (VEGF) and platelet-derived endothelial growth factor blockade can provoke a range of pathological consequences. Many of the non-targeted drugs are cytotoxic, suppressing haematopoiesis as well as provoking cutaneous eruptions and vascular, lung and liver injury. Cytotoxic side effects of the targeted drugs occur less often and usually with less severity, but they show their own unusual adverse effects including, for example, a lengthened QT interval, a characteristic papulopustular rash, nail disorders and a hand–foot skin reaction variant. The term hypersensitivity is widely used across a number of disciplines but not always with the same definition in mind, and the terminology needs to be standardised. This is particularly apparent in cancer chemotherapy where anti-neoplastic drug-induced thrombocytopenia, neutropenia, anaemia, vascular disorders, liver injury and lung disease as well as many dermatological manifestations sometimes have an immune basis. The most insidious of all adverse consequences of targeted therapies, however, are tumour adaptation, increased malignancy and the invasive metastatic switch seen with anti-angiogenic drugs that inhibit the VEGF-A pathway. Adverse reactions to 44 non-targeted and 33 targeted, frequently used, chemotherapeutic drugs are presented together with discussions of diagnosis, premedications, desensitizations and importance of understanding the mechanisms underlying the various drug-induced reactions. There is need for wide-ranging acceptance of what constitutes a hypersensitivity reaction and for allergists to be more involved in the diagnosis, treatment and prevention of chemotherapeutic drug-induced hypersensitivity reactions.

Research development of the relationship between thymidine phosphorylase expression and colorectal carcinoma.

Thymidine phosphorylase (TP) is a key enzyme that contributes to the composition and decomposition of pyrimidine nucleotides. TP seems homologous to platelet-derived endothelial cell growth factor, and its effects on inducing vascularization and anti-apoptosis are closely related to growth and metastasis of colorectal carcinoma. In addition, TP is a key enzyme that catalyzes the transformation from 5-fluorouracil (FU) prodrugs of 5′-deoxy-5-fluorouridine (5′-DFUR) to 5-FU. The activity of TP is closely related to the sensitivity of colorectal carcinoma cells to fluorouracil drugs and targeted therapy. Given the important functions of TP in growth, metastasis, tumor treatment, and prognosis, determining its expression mechanism is significant. This article summarizes the research development of TP expression in colorectal carcinoma, tumor neovascularization, cytotoxicity activation of 5′-DFUR, and colorectal carcinoma therapy.

Role of Thymidinekinase and Thymidine Phosphorylase as Enzymatic Test for Efficacy of Oncological Patients Treatment

The treatment of breast cancer has been undergoing an incredible sequence of changes. The role of individual treatment of women with breast cancer is not clearly defined. Since last century the drug 5-fluorouracil with another anticancer agents and prodrugs from group of fluoropyrimidines are widely used. Thymidine phosphorylase is the enzyme which can also catalyze the interconversion of uracil as well as several fluoropyrimidines. Thymidine Phosphorylase (TP) and Thymidine Kinase (TK) also play an important role in thymidine homeostasis and thus in DNA synthesis. Thymidine kinase is used as cells proliferation marker. Thymidine phosphorylase is similar to the platelet-derived endothelial cells growth factor. High expression of the enzyme is related to malignant angiogenesis and invasion. That is why we investigated the activity of TK and TP both in healthy women and patients with breast cancer (BC) of the I–IV stages and of the same age. Analysis of biochemical and morphological data of these patients revealed that the patients are initially divided according to the activity of blood plasma TP also had different morphological structure of the tumor. In the 1-st group the initial activity of TP was sharply reduced and in the 2nd group TP activity ranged normally. During the treatment of women from the 1st group the activity of TP was not changed, but the activity of TK was increased 3 times. In patients from the 2nd group the activity of TP was authentically increased, but TK activity was reduced. The follow-up analysis showed that four-year lethality in the 1-st group constituted 25%, and there was no lethality in the the 2nd group. Therefore the studied enzymes activity may be used as the informative test for monitoring of patients with breast cancer and optimization of drug treatment.

