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Despite recent improvements in surgical techniques and chemotherapy, advanced cancers of the stomach and gastroesophageal junction (GEJ) continue to have poor clinical outcomes. However, molecules intimately related to cancer cell proliferation, invasion, and metastasis have been studied as candidates for molecular targeted agents. Target molecules, such as the epidermal growth factor receptor, vascular endothelial growth factor receptor, and P13k/Akt/mTor pathway, as well as the insulin-like growth factor receptor, c-Met pathways, fibroblast growth factor receptor, and other pathways are considered to be promising candidates for molecular targeted therapy for gastric and GEJ cancer. In this review we focus on the recent developments in targeting relevant pathways in these types of cancer. [ABSTRACT FROM AUTHOR]

We investigated the correlation of vascular endothelial growth factor C, matrix metalloproteinase-2, E-cadherin to explore mechanisms of vascular endothelial growth factor C in the metastasis of ovarian cancer and the relationship of prognosis. We applied immunohistochemistry to investigate the expression of vascular endothelial growth factor C, matrix metalloproteinase-2 and E-cadherin in ovarian tissues of 227 patients. We adopted Pearson chi- square test, Spearman correlation coefficient, univariate analysis, multivariate analysis, and Kaplan-Meier method. The positive rate of vascular endothelial growth factor C, matrix metalloproteinase-2 and E-cadherin in ovarian cancer was higher than that in borderline and benign tumor ( P < 0.01). Vascular endothelial growth factor C was positively correlated with matrix metalloproteinase-2 ( r = 0.665, P < 0.01) while negatively with E-cadherin( r = −0.185, P < 0.05). Univariate analysis showed clinical stage, pathologic grade, lymphatic metastasis, residual disease, chemotherapy, ascites, vascular endothelial growth factor C, and matrix metalloproteinase-2-influenced survival time ( P < 0.05). In Cox multivariate analysis, all the aforementioned factors were found to be independent prognostic factors except pathologic grade. Vascular endothelial growth factor C was a new target to assess the prognosis of ovarian cancer. The expression of vascular endothelial growth factor C in ovarian cancer was related to matrix metalloproteinase-2 and E-cadherin. [ABSTRACT FROM AUTHOR]

The article presents a study on c-MET overexpression and its relationship with clinicopathological variables in gastric cancer in the Iranian population. The study used representative paraffin blocks of 130 gastric carcinoma patients in university hospitals in Tehran, Iran, which were collected in tissue microarray and c-MET expression. The result showed that the c-MET oncogene protein is related to clinicopathological characteristics such as tumor type, depth of invasion and neural invasion.

Background: [ABSTRACT FROM AUTHOR]

Background:The potential prognostic value of several commonly investigated immunohistochemical markers in resected pancreatic cancer is variably reported. The objective of this study was to conduct a systematic review of literature evaluating p53, p16, smad4, bcl-2, bax, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression as prognostic factors in resected pancreatic adenocarcinoma and to conduct a subsequent meta-analysis to quantify the overall prognostic effect.Methods:Relevant literature was identified using Medline, EMBASE and ISI Web of Science. The primary end point was overall survival assessed on univariate analysis. Only studies analysing resected pancreatic adenocarcinoma were eligible for inclusion and the summary loge hazard ratio (logHR) and variance were pooled using an inverse variance approach. Evidence of heterogeneity was evaluated using the χ2 test for heterogeneity and its impact on the meta-analysis was assessed by the I2 statisic. Hazard ratios greater than one reflect adverse survival associated with positive immunostaining.Results:Vascular endothelial growth factor emerged as the most potentially informative prognostic marker (11 eligible studies, n=767, HR=1.51 (95% confidence interval, CI=1.18-1.92)) with no evidence of any significant publication bias (Egger's test, P=0.269). Bcl-2 (5 eligible studies, n=314, HR=0.51 (95% CI=0.38-0.68)), bax (5 studies, n=274, HR=0.63 (95% CI=0.48-0.83)) and p16 (3 studies, n=229, HR=0.63 (95% CI=0.43-0.92)) also returned significant overall survival differences, but in smaller patient series due to a lack of evaluable literature. Neither p53 (17 studies, n=925, HR=1.22 (95% CI=0.96-1.56)), smad4 (5 studies, n=540, HR=0.88 (95% CI=0.61-1.27)) nor EGFR (4 studies, n=250, HR=1.35 (95% CI=0.80-2.27)) was found to represent significant prognostic factors when analysing the pooled patient data. There was evidence of significant heterogeneity in four of the seven study groups.Conclusion:These results support the case for immunohistochemical expression of VEGF representing a significant and reproducible marker of adverse prognosis in resected pancreatic cancer. [ABSTRACT FROM AUTHOR]

