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Expression patterns of maspin, vascular endothelial growth factor A (VEGFA), VEGFC, and VEGFD in ovarian carcinomas
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The vascular endothelial growth factor (VEGF) family, including VEGFA, VEGFC, and VEGFD, plays an essential role in the angiogenesis of both pathologic and nonpathologic conditions. Maspin belongs to the serpin superfamily and has been identified as a tumor suppressor because it inhibits motility, invasion, and angiogenesis. Few studies have compar...
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Context 2
... Table 1). Expression levels of VEGFA, VEGFC, and VEGFD were lower in mucinous carcinoma than in the other tumor types, but the difference was not statistically significant ( Table 2). ...
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Citations
... Lin et al. [17] reported that maspin expression in ovarian cancer was related to high grade and high MVD. Similarly, Bolat et al. [28] showed that maspin positivity in ovarian carcinoma was associated with the expression of vascular endothelial growth factors (VEGFA, VEGFC, and VEGFD). ...
Maspin (Mammary serine protease inhibitor) is a tumor suppressor serine. Its clinical significance and role in breast carcinoma are contradictory and inconclusive. Researches demonstrated that the function of maspin differs according to its subcellular localization. This study was conducted to investigate the expression of maspin in invasive ductal carcinoma (IDC) of the breast with special emphasis on its subcellular localization and to evaluate its prognostic role in relation to clinicopathological parameters and microvessel density (MVD) of the tumor. The expression of maspin was evaluated immunohistochemically in 45 IDC cases. The positive rate of maspin expression was 73.3%. Maspin positivity was significantly related to higher tumor grade (p value = 0.041), nodal metastasis (p value = 0.044), perineural invasion (p value = 0.047), and high CD34+MVD (p value = 0.002). Nuclear maspin was detected in 36.6% whereas cytoplasmic maspin was detected in 63.4% of maspin positive cases. A significant inverse relationship was observed between nuclear maspin and high tumor grade (p value = 0.016), and nodal metastasis (p value = 0.047). These results suggest that maspin expression has a prognostic role in breast cancer. Maspin expression is related to increased angiogenesis. Subcellular localization of maspin can strongly affect cancer prognosis. Cytoplasmic maspin relates to poor prognostic parameters whereas nuclear maspin relates to good prognostic ones.
... Along with tumor angiogenesis, VEGF functions as an autocrine and paracrine growth factor that induces the proliferation of tumor cells. A connection between VEGF levels and metastases and/or bad prognosis was found in many tumors within the body (12)(13)(14). Studies in the literature regarding VEGF and testicular tumors are lacking. ...
Background/aim:
We aimed to evaluate the importance of maspin expression in testicular tumors with germ cells, its effect on prognosis, and the relation with angiogenesis factors.
Materials and methods:
The paraffin blocks of the orchiectomy materials of 32 patients who had undergone orchiectomy due to testicular tumors were taken within the scope of the study. The specimens of the cases included in the study group were reexamined under light microscope.
Results:
While just one maspin-positive sample was found in the seminoma cases, maspin stained positively in 6 of the nonseminoma germ cell tumors (NSGCTs). No statistical difference was found between maspin and tumor stage, size, alpha fetoprotein values, vascular endothelial growth factor, Ki-67, and CD31. A statistically positive correlation was only determined between maspin and p53 (P < 0.001).
Conclusion:
Maspin protein, whose expression in some tumors is accepted as a poor prognostic factor, is also expressed in testicular tumors with germ cells. However, according to our study, it is difficult to say whether this protein is a favorable or poor prognostic factor in testicular tumors and to understand how the effect mechanism works. The positive correlation between maspin and p53 in the NSGCTs makes us think that maspin might have displayed an effect on the p53 pathway.
... The most significant upregulation was indicated for the VEGFA and VEGFD genes only in MCS cells (Figure 4a,b). A simultaneous upregulation of both genes had already been observed in de-differentiated human ovarian carcinomas [26]. Regarding Recent pathway analyses demonstrated that enhanced concentrations of plasminogen might inhibit spheroid formation [21,22]. ...
... The most significant upregulation was indicated for the VEGFA and VEGFD genes only in MCS cells (Figure 4a,b). A simultaneous upregulation of both genes had already been observed in de-differentiated human ovarian carcinomas [26]. Regarding VEGFA, not only the gene was upregulated, but also the quantities of VEGFA proteins released in the supernatant were enhanced (Figure 4e) In our system, i.e., in the presence of enhanced external VEGFA protein, the MCS-cells with enhanced simultaneous VEGFA and VEGFD mRNA expression showed a significant downregulation of the α/β-actin expression, while the AD cells kept their actin expression rates similar to the 1g-control cells. ...