ADAMTS5 Functions as an Anti-Angiogenic and Anti-Tumorigenic Protein Independent of Its Proteoglycanase Activity

ADAMTS5 is a member of the A Disintegrin-like And Metalloproteinase with ThromboSpondin motifs (ADAMTS) family of secreted metalloproteinases with multiple proteoglycan substrates. Although well characterized for its role in cartilage degradation and arthritis, how it influences cancer remains unclear. We have previously shown that the first thrombospondin type 1 repeat (TSR1, the central TSR) but not TSR2 (the C-terminal TSR) of ADAMTS5 is anti-angiogenic in vitro. Coupled with previous reports that ADAMTS5 expression is altered in several human cancers, we hypothesized that this proteoglycanase may play an important role in cancer and angiogenesis. Here, we demonstrated that overexpression of full-length ADAMTS5 suppressed B16 melanoma growth in mice. The reduced tumor growth is correlated with diminished tumor angiogenesis, together with reduced tumor cell proliferation and increased tumor cell apoptosis. Catalytically active ADAMTS5 proteolytic fragment also suppressed angiogenesis in vitro. The catalytic activity of ADAMTS5 is dispensable for its anti-tumorigenic function, as the full-length active site mutant E411A presented similar tumor suppression activity. Domain mapping and mechanistic studies revealed that ADAMTS5 inhibits B16 tumorigenesis through its TSR1 by suppressing tumor angiogenesis, likely by down-regulating pro-angiogenic factors such as vascular endothelial growth factor (VEGF), placenta growth factor (PlGF), and platelet-derived endothelial growth factor (PD-ECGF) in the tumor milieu. This is the first report that ADAMTS5 is an anti-angiogenic and anti-tumorigenic protein independent of its proteoglycanase activity.

Abstract 2324: LHT-7 as multi-targeting and anti-angiogenic agent to growth factor receptors

Abstract Angiogenesis is a highly regulated process that is critical for tumor growth and metastasis. Angiogenesis depends on the balance between different molecules released by the host and tumor cells such as vascular endothelial growth factor (VEGF), fibroblast growth factor basic (bFGF), platelet-derived endothelial cell growth factor (PDGF), insulin-like growth factors (IGF-1 and IGF-2) and scatter factor, which are potential targets for development of angiogenesis inhibitor and depend on heparin sulfate for their biological functions. Heparan sulfate is located in cell surface and in the extracellular matrix and plays crucial regulatory roles in some growth factors. For this reason, heparin has been highlighted as a therapeutic agent as well as anticoagulant. In a previous study, we reported new angiogenesis inhibitor, low molecular weight heparin derivative (heparin-taurocholic acid conjugate; LHT-7) and it showed delay of in vivo tumor growth in MDA-MB231 human breast cancer and inhibited phosphorylation of VEGFR2 through the interaction with VEGF in human umbilical vein endothelial cells (HUVECs). In present study, we revealed LHT-7 as multi-targeting agent to several growth factors and on their actions. LHT7 inhibited phosphorylation of VEGFR2 and binding of LHT7 was increased in VEGFR2 over-expressing HEK293 by FACS analysis. In HUVECs, binding of LHT-7 was shown in a dose-dependent manner by FACS analysis and co-localized with VEGFR2 by immunofluorescence. LHT-7 also inhibited vessel formation enhanced by PDGF-bb in matrigel plug assay and phosphorylation of PDGFR-ß in human vascular smooth muscle cell (HuVSMC). Binding of LHT-7 was increased in a dose-dependent manner by FACS analysis and decreased in PDGFR-ß-siRNA HuVSMC by immunofluorescence. Finally, LHT-7 inhibited phosphorylation of FGFR-1 in HUVECs and binding of LHT-7 was decreased in FGFR-1-siRNA MDA-MB-361. Overall, LHT-7 has inhibitory effect on phosphorylation of growth factors and binding of LHT-7 was increased in a dose-dependent manner but decreased in a growth factor down-regulated cell. Therefore we suggest that LHT7 would target to VEGFR2, PDGFR- ß and FGFR-1 and inhibit their angiogenic roles. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2324. doi:1538-7445.AM2012-2324

Changes of angiogenic factors in patients with type 2 diabetes mellitus

Serum levels of human CXC-chemokine ligand 16,basic fibroblast growth factor,plateletderived endothelial cell growth factor,and number of endothelial progenitor cells were determined in 80 patients with type 2 diabetes mellitus and 40 normal control subjects.It was found that there were some disturbances of angiogenesis in diabetic patients.These abnormalities were more pronounced in these patients with old age,hyperglycemia,raised HbA1c,and presence of vascular diseases. Key words: Diabetes mellitus, type 2; Angiogenesis; Human CXC-chemokine ligand 16

Experimentally induced puromycine aminonucleoside nephrosis (PAN) in rats: evaluation of angiogenic protein platelet-derived endothelial cell growth factor (PD-ECGF) expression in glomeruli.