NF-κB is constitutively activated in most human pancreatic adenocarcinoma, which is a deadly malignancy with a 5-year survival rate of about 5%. In this work, we investigate whether microRNAs (miRNAs) contribute to NF-κB activation in pancreatic cancer. We demonstrate that miR-301a down-regulates NF-κB-repressing factor (Nkrf) and elevates NF-κB activation. As NF-κB promotes the transcription of miR-301a, our results support a positive feedback loop as a mechanism for persistent NF-κB activation, in which miR-301a represses Nkrf to elevate NF-κB activity, which in turn promotes miR-301a transcription. Nkrf was found down-regulated and miR-301a up-regulated in human pancreatic adenocarcinoma tissues. Moreover, miR-301a inhibition or Nkrf up-regulation in pancreatic cancer cells led to reduced NF-κB target gene expression and attenuated xenograft tumour growth, indicating that miR-301a overexpression contributes to NF-κB activation. Revealing this novel mechanism of NF-κB activation by an miRNA offers new avenues for therapeutic interventions against pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Our study aims to evaluate the anti-growth effects of recombinant immunotoxin (IT) anti-c-Met/ PE38KDEL on gastric cancer cells, and its mechnisms. Methods: Gastric cancer cells were treated with increasing doses of IT and c-Met protein was quantified by Western blotting. Cell proliferation was determined by Cell Counting Kit-8 assay (CCK). [3H]-leucine incorporation assay was used to evaluate IT inhibition of protein synthesis. Cell apoptosis was quantified by flow cytometry. Caspase activities were measured using colorimetric protease assays. Results: Cell growth and protein synthesis of the gastric cancer cell lines were suppressed by IT in a dose- and time-dependent manner. IT also induced apoptosis in a dose-dependent manner. The apoptosis rates of gastric cancer cell lines MKN-45 and SGC7901 were 19.19% and 27.37%, respectively when treated with 50 ng/ml of IT. There were significant increase ofcaspase-3 activity at 24 hr of IT treatment (100 ng/ml) (P < 0.01) in these gastric cancer cell lines. Conclusions: IT anti-c-Met/PE38KDEL has anti-growth effects on the gastric cancer cell lines in vitro, and it provides an experimental basis for c-Met-targeted therapy towards in vivo testing. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the roles played by vitreous-derived cells in the pathogenesis of vitreoretinal vascular diseases. Methods: The vitreous was removed from porcine eyes and small pieces were cultured from which vitreous-derived cells were isolated. Polymerase chain reaction and ELISA were performed to determine the expression of vascular endothelial growth factor (VEGF) and interleukin 6 (IL-6) at the mRNA and protein levels, respectively. The viability of human retinal endothelial cells (HRECs) exposed to vitreous-derived cells was assessed by MTT assay. Results: Expression of the mRNA and protein of VEGF and IL-6 was increased by exposing the porcine vitreous-derived cells (PVDCs) to interleukin-1α (IL-1α), interleukin-1β (IL-1β) and tumour necrosis factor α (TNFα), but not to VEGF or IL-6. The percentage of living human vascular endothelial cells was increased by including VEGF and IL-6 in the culture media. The viability of HRECs was affected by co-culturing them with PVDCs that had been exposed to IL-1α, IL-1β, IL-6, TNFα and VEGF. Conclusions: Porcine vitreous-derived cells are stimulated by IL-1α, IL-1β and TNFα, and produce VEGF and IL-6, which then enhance the proliferation of vascular endothelial cells. This network, including the cytokines and different types of cells, may contribute to the pathogenesis of proliferative vitreoretinal diseases. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor receptors (VEGFRs) are mainly expressed by endothelial cells, but they are also expressed by some cancer cells, including pancreatic cancer. The objective of this study was to evaluate the significance of VEGFRs expression in pancreatic cancer cells. A total of 107 primary pancreatic tumors were stained with antibodies against VEGFR-1, VEGFR-2, phospho-VEGFR-2 (pVEGFR-2), VEGFR-3, VEGF-A, VEGF-C, and VEGF-D. VEGFR-2 and pVEGFR-2 expression were positive in 74 (69%) and 54 (50%) of 107 pancreatic cancers. There was a significant correlation ( P < 0.001) between VEGFR-2 expression and pVEGFR-2 expression. pVEGFR-2 was significantly associated with invasion to the anterior capsule of pancreas ( P = 0.032) and arterial invasion ( P = 0.012). In contrast, VEGFR-1 and VEGFR-3 expression was only observed in 13 (12%) and 15 (14%) of 107 pancreatic cancers, and was not associated with any clinicopathological features. The prognosis of pVEGFR-2 positive patients with stage IIA tumors was significantly ( P = 0.0441) poorer than that of pVEGFR-2-negative patients. VEGF-A, VEGF-C, and VEGF-D expression was positive in 42 (39%), 82 (77%), and 39 (36%) of 107 pancreatic cancers, respectively. The prognosis for VEGF-A-positive patients was significantly ( P = 0.0425) poor, but not for VEGF-C-positive and VEGF-D-positive patients. A multivariate analysis indicated pVEGFR-2 expression to be an independent prognostic factor, but not VEGF-A. These findings suggested that VEGFR-2 signaling might therefore be associated with the prognosis of patients with pancreatic cancer. The expression of pVEGFR-2 might be a novel predictive prognostic marker for patients with pancreatic cancers, especially at clinical stage IIA. ( Cancer Sci 2010) [ABSTRACT FROM AUTHOR]