Microgravity induces three-dimensional (3D) growth in numerous cell types. Despite substantial efforts to clarify the underlying mechanisms for spheroid formation, the precise molecular pathways are still not known. The principal aim of this paper is to compare static 1g-control cells with spheroid forming (MCS) and spheroid non-forming (AD) thyroid cancer cells cultured in the same flask under simulated microgravity conditions. We investigated the morphology and gene expression patterns in human follicular thyroid cancer cells (UCLA RO82-W-1 cell line) after a 24 h-exposure on the Random Positioning Machine (RPM) and focused on 3D growth signaling processes. After 24 h, spheroid formation was observed in RPM-cultures together with alterations in the F-actin cytoskeleton. qPCR indicated more changes in gene expression in MCS than in AD cells. Of the 24 genes analyzed VEGFA, VEGFD, MSN, and MMP3 were upregulated in MCS compared to 1g-controls, whereas ACTB, ACTA2, KRT8, TUBB, EZR, RDX, PRKCA, CAV1, MMP9, PAI1, CTGF, MCP1 were downregulated. A pathway analysis revealed that the upregulated genes code for proteins, which promote 3D growth (angiogenesis) and prevent excessive accumulation of extracellular proteins, while genes coding for structural proteins are downregulated. Pathways regulating the strength/rigidity of cytoskeletal proteins, the amount of extracellular proteins, and 3D growth may be involved in MCS formation.
... VEGFD was isolated as a cFos oncogene-inducible mitogen [27], and it is primarily found in skeletal muscle, heart, lung, and intestine [28]. More and more evidences proved that high VEGFD expression was related with tumor growth and metastasis [16][17][18][19][29][30][31]. In addition, there are some reports about the promotion of VEGFD on the tumor growth and metastasis of hepatocellular carcinoma [32,33]. ...
... The few patients might account for the lack of statistical significance of our results; thus, further studies on larger patient populations are needed to establish a correlation between plasma VEGFC and the disease outcome. Nonetheless, our findings are in agreement with other reports based on IHC analysis 13,35 and RT-PCR 36 that found an association between VEGFC production in tumor tissues and epithelial ovarian cancer malignancy. ...
Vascular endothelial growth factor C (VEGFC) has been reported to promote tumor progression in several tumor types, mainly through the stimulation of lymphangiogenesis and lymphatic metastasis. However, the expression and biological significance of the VEGFC/VEGF receptor (VEGFR)-3 pathway in ovarian cancer growth and dissemination are unclear, and have been investigated in this study. Soluble VEGFC was detected in the plasma and ascites of patients with ovarian carcinoma, and VEGFR3 expression was found in their tumor tissues. In human ovarian carcinoma xenograft models, high levels of soluble VEGFC in ascites and serum were detected, in association with disease progression, tumor burden, and volume of ascites. Peak VEGFC expression preceded para-aortic lymph node infiltration by HOC8 neoplastic cells. Histological detection of tumor cells in blood and lymphatic vessels indicated both hematogenous and lymphatic dissemination. Overexpression of VEGFC in the VEGFR3-positive and luciferase-expressing IGROV1 cells promoted carcinoma dissemination after orthotopic transplantation in the ovary of immunodeficient mice. In vitro, VEGFC released by the tumor cells stimulated tumor cell migration in an autocrine manner. Cediranib, an inhibitor of VEGFR1-3 and c-kit, inhibited in vivo metastasis of VEGFC-overexpressing IGROV1 and in vitro autocrine effects. These findings suggest that the VEGFC/VEGFR3 pathway acts as an enhancer of ovarian cancer progression through autocrine and paracrine mechanisms, hence offering a potential target for therapy.
... The combination of VEGFD, intratumoural lymphatics and lymphatic invasion were all prognostic factors for survival (Tam et al., 2010). VEGFC and VEGFD expression in human ovarian carcinoma (serous papillary carcinoma, endometrioid carcinoma, ovarian mucinous) was associated with high tumour grade, clinical stage, presence of ascites and lymph node metastasis (Bolat et al., 2008). Recently, experiments in mouse models of ovarian cancer have identified leaky, dysfunctional lymphatic vasculature, associated with the presence of growth factor-producing immune cells (Jeon et al., 2008) and implicating the lymphatic vasculature in the pathological onset of ascites. ...