BackgroundIn experimentally induced puromycine aminonucleoside nephrosis (PAN) animal models, nephrotic syndrome with minimal change disease and focal and segmental sclerosis-like nephritis similar to that in human is demonstrated; however, the real mechanism of PAN is not yet elucidated. Platelet derived endothelial cell growth factor (PD-ECGF), an endothelial mitogen protein, is believed to take part in microvessel formation and in stimulation of angiogenesis and its expression has not been totally demonstrated in PAN rats yet. In this study, we aimed to examine PD-ECGF expression in acute and chronic PAN induced in rats and find out the association between its expression and the stages of angiogenesis in kidney.MethodsFor the experiment, twenty-four Male Wistar Albino rats were used and divided into four groups; control group (n = 6), pre-proteinuria group (n = 6), acute group (n = 6) and chronic group (n = 6). We compared statistically all data by One-way ANOVA Test followed by Dunn Multiple Comparison Test.ResultsProteinurea levels in control and pre-proteinuria groups were not statistically different; however, it was remarkably higher in the acute nephrosis group and significantly greater in the chronic nephrosis group than control group (p < 0.0025). In pre-proteinuria group, the serum albumin and creatinine clearances also did not significantly differ from the control group. On the other hand, in the acute and chronic nephrosis groups, serum albumin and creatinine clearances progressively decreased (p < 0.05). In our immunohistochemical studies, we showed elevated PD-ECGF expression in glomeruli of acute and chronic PAN rats. Microscopic and ultrastructural appearances of the glomeruli of acute and chronic PAN showed various sequential steps of angiogenesis, macrophages and immature capillaries with primitive lumens and apoptotic endothelial cells in the increased mesangial matrix.ConclusionsIt is reported that acute and chronic PAN progressively increase PD-ECGF expression and following induction of angiogenesis in the affected glomeruli.

Angiogenic Factors Play a Significant Role in Nasal Airway Remodeling in Allergic Rhinitis

Angiogenic Factors Play a Significant Role in Nasal Airway Remodeling in Allergic Rhinitis

Deoxyribose Protects Against Rapamycin-Induced Cytotoxicity in Colorectal Cancer Cells In Vitro

Thymidine phosphorylase (TPase) is also known as the platelet-derived endothelial cell growth factor (PD-ECGF) and plays a role in angiogenesis. Deoxyribose (dR; a downstream TPase-product) addition to endothelial cells may stimulate FAK and p70/S6k signaling, which can be inhibited by rapamycin. Rapamycin is a specific mammalian target of the rapamycin (mTOR) inhibitor, a kinase that lies directly upstream of p70/S6k. This suggests a role for TPase in the mTOR/p70/S6k pathway. In order to study this in more detail, we exposed cells with and without TPase expression to dR and rapamycin and determined the effect on cell growth. We observed protection in cytotoxicity in Colo320 cells, but not Colo320 TP1 cells. This was in part mediated by activation of p70/S6k and inhibition of autophagy. Further studies are recommended to elucidate the mechanism behind the protective effect of dR.

The role of PD-ECGF and VEGF in proliferative and involuted mechanism of the infantile capillary hemangiomas

To explore the relation between the expressions of PD-ECGF and VEGF and the evolution of capillary hemangioma, so as to provide theoretical basis for treatment. Fourty cases with capillary hemangioma, proved by pathologic method, were randomly selected and divided into proliferative (n=22) and involuted groups (n=18), according to the Mulliken standard. 8 specimens from 8 children with prepuce operation were used as control group. All the specimens were fixed, embedded and underwent HE staining. The expression of PD-ECGF, VEGF and CD34 in endothelial cells were detected by immunohistochemistry. The microvessel-density (MVD) was also calculated. The results were analyzed by SPSS12.0. The positive expression rates of PD-ECGF and VEGF were 95.45% (21/22) and 86.36% (19/22) in proliferative hemangioma, 77.78% (14/18) and 66.67% (12/ 18) in involuted hemangioma, 37.50% (3/8) and 37.50% (3/8) in normal skin. MVD in proliferative and involuted hemangioma and normal skin was 93.68 +/- 20.56, 51.94 +/- 20.73 and 17.50 +/- 5.30, respectively. There was a significant difference in PD-ECGF expression and MVD between the proliferative and involuted groups, or between the hemangioma and control groups (P < 0.05). The VEGF was significantly different between the proliferative and involuted groups, or between the proliferative and control groups (P < 0.05), but not between the involuted and control groups (P > 0.05). The expression of VEGF, PD-ECGD and MVD showed a positive relationship. PD-ECGF and VEGF have a synergetic effect in the proliferation of micro-vessels. PD-ECGF may enhance the activity of thymidine phosphorylase. They play an important role in the proliferation and involution of hemangioma.