Background RNA interference is a powerful method for the knockdown of pathologically relevant genes. The in vivo delivery of siRNAs, preferably through systemic, nonviral administration, poses the major challenge in the therapeutic application of RNAi. Small interfering RNA (siRNA) complexation with polyethylenimines (PEI) may represent a promising strategy for siRNA-based therapies and, recently, the novel branched PEI F25-LMW has been introduced in vitro. Vascular endothelial growth factor (VEGF) is frequently overexpressed in tumors and promotes tumor growth, angiogenesis and metastasis and thus represents an attractive target gene in tumor therapy. Methods In subcutaneous tumor xenograft mouse models, we established the therapeutic efficacy and safety of PEI F25-LMW/siRNA-mediated knockdown of VEGF. In biodistribution and siRNA quantification studies, we optimized administration strategies and, employing chemically modified siRNAs, compared the anti-tumorigenic efficacies of: (i) PEI/siRNA-mediated VEGF targeting; (ii) treatment with the monoclonal anti-VEGF antibody Bevacizumab (Avastin®); and (iii) a combination of both. Results Efficient siRNA delivery is observed upon systemic administration, with the biodistribution being dependent on the mode of injection. Toxicity studies reveal no hepatotoxicity, proinflammatory cytokine induction or other side-effects of PEI F25-LMW/siRNA complexes or polyethylenimine, and tumor analyses show efficient VEGF knockdown upon siRNA delivery, leading to reduced tumor cell proliferation and angiogenesis. The determination of anti-tumor effects reveals that, in pancreas carcinoma xenografts, single treatment with PEI/siRNA complexes or Bevacizumab is already highly efficacious, whereas, in prostate carcinoma, synergistic effects of both treatments are observed. Conclusions PEI F25-LMW/siRNA complexes, which can be stored frozen as opposed to many other carriers, represent an efficient, safe and promising avenue in anti-tumor therapy, and PEI/siRNA-mediated, therapeutic VEGF knockdown exerts anti-tumor effects. Copyright © 2010 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: The elevated expression of vascular endothelial growth factor C (VEGF-C) is correlated with clinical cervical cancer metastasis and patient survival, which is interpreted by VEGF-C functions to stimulate angiogenesis and lymphatic genesis. However, the direct impact of VEGF-C on cervical cancer cell motility remains largely unknown. Methods: In this study, we investigated the effects of VEGF-C on actin cytoskeleton remodeling and on cervical cancer cell migration and invasion and how the actin-regulatory protein, moesin regulated these effects through RhoA/ROCK- 2 signaling pathway. Results: On cervical carcinoma cell line SiHa cells, exposure of VEGF-C triggered remodeling of the actin cytoskeleton and the formation of membrane ruffles, which was required for cell movement. VEGF-C significantly enhanced SiHa cells horizontal migration and three-dimensional invasion into matrices. These actions were dependent on increased expression and phosphorylation of the actin-regulatory protein moesin and specific moesin siRNA severely impaired VEGF-C stimulated-cell migration. The extracellular small GTPase RhoA/ROCK-2 cascade mediated the increased moesin expression and phosphorylation, which was discovered by the use of Y-27632, a specific inhibitor of Rho kinase and by transfected constitutively active, dominant-negative RhoA as well as ROCK-2 SiRNA. Furthermore, in the surgical cervical specimen from the patients with FIGO stage at cervical intra-epithelial neoplasia and I-II cervical squamous cell carcinoma, the expression levels of moesin were found to be significantly correlated with tumor malignancy and metastasis. Conclusions: These results implied that VEGF-C promoted cervical cancer metastasis by upregulation and activation of moesin protein through RhoA/ROCK-2 pathway. Our findings offer new insight into the role of VEGF-C on cervical cancer progression and may provide potential targets for cervical cancer therapy. [ABSTRACT FROM AUTHOR]