BACKGROUND
The remodelling of the blood vasculature has been the subject of much research while rapid progress in the understanding of the factors controlling lymphangiogenesis in the ovary has only been reported more recently. The ovary undergoes cyclic remodelling throughout each menstrual/estrous cycle. This process requires significant vascular remodelling to supply each new cohort of growing follicles.METHODS
Literature searches were performed to review studies on the ovarian lymphatic vasculature that described spatial, temporal and functional data in human or animal species. The role of ovarian blood and lymphatic vasculature in the pathogenesis of ovarian disease and dysfunction was also explored.RESULTSResearch in a number of species including zebrafish, rodents and primates has described the lymphatic vasculature within the remodelling ovary, while recent research in mouse has confirmed hormonal regulation of lymphangiogenic growth factors, their receptors and also a role for the protease, ADAMTS1 in the development of the lymphatic vasculature. With a critical role in the maintenence of fluid homeostasis, the ovarian lymphatic vasculature is important for normal ovarian function and has been linked to syndromes involving ovarian fluid imbalance, including ovarian hyperstimulation syndrome and massive ovarian edema. The lymphatic vasculature has also been heavily implicated in the metastatic cancer process.CONCLUSION
The spatial and temporal regulation of the ovarian lymphatic vasculature has now been reported in a number of species and the data also implicate the ovarian lymphatic vasculature in ovarian pathologies, including cancer and those linked with use of artificial reproduction technologies.
... It has been proposed that VEGF expression is associated with the malignant behavior of ovarian cancer. Patients with high VEGF expression more frequently undergo lymph node and hepatic metastasis compared with VEGF-negative patients (14,16). In the present study, the VEGF expression level in the patients with lymph node metastasis was 85.7%, significantly higher than that in the patients without lymph node metastasis (40%; P= 0.0009) However, there was no significant difference between the patients with hepatic metastasis, which was possibly associated with the smaller number of cases of patients with hepatic metastasis. ...
The present study aimed to investigate the correlation between the expression of vascular endothelial growth factor (VEGF) and its receptors, the Flt-1 and KDR proteins, with clinical pathology and microvessel density (MVD) in ovarian cancer tissue. The protein expression levels of VEGF and its receptors, Flt-1 and KDR/Flk-1, were detected in 48 cases of ovarian cancer using the streptavidin-biotin complex (SABC) immunohistochemical method, and tumor MVD was evaluated using F8 factor (FVIII-RA). The expression of the VEGF, Flt-1 and KDR proteins was not significantly associated with the pathological type, extent of differentiation or clinical stage of ovarian cancer. However, the co-expression of VEGF and Flt-1 was markedly correlated with differentiation and clinical stage (P<0.01). The co-expression levels of VEGF and receptor Flt-1 in malignant neoplasms with lymph node metastasis was significantly higher compared with malignant neoplasms without lymph node metastasis (P<0.05). The expression level of KDR in patients with hepatic metastasis was significantly higher compared with patients without hepatic metastasis (P<0.05). The co-expression level of VEGF and KDR in patients with hepatic metastasis was significantly higher compared with patients without hepatic metastasis (P<0.05) and the Flt-1 expression level in patients with ascites <1,000 ml was significantly lower than that in patients with ascites ≥1000 ml (P<0.05). The mean MVD of VEGF- and KDR-positive patients was significantly higher compared with VEGF- and KDR-negative patients (P<0.05). The expression of VEGF and its receptors is involved in the malignant transformation of ovarian tumors, tumor progression and metastasis, as well as ascites formation and angiogenesis.
... In a recent study, over-expression of maspin, VEGFC, and VEGFD was significantly associated with unfavorable clinico-pathologic features and poor prognosis in 60 ovarian carcinoma tissues. Similar results were obtained by Sood et al. that assessed maspin expression in 104 ovarian tissue specimens [101]. ...