Abstract 3487: Molecular basis for induction of IL-8 expression by thymidine phosphorylase

Abstract Thymidine phosphorylase (TP) is identical to platelet-derived endothelial cell growth factor (PD-ECGF) and has an angiogenic activity. 2-Deoxy-D-ribose, one of the degradation products of thymidine, is a down stream mediator of the TP function. We investigated the molecular basis for the induction of an angiogenic factor, interleukin-8 (IL-8) by TP. First we confirmed that the enzymatic activity of TP is needed for the induction of IL-8 by TP in KB cells, and 2-deoxy-D-ribose increased the expression level of IL-8. ROS generated by TP augmented the expression of heme oxygenase-1 (HO-1) and increased the expression of IL-8. Two inhibitors of NADPH oxidase, apocynin and diphenyleneiodonium, suppressed the expression of HO-1 and IL-8 in TP-overexpressing KB/TP cells. Knock down of the component of NADPH oxidase, Nox2 or p22phox, also suppressed the enhanced expression of IL-8 in KB/TP cells. ROS generated by TP activated NFκB, which subsequently enhanced the promoter activity of IL-8. Our findings suggest that NADPH oxidase is involved in the ROS generation by TP, and the ROS caused the activation of NF-κB, which subsequently enhanced the expression of IL-8. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3487. doi:10.1158/1538-7445.AM2011-3487

Abstract 5139: Thymidine phosphorylase expression correlate with lymphangiogenesis and angiogenesis in metastatic gastric cancer

Abstract Thymidine Phosphorylase (TP) (platelet-derived endothelial cell growth factor, PD-ECGF) is known as a proangiogenic factor. High TP expression in the primary tumor has been thought as a risk factor for hepatic and lymph node metastasis in patients with gastric adenocarcinoma. However, the molecular basis for induction of invasion and lymph node metastasis by TP and its therapeutic implication is largely unknown. First, as a pilot study, the (lymph)angiogenic activity (D2-40, LYVE-1, VEGFC, VEGFR3) and TP expressions were evaluated in resected tumor samples. Sixty patients of gastric cancer with metastatic lymph nodes and in 46 patients without lymph node metastasis were included. With immunohistochemical study, we demonstrated that tumoral and stromal TP expressions were moderately correlated (Pearson correlation = 0.455). TP expression was also correlated with depth of invasion and nodal stage. TP-positive tumors had also increased lymphovascular invasion compared with TP-negative tumors (P = 0.044), and node positive tumor had higher density of lymphatic vessels, and it is correlated with TP expression (P = 0.023). Then, we have shown that nude mice injected intraperitoneally with TP-overexpressing MKN-45 cells (MKN-45/TP) had decreased survival times compared with those injected with control cells (MKN-45/CV). MKN-45/TP tumors were more angiogenic (positive for CD31) and lymphangiogenic (positive for D2-40 and LYVE-1), and they were more invasive than MKN-45/CV tumors. A specific TP inhibitor, TPI, partially extended the survival period of TP tumor bearing mice, and its angiogenic activity was significantly reduced. All these findings imply that TP expression may be related to lymphangiogenesis in gastric cancer, and it could be further investigated as therapeutic targets for anti-metastatic therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5139. doi:10.1158/1538-7445.AM2011-5139

Vasculopathy in type 2 diabetes mellitus: role of specific angiogenic modulators

Type 2 diabetes mellitus (T2DM) is largely defined by hyperglycemia that promotes vascular complications. Abnormal angiogenesis has been claimed to have a role in this disease. This study aimed to investigate serum levels of both conventional and other markers of angiogenesis not well studied before in diabetes, and to correlate findings with age of the patients, glycemic control, presence of microvascular complications, and oxidative stress. Thirty-eight patients with T2DM and 13 age- and sex-matched healthy persons representing controls were recruited. Serum levels of basic fibroblast growth factor (b-FGF) was measured by immunosorbent assay kit; advanced glycosylation end products, platelet-derived endothelial cell growth factor (PD-ECGF), cathepsin-D (CD), gangliosides, hyaluronic acid (HA), nitric oxide (NO), lipid peroxides (LPER), superoxide dismutase, and total thiols by chemical methods; and copper (Cu) by atomic absorption flame photometry. Advanced glycosylation end products and angiogenic factors (b-FGF, PD-ECGF, CD, gangliosides, HA, and Cu) were significantly higher in patients than controls. Oxidative stress markers, NO, and LPER were significantly higher while total thiols were significantly lower in patients than controls. These changes were more pronounced with age, poor glycemic control, and presence of microvascular complications. Angiogenesis dysfunction coinciding with elevated levels of many angiogenic growth factors may point to their malfunctioning due to oxidative stress and/or protein glycation at the factor and the receptor levels. This necessitates further investigations.