Copyright of European Surgery: ACA Acta Chirurgica Austriaca is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The Notch signaling pathway is crucial in both adipogenesis and tumor development. It serves a vital role in the development and stability of blood vessels and may be involved in the proliferative phase of infantile hemangiomas, which express various related receptors. Therefore, it was hypothesized that the Notch signaling pathway inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a γ-secretase inhibitor, might help accelerate the regression of infantile hemangiomas. The present in vitro study evaluated whether inhibition of the Notch signaling pathway using DAPT could alter adipogenesis in hemangioma stem cells (HemSCs) derived from infantile hemangioma (IH) specimens. A total of 20 infants (age, ≤6 months) with hemangiomas who had not yet received any treatment were selected, and their discarded hemangioma tissues were obtained. HemSCs were isolated from the fresh, sterile IH specimens and treated with DAPT. Reverse transcription-quantitative PCR and western blotting were used to demonstrate the inhibition of the Notch signaling pathway by DAPT. A proliferation assay (Cell Counting Kit-8), oil red O staining, flow cytometry and a transwell assay were used to detect proliferation, adipogenesis, apoptosis and migration of HemSCs. Treatment with DAPT upregulated the expression levels of CCAAT/enhancer-binding protein (C/EBP) α, C/EBPβ, peroxisome proliferator-activated receptor-γ, adiponectin and insulin-like growth factor 1, and promoted the proliferation, apoptosis, migration and lipid accumulation in HemSCs in vitro. Targeting the Notch signaling pathway using DAPT may potentially accelerate the regression of infantile hemangiomas. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer responsible for over 20% of deaths due to gastrointestinal malignancies. PDAC is usually diagnosed at an advanced stage which, in part, helps to explain its high resistance to chemotherapy and radiotherapy. In addition, the cancer cells in PDAC have a high propensity to metastasize and to aberrantly express several key regulators of angiogenesis and invasion. Chemotherapy has only provided a modest impact on mean survival and often induces side effects. Targeting angiogenesis alone or in combination with other modalities should be investigated to determine if it may provide for increased survival. This review summarizes the alterations in PDAC that play a critical role in angiogenesis and provides an overview of current and therapeutic strategies that may be useful for targeting angiogenesis in this malignancy. [ABSTRACT FROM AUTHOR]

Functional inactivation of the tumour suppressor protein p16(INK4a) constitutes a key event in the multistep process of pancreatic ductal cell transformation. However, the significance of p16 inactivation for complex and tissue-specific aspects of pancreatic cancer progression, such as angiogenesis and metastasis, is less understood. Here, we inducibly re-expressed p16 in vivo in an orthotopic model of pancreatic cancer and examined the impact on these clinically relevant aspects of pancreatic cancer tumour biology. Consistent with previous work in subcutaneous xenograft models, we found p16 capable of reducing primary tumour growth. In addition, p16 restitution resulted in a marked reduction of tumour angiogenesis, largely accounted for by a p16-dependent inhibition of lymphangiogenesis. In excellent agreement with the antilymphangiogenic effect, re-expression of p16 almost completely prevented lymph node metastases of MiaPaca-2 pancreatic tumours. To our knowledge, this is the first report that experimentally links the tumour suppressor p16 to the process of lymphangiogenesis. [ABSTRACT FROM AUTHOR]

Aims: The clinical significance of chemokine receptor CCR7 expression in pancreatic ductal cancer was investigated. Methods: Immunohistochemical staining of 89 pancreatic cancers treated macroscopically with curative resection without hematogenous metastases or peritoneal dissemination were analyzed in association with clinicopathological data. Results: The positivity of CCR7 in pancreatic cancer was 32.6% (29/89). A significant correlation was detected between CCR7-positive expression and lymph node metastasis. Patients with CCR7-positive tumors had significantly shorter survival times than those with CCR7-negative tumors (median, 12.8 vs. 21.9 months, respectively; p = 0.0039). CCR7 expression was an independent prognostic factor (hazard ratio, 1.949; p = 0.0364) by multivariate survival analysis; however, it was not an indicator for any particular site of recurrence. Conclusion: The survival impact of CCR7 expression on resectable pancreatic cancer may be associated with lymphatic spread. The results from the present study should foster further investigation of treatments using an inhibitor for the CCR7 protein to improve the survival of pancreatic cancer. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article looks at the role played by interleukin-6 (IL-6) and its receptor in cancer. IL-6 is a pleiotropic cytokine is said to be involved in the physiology of virtually every organ system and its elevated levels are strongly associated with several phenotypic features of cancers. It cites that therapeutic targeting of IL-6 and its receptor in cancer may be beneficial in the treatment of the disease. It discusses several studies on the association between high levels of IL-6 and breast cancer.

The article discusses on the molecular mechanisms of pancreatic cancer and its target of treatment. It was said that amidst advances in surgery and oncological therapy regimens, pancreatic cancer stays to encounter diagnostic and therapeutic problems. The aggressive nature of the disease and hard clinical manifestation raise the demands of more effective treatment methods since uncontrolled cell division resulted to inflammation and lengthens changes in the cellular signaling pathways.