Maspin (mammary serine protease inhibitor), is a member of the serine protease inhibitor/non-inhibitor superfamily. Its expression is down-regulated in breast, prostate, gastric and melanoma cancers but over-expressed in pancreatic, gallbladder, colorectal, and thyroid cancers suggesting that maspin may play different activities in different cell types. However, maspin expression seems to be correlated with better prognosis in prostate, bladder, lung, gastric, colorectal, head and neck, thyroid and melanoma cancer. In breast and ovarian cancer maspin significance is associated with its subcellular localization: nucleus maspin expression correlates with a good prognosis, whilst in pancreatic cancer it predicts a poor prognosis. Since tumor metastasis requires the detachment and invasion of tumor cells through the basement membrane and stroma, a selectively increased adhesion by the presence of maspin may contribute to the inhibition of tumor metastasis. Furthermore the different position of maspin inside the cell or its epigenetic modifications may explain the different behavior of the expression of maspin between tumors. The expression of maspin might be useful as a prognostic and possibly predictive factor for patients with particular types of cancer and data can guide physicians in selecting therapy. Its expression in circulating tumor cells especially in breast cancer, could be also useful in clinical practice along with other factors, such as age, comorbidities, blood examinations in order to select the best therapy to be carried out. Focusing on the malignancies in which maspin showed a positive prognostic value, therapeutic approaches studied so far aimed to re-activate a dormant tumor suppressor gene by designed transcription factors, to hit the system that inhibits the expression of maspin, to identify natural substances that can determine the activation and the expression of maspin or possible “molecules binds” to introduce maspin in cancer cell and gene therapy capable of up-regulating the maspin in an attempt to reduce primarily the risk of metastasis.
Further studies in these directions are necessary to better define the therapeutic implication of maspin.
... However, conflicting information exists that maspin and VEGFC are expressed in ovarian tumors with poor prognostic parameters, and seem to play a role in ovarian cancer progression and lymph node metastases. [41]. Thus, maspin might have important roles in the development of different tumor entities, including bladder cancer, and might act through crosstalk with VEGF-C. ...
Background
Overexpression of vascular endothelial growth factor-C (VEGF-C) has been found to play an important role in malignant progression of various cancer cells, in addition to lymphangiogenesis. However, the mechanisms involved are still largely unknown. Our early research has confirmed that the expression of VEGF-C in bladder cancer was markedly higher than that in normal bladder tissues. VEGF-C can also obviously promote proliferation and invasion of bladder cancer T24 cells. In the present work, we attempted to use proteomic analysis to screen out potential VEGF-C-associated proteins involved in malignant progression of the bladder cancer T24 cells.
Material/Methods
Lentivirus vector-based RNA interference (RNAi) was employed to diminish VEGF-C expression of bladder cancer T24 cells. Then we performed comparative proteome analysis to explore differentially expressed proteins in T24 cells with and without VEGF-C siRNA, by two-dimensional difference gel electrophoresis (2D-DIGE).
Results
Twenty-three proteins were identified. Some proteins (matrix metalloproteinase-9, Keratin 8, Serpin B5, Annexin A8) with significant differences were further confirmed by Western blotting.
Conclusions
The 23 potential VEGF-C-associated proteins identified in our study provide us with further insights into the mechanism of VEGF-C promoting malignant progression of bladder cancer cells.
... Formation of malignant ascites has been directly linked to VEGF expression in ovarian cancers [33]. VEGF overexpression is correlated with a shorter disease-free survival [34]. Similarly, tumor microvessel density in advanced ovarian carcinoma is associated with a poorer overall survival [35]. ...
Persistent inflammation and neovascularization are critical to cancer development. In addition to upregulation of positive control mechanisms such as overexpression of angiogenic and inflammatory factors in the cancer microenvironment, loss of otherwise normally functioning negative control mechanisms is likely to be an important attribute. Insights into the down-modulation of such negative control mechanisms remain largely unclear, however. We show here that tumor necrosis factor superfamily-15 (TNFSF15), an endogenous inhibitor of neovascularization, is a critical component of the negative control mechanism that operates in normal ovary but is missing in ovarian cancer. We show in clinical settings that TNFSF15 is present prominently in the vasculature of normal ovary but diminishes in ovarian cancer as the disease progresses. Vascular endothelial growth factor (VEGF) produced by cancer cells and monocyte chemotactic protein-1 (MCP-1) produced mainly by tumor-infiltrating macrophages and regulatory T cells effectively inhibits TNFSF15 production by endothelial cells in vitro. Using a mouse syngeneic tumor model, we demonstrate that silencing TNFSF15 by topical shRNA treatments prior to and following mouse ovarian cancer ID8 cell inoculation greatly facilitates angiogenesis and tumor growth, whereas systemic application of recombinant TNFSF15 inhibits angiogenesis and tumor growth. Our findings indicate that downregulation of TNFSF15 by cancer cells and tumor infiltrating macrophages and lymphocytes is a pre-requisite for tumor neovascularization.