Papillary thyroid cancer (PTC) is the most frequently occurring human thyroid cancer with good prognosis following appropriate treatment. Lymph node (LN) metastases are the main way through which PTC spread cancer cells. The mechanisms underlying PTC with local invasion, LN metastases and distant metastases are not well investigated. Tumor secrete cytokines, such as vascular endothelial growth factor (VEGF)-C and -D bind to VEGF receptors on lymphatic endothelial cells and induce proliferation (budding) from nearby lymphatic capillaries and growth of new lymphatic capillaries. About one-third of patients can be diagnosed at the time of surgical findings. Different image studies, such as ultrasonography with fine needle aspiration cytology, scintigraphic localization and positron emission tomography were reported to detect LN metastases. Important factors in predicting LN metastases are vascular invasion, male gender, absence of tumor capsule, and perithyroid involvement. Tumor recurrence in LN after primary treatment of PTC had an independent and highly significant negative effect on survival in patients over 45 year-old. Recombinant adeno-associated virus-mediated gene transfer of sVEGFR3-Fc is a feasible therapeutic scheme for blocking lymphogenous metastasis. In conclusion, aggressive surgical procedures performed by experienced surgeons or postoperative radioactive iodine therapy to minimize local recurrence of LN for PTC patients with high risk. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer remains one of the most lethal of all solid tumours of the gastrointestinal tract. It is characterized by late diagnosis, aggressive local invasion, early metastasis and resistance to chemoradiotherapy. Increasing knowledge regarding the molecular events behind the growth and invasion of pancreatic cancer may lead to new targets for intervention. Methods: A search of Pubmed and Medline databases was undertaken using the keywords pancreatic cancer, gastrointestinal cancer, hypoxia, angiogenesis and anti-angiogenesis therapy. Results: Hypoxia is the driving force behind angiogenesis in pancreatic cancers. Research into angiogenesis has shown many different sites that can be targeted by agents such as tyrosine kinase inhibitors. Conclusion: Anti-angiogenic therapy could be an important adjunct to conventional chemotherapy treatment of gastrointestinal neoplasia. [ABSTRACT FROM AUTHOR]

A positive association between vascular endothelial growth factor-C (VEGF-C) expression and lymph node metastasis has been reported in several cancers. However, the relationship of VEGF-C and lymph node metastasis in some cancers, including non-small cell lung cancer (NSCLC), is controversial. We evaluated the VEGF-C and vascular endothelial growth factor receptor-3 (VEGFR-3) expression in NSCLC samples from patients who had undergone surgery between 1998 and 2002 using real-time quantitative RT–PCR and immunohistochemical staining. We failed to find a positive association between VEGF-C and VEGFR-3 mRNA expression and lymph node metastasis in NSCLC. An immunohistological study demonstrated that VEGF-C was expressed not only in cancer cells, but also in macrophages in NSCLC, and that VEGFR-3 was expressed in cancer cells, macrophages, type II pneumocytes and lymph vessels. The VEGF-C/VEGFR-3 ratio of the node-positive group was significantly higher than that of the node-negative group. Immunohistochemical staining showed that VEGFR-3 was mainly expressed in cancer cells. The immunoreactivity of VEGF-C and VEGFR-3 was roughly correlated to the mRNA levels of VEGF-C and VEGFR-3 in real-time PCR. VEGF-C mRNA alone has no positive association with lymph node metastasis in NSCLC. The VEGF-C/VEGFR-3 ratio was positively associated with lymph node metastasis in NSCLC. This suggests that VEGF-C promotes lymph node metastasis while being influenced by the strength of the VEGF-C autocrine loop, and the VEGF-C/VEGFR-3 ratio can be a useful predictor of lymph node metastasis in NSCLC.British Journal of Cancer (2006) 95, 75–79. doi:10.1038/sj.bjc.6603209 www.bjcancer.comPublished online 6 June 2006 [ABSTRACT FROM AUTHOR]

Invasion to lymphatic vessels and metastasis to lymph nodes are frequent complications in invasive micropapillary carcinoma (IMPC) of human breast cancer. Vascular endothelial growth factor-C (VEGF-C) and its receptor, VEGFR-3 have been implicated as the important factors in the formation of lymphatic vessels and recent experimental evidence strongly suggests that lymphangiogenesis in tumor promotes lymphatic metastasis. To clarify the mechanism of its occurrence, the expression of VEGF-C, VEGFR-3 and lymphatic vessel density (LVD) was examined in 40 cases of IMPC (pure and mixed type) and in 40 cases of pseudo-IMPC. Cytoplasmic expression of VEGF-C and VEGFR-3 were more frequent in tumor cells of IMPC compared to those of pseudo-IMPC. A significant positive correlation was found between the expression of VEGF-C and VEGFR-3 in both IMPC and pseudo-IMPC. The expression of VEGF-C was also significantly associated with higher peritumoral LVD, lymphatic invasion and number of lymph node metastasis in IMPC. These findings suggest that VEGF-C promotes the proliferation of peritumoral lymphatic vessels and that lymphatic invasion and metastasis to lymph nodes are frequently induced in IMPC of breast. [ABSTRACT FROM AUTHOR]

OBJECTIVE To investigate the relationship between lymphatic vessel density and lymph node metastasis of invasive micropapillary carcinoma (IMPC) of the breast. METHODS The immunohistochemical study for vascular endothelial growth factor-c (VEGF-C), VEGF Receptor-3 (VEGFR-3) and lymphatic vessel density of 51 cases of IMPC were performed, and lymph node metastases were examined by microscopic analysis of these cases. RESULTS In IMPC, VEGF-C was expressed in the cytoplasm and/or on the membrane of the tumor cells, and the expression of VEGF-C showed a positive correlation with lymph node metastasis ( P<0.01). Lymphatic vessel density was determined by the number of micro-lymphatic vessels with VEGFR-3 positive staining. Lymphatic vessel density was positively correlated with VEGF-C expression ( P<0.01) and lymph node metastasis ( P<0.01). The percentage of IMPC in the tumor was not associated with the incidence of lymph node metastasis. The metastatic foci in lymph nodes were either pure or predominant micropapillary carcinoma. CONCLUSION The results suggested that VEGF-C overexpression stimulated tumor lymphangiogenesis, and the increased lymphatic vessel density may be the key factor that influenced lymph node metastasis of IMPC. [ABSTRACT FROM AUTHOR]

Copyright of European Surgery: ACA Acta Chirurgica Austriaca is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Stacker SA, Williams RA, Achen MG. Lymphangiogenic growth factors as markers of tumor metastasis. APMIS 2004;112:539–49.Understanding the complex process of tumor metastasis is a problem which has challenged both clinician and scientist for well over 100 years. Defining molecular markers which reflect the metastatic potential of a tumor has also proved elusive. Recently, members of the vascular endothelial growth factor (VEGF) family of glycoproteins have been demonstrated to be potent mediators of both blood vessel and lymphatic vessel formation in the context of tumor biology. Experimental studies in animal models combined with extensive clinicopathological data provide a compelling case indicating that members of the VEGF family play a key role in the formation of metastases in a broad range of solid tumors. The question of whether VEGF signaling pathways can now serve as therapeutic targets alone, or in combination with other forms of anti-cancer agents, needs to be addressed. [ABSTRACT FROM AUTHOR]

Purpose: Dendritic cells (DCs) play an important role in the host’s immunosurveillance against cancer. It has been shown that the function of DCs is impaired and their population decreased in a cancer-bearing host. In the present study, we investigated the mechanism of down-regulation of DCs in a cancer-bearing host. Methods: We evaluated the relationship between DC infiltration and production of vascular endothelial growth factor (VEGF) in carcinoma tissue by immunohistochemistry. Furthermore, functional and phenotypical alterations of DCs were evaluated when monocyte-derived, mature DCs were treated with VEGF in vitro. Monocyte-derived DCs were generated in a culture of monocyte with interleukin 4 (IL-4) and granulocyte-macrophage colony-stimulating factor, and the maturation of DCs was induced by either lipopolysaccharide (LPS) or a proinflammatory cytokine cocktail: tumor-necrosis factor α, prostaglandin E2, IL-6, and IL-1β. Results: A significant inverse correlation was found between the density of DCs and the quantity of VEGF production in gastric carcinoma tissue (r=-0.39, p<0.05). In LPS-induced maturation, the ability of mature DCs to stimulate allogenic T cells and produce IL-12 (p70 heterodimer) was suppressed by the addition of VEGF in a dose-dependent manner. A lesser expression of costimulatory molecules (CD80 and CD86) was seen in DCs treated with exogenous VEGF than in DCs not treated with VEGF. The population of dead DCs (early and late apoptosis) treated with VEGF increased more than that without VEGF treatment, using the annexin V and propidium iodide evaluation in DCs matured by LPS. In contrast, in DCs matured by the proinflammatory cytokine cocktail, the down-regulation of costimulatory molecules and induction of DC apoptosis was not seen. Conclusions: These findings show that the inhibition of DC maturation by VEGF differs depending on the maturation status of the DCs. [ABSTRACT FROM AUTHOR]

Purpose. Vascular endothelial growth factor C (VEGF-C) is known to be associated with the development of the lymphatic vessel system. Recently, VEGF-C is thought to be correlated with lymph node metastasis in some malignant tumors. In this study, we investigated the correlation between VEGF-C expression and lymph node metastasis in early carcinoma of the colon and rectum. Methods. Two hundred and twenty-one endoscopically biopsied specimens from patients with T1 colorectal carcinoma prior to operation were investigated by an immunohistochemical study. Results. VEGF-C expression was more frequently observed in the tumors with nodal metastasis than in those without metastasis. Moreover, a multivariate analysis indicated that VEGF-C expression is an independent predictor of lymph node metastasis. Conclusion. VEGF-C staining using endoscopically biopsied specimens prior to operation could be of use in the prediction of lymph node metastasis and in preoperative selection of treatment in patients with T1 colorectal carcinoma. [ABSTRACT FROM AUTHOR]

The lymphatic system transports interstitial fluid and macromolecules from tissues back to the blood circulation, and plays an important role in the immune response by directing the traffic of lymphocytes and antigen-presenting cells. The lymphatic system also constitutes one of the most important pathways of tumor dissemination. In many human cancers, increased expression of vascular endothelial growth factor-C (VEGF-C) is correlated with regional lymph node metastases. Experimental studies using transgenic mice overexpressing VEGF-C or xenotransplantation of VEGF-C-expressing tumor cells into immunodeficient mice have demonstrated a role for VEGF-C in tumor lymphangiogenesis and the subsequent formation of lymph node metastases. However, there is at present little evidence for lymphangiogenesis in human tumors and the relative importance of preexisting vs. newly formed lymphatics for metastasis in humans remains to be determined. Nonetheless, the striking correlation between the levels of VEGF-C in primary human tumors and lymph node metastases predicts its importance in cancer spread. Aside from promoting lymphangiogenesis, VEGF-C may also activate lymphatics to promote tumor cell chemotaxis, lymphatic intravasation and hence tumor cell dissemination. [ABSTRACT FROM AUTHOR]

Vascular endothelial growth factor-C (VEGF-C) and VEGF-D are members of the VEGF family of cytokines and have angiogenic and lymphangiogenic actions. In gastric adenocarcinoma, VEGF-C mRNA and tissue protein expression correlate with lymphatic invasion, lymph node metastasis and in some reports, venous invasion and reduced 5-year survival. Patients with gastric adenocarcinomas containing high levels of VEGF-C expression have significantly reduced 5-year survival rates, and VEGF-C expression is an independent prognostic risk factor for death. The role of VEGF-C in oesophageal squamous and colorectal cancer and VEGF-D in colorectal cancer is not clear, with conflicting reports in the published literature. In order to exploit potential therapeutic applications, further research is necessary to define the precise roles of these cytokines in health and disease. [ABSTRACT FROM AUTHOR]

Background. Gastric cancers producing α-fetoprotein (AFP) are known to have a poor prognosis and to show a high incidence of liver metastasis. Vascular endothelial growth factor (VEGF) and its isoform VEGF-C are reported to be associated with tumor progression through an angiogenic or lymphangiogenic function. In the present study, to clarify the cellular characteristics of AFP-producing gastric cancers, the expression of VEGF and that of VEGF-C in AFP-producing gastric cancer was compared with their expression in gastric cancers that do not produce AFP. Methods. Twenty-six patients with AFP-producing gastric cancers [AFP(+)] and 26 patients with stage-matched gastric cancers that did not produce AFP [AFP(-)] were evaluated for VEGF and VEGF-C expression and vessel density, using immunohistochemical analysis. Results. The survival rate of the AFP(+) group was significantly worse than that of the stage-matched AFP(-) group (P < 0.05). The frequency of VEGF-C expression was significantly higher in the AFP(+) group than in the AFP(-) group (P < 0.01). There was no significant difference in VEGF expression between the AFP(+) and AFP(+) groups. The microvessel density was higher in the AFP(+) group than in the AFP(-) group (P < 0.05). Conclusions. A higher expression of VEGF-C might be one explanation for the poorer prognosis of AFP-producing gastric cancers. [ABSTRACT FROM AUTHOR]

Early metastasis to lymph nodes is a frequent complication in human breast cancer. However, the extent to which this depends on lymphangiogenesis or on invasion of existing lymph vessels remains controversial. Although proliferating intratumoural lymphatics that promote nodal metastasis have been demonstrated in experimental breast tumours overexpressing VEGF-C, it has yet to be determined whether the same phenomena occur in spontaneous human breast cancers. To address this important issue, the present study investigated the lymphatics in primary human breast carcinoma (75 cases of invasive ductal and lobular breast cancer) by quantitative immunohistochemical staining for the lymphatic endothelial hyaluronan receptor LYVE-1, the blood vascular marker CD34, and the nuclear proliferation marker pKi67. None of the breast carcinomas was found to contain dividing lymph vessels, even in areas of active haemangiogenesis. Furthermore, the majority of non-dividing lymph vessels were confined to the tumour periphery where their incidence was low and unrelated to tumour size, grade or nodal status; rather, their density was inversely correlated with tumour aggressiveness as assessed by macrophage density (p = 0.009), and blood microvessel density (p = 0.05, Spearman Rank), as well as with distance from the tumour edge. Finally, a proportion of the peritumoural lymphatics contained tumour emboli associated with hyaluronan, indicating a possible role for LYVE-1/hyaluronan interactions in lymphatic invasion or metastasis. These results suggest that naturally occurring breast carcinomas invade and destroy lymph vessels rather than promoting their proliferation; that breast tumour lymphangiogenesis may not always occur at physiological VEGF-C levels; and that nodal metastasis can proceed via pre-existing lymphatics. Copyright © 2003 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease. Although the specific mechanisms that dictate its biological aggressiveness are not clearly established, it is characterized by a variety of molecular alterations as well as by the overexpression of mitogenic and angiogenic growth factors and their receptors. PDACs also express high levels of vascular endothelial growth factor (VEGF). Recent studies indicate that suppression of VEGF expression attenuates pancreatic cancer cell tumorigenicity in a nude mouse model, and that VEGF can exert direct mitogenic effects on some pancreatic cancer cells. These findings suggest that cancer cell derived VEGF promotes pancreatic cancer growth in vivo via a paracrine angiogenic pathway and an autocrine mitogenic pathway, and provide novel opportunities for therapeutic intervention in this deadly disease. [ABSTRACT FROM AUTHOR]

Discusses the impact of lymphatic vessels on animal and human tumor. Invasion of peritumor lymphatics; Consideration of poor prognostic factor for patients with tumor; Molecule mechanisms of lymphagiogenesis.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with poor prognosis. Peroxisome proliferator-activated receptor γ (PPARγ) is involved in the development of various tumor types. However, its role in hepatocellular carcinoma (HCC) remains unclear. Multiple databases including The Cancer Genome Atlas, Gene Expression Omnibus and Kaplan-Meier plotter were used for bioinformatics analysis of the PPARγ gene or protein. Immunohistochemical labeling of tumor and adjacent normal tissues obtained from 125 patients with HCC was performed to analyze the relationship between PPARγ expression and overall survival (OS) rate. PPARγ was evaluated using functional enrichment analyses and Lasso regression was used to conduct a dimensionality reduction analysis of 43 clinical factors for HCC. An OS prognostic nomogram was then established using seven independent risk factors screened via Lasso regression. PPARγ expression in HCC tumor tissues was higher compared with that in normal liver tissues, and its high expression was associated with poor prognosis, as indicated by bioinformatics analysis. However, opposite results were obtained using the clinical specimens. Functional enrichment analysis indicated that PPARγ was enriched in the 'fatty acid metabolism' pathway. Lasso regression identified seven clinical factors associated with prognosis, including Tumor-Node-Metastasis stage, grade, vascular invasion, α fetoprotein, carbohydrate antigen 199, γ-glutamyl transpeptidase and the PPARγ protein. These seven clinical factors were to construct an OS prognostic nomogram. Overall, PPARγ was highly expressed in the livers of patients with HCC and can be included in an OS prognostic nomogram. However, the factors underlying the differential association of PPARγ expression with HCC prognosis in different datasets should be further investigated. [ABSTRACT FROM AUTHOR]

Sb2S3 quantum dot is prepared as the optical absorber on the ZnO nanorod films to fabricate high-efficiency quantum dot–sensitized solar cells. The band energy of the solar cells is modulated by the different concentration of Cu-doping. Meanwhile, the optical absorption spectra and photoluminescence spectra of different ZnO/Sb2S3 photoelectrodes are investigated, which had exhibited the enhancement on optical absorption property and charge separation property by Cu-doping process. The charge transfer properties of the solar cells had also been enhanced by the modulation on band energy structure by different Cu-doping concentration. With the relatively larger optical absorption edge, the 0.3 mM Cu–doped ZnO/Sb2S3 quantum dot–sensitized solar cells have exhibited optimal band energy structure for charge transfer, which can obtain higher current density to enhance the photovoltaic power conversion efficiency from 2.55 to 3.14%. [ABSTRACT FROM AUTHOR]

Background: Altered glycosylation associated with hepatocellular carcinoma (HCC) is well documented. However, few reports have investigated the association between dedifferentiation and glycosylation. Therefore, the aim of this study was to analyze glycosylation associated with dedifferentiation of HCC within the same nodule and to investigate glycosyltransferase related to the glycosylation.Methods: We analyzed resected HCC specimens (n = 50) using lectin microarray to comprehensively and sensitively analyze glycan profiles, and identify changes to glycosylation between well- and moderately-differentiated components within the same nodule. Moreover, we performed immunohistochemical staining of mannosyl(α-1,3-)-glycoprotein β-1,2-N-acetylglucosaminyltransferase (MGAT1), which is an essential glycosyltransferase that converts high-mannose glycans to complex- or hybrid-type N-glycans.Results: Four lectins from Narcissus pseudonarcissus agglutinin (NPA), Concanavalin A, Galanthus nivalis agglutinin, and Calystegia sepium agglutinin were significantly elevated in moderately-differentiated components of HCC compared with well-differentiated components, and all lectins showed binding specificity to high-mannose glycans. Therefore, these structures were represented to a greater extent in moderately-differentiated components than in well-differentiated ones. Immunohistochemical staining revealed significantly increased NPA expression and decreased MGAT1 expression in moderately-differentiated components. Low MGAT1 expression in moderately-differentiated components of tumors was associated with intrahepatic metastasis and had tendency for poor prognosis.Conclusion: Dedifferentiation of well-differentiated HCC is associated with an increase in high-mannose glycans. MGAT1 may play a role in the dedifferentiation of HCC. [ABSTRACT FROM AUTHOR]