Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The angiogenic and lymphangiogenic vascular endothelial growth factor (VEGF)-D is the only member of the VEGF family that is not induced by hypoxia or by serum factors, but its induction is mediated by direct cell-cell contact. Here we show that VEGF-D mRNA is down-modulated either by beta-catenin mobilization from the cell membrane, by activation of the Wnt signaling pathway, or by transfection with the beta-catenin stable mutant. Down-modulation of beta-catenin by means of RNA interference showed an increase of VEGF-D mRNA steady state in fibroblasts. The beta-catenin-dependent decrease of VEGF-D mRNA is indirect and mainly due to reduced VEGF-D mRNA stability, as demonstrated by experiments of mRNA decay in the presence of transcription or translation inhibitors. By transient transfection of chimeric constructs carrying fusion of VEGF-D sequences under the control of the cytomegalovirus early promoter, we demonstrated that beta-catenin negative regulation is on the VEGF-D mRNA 3'-untranslated region. We mapped the VEGF-D mRNA-destabilizing element to a sequence, conserved between mouse and human VEGF-D, which contains an AU-rich element of group I. These results unveiled a new regulatory pathway for VEGF-D, which explains, at least in part, VEGF-D regulation in tumor progression.
 ...
PMID:Beta-catenin inversely regulates vascular endothelial growth factor-D mRNA stability. 1292 Jan 28

An important critical point in tumor progression is the acquisition of metastatic potential. The presence of metastases in regional lymph nodes is an indicator of poor survival. The vascular endothelial growth factor (VEGF) family of growth factors and receptors is involved in vasculogenesis and angiogenesis. Among them, VEGF-C and VEGF-D regulate the lymphatic vessels development and growth via their binding to their receptor VEGFR3. The expression of VEGF-C or VEGF-D is demonstrated in various human tumors and can be used as pronostic factors in some of them. With the aid of these molecules and the discovery of specific lymphatic markers, lymphatic endothelial cells can be isolated and lymphatic vessels can be identified within tumors. The role of lymphangiogenesis in promoting the metastatic spread of tumor cells has been studied in animal models.
 ...
PMID:[Mechanisms and role of lymphangiogenesis in cancer metastasis]. 1295

Cyclooxygenase (COX)-2, the inducible isoform of prostaglandin H synthase, has been implicated in the progression of human lung adenocarcinoma. However, the mechanism underlying COX-2's effect on tumor progression remains largely unknown. Lymphangiogenesis, the formation of new lymphatic vessels, has recently received considerable attention and become a new frontier of tumor metastasis research. Here, we study the interaction between COX-2 and the lymphangiogenic factor, vascular endothelial growth factor (VEGF)-C, in human lung cancer cells and their implication in patient outcomes. We developed an isopropyl-beta-D-thiogalactopyranoside-inducible COX-2 gene expression system in human lung adenocarcinoma CL1.0 cells. We found that VEGF-C gene expression but not VEGF-D was significantly elevated in cells overexpressing COX-2. COX-2-mediated VEGF-C up-regulation was commonly observed in a broad array of non-small cell lung cancer cell lines. The use of pharmacological inhibitors or activators and genetic inhibition by EP receptor-antisense oligonucleotides revealed that prostaglandin EP(1) receptor but not other prostaglandin receptors is involved in COX-2-mediated VEGF-C up-regulation. At the mechanistic level, we found that COX-2 expression or prostaglandin E(2) (PGE(2)) treatment could activate the HER-2/Neu tyrosine kinase receptor through the EP(1) receptor-dependent pathway and that this activation was essential for VEGF-C induction. The transactivation of HER-2/Neu by PGE(2) was inhibited by way of blocking the Src kinase signaling using the specific Src family inhibitor, PP1, or transfection with the mutant dominant negative src plasmid. Src kinase was involved in not only the HER-2/Neu transactivation but also the following VEGF-C up-regulation by PGE(2) treatment. In addition, immunohistochemical staining of 59 lung adenocarcinoma specimens showed that COX-2 level was highly correlated with VEGF-C, lymphatic vessels density, and other clinicopathological parameters. Taken together, our results provided evidence that COX-2 up-regulated VEGF-C and promotes lymphangiogenesis in human lung adenocarcinoma via the EP(1)/Src/HER-2/Neu signaling pathway.
 ...
PMID:Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. 1474 69

Extensive studies have identified reliable markers of lymphatic endothelial cells, and mechanisms and molecules that regulate development and growth of the lymphatic vessels. Vascular endothelial growth factors (VEGF)-C and VEGF-D, and their cognate receptor tyrosine kinase, VEGF receptor-3 (VEGFR-3), are critical regulators of lymphangiogenesis. By binding to its endothelial cell surface receptors VEGFR-1 and VEGFR-2, VEGF-A mediates vascular leakage, endothelial proliferation and migration. Angiopoietin-2 (Ang-2) is expressed at sites of blood vessel remodeling and invasion, and factors that induce angiogenesis in vivo, such as VEGF-A, upregulate Ang-2 in endothelial cells. In this review, we summarize the literature concerning the crosstalk between angiogenesis and lymphangiogenesis in tumor progression, that is, involvement of VEGF-C, VEGF-D and VEGFR-3 in angiogenesis, and the role played by VEGF-A and Ang-2 in lymphangiogenesis, respectively.
 ...
PMID:Crosstalk between angiogenesis and lymphangiogenesis in tumor progression. 1505 48

The expression of vascular endothelial growth factors (VEGFs) in tumors including lung cancer is considered to be associated with tumor development via capillary and lymph vessel neogenesis. Dissemination of the tumor cells to the pleura or regional lymph nodes is a critical poor prognostic factor for lung cancer patients. To investigate how VEGFs expressed in the intrathoracic infiltrating lung cancer cells participate in disease progression, we established stably VEGF-A-, VEGF-C-, VEGF-D-, VEGF-A and VEGF-C-, and VEGF-A and VEGF-D-expressing large cell lung cancer clones (TKB5/VEGF-A, TKB5/VEGF-C, TKB5/VEGF-D, TKB5/VEGF-A/C, and TKB5/VEGF-A/D), orthotopically inoculated these into the right thoracic cavity (i.t.) of nude mice, and evaluated the subsequent development of lung lesion, pleural effusion, pleural dissemination, and lymph node metastasis. While there were no significant differences either in culture or in subcutaneous tumor cell growth between the empty vector-transfected group (TKB5/empty) and each transfectant, the i.t. model demonstrated significantly different biological properties between the transfectants. TKB5/empty-inoculated mice frequently developed a large tumor on the pleura without pleural effusion, dissemination, or lymph node (LN) metastasis. In contrast, VEGF-A promoted a bloody pleural effusion (6/14), and VEGF-A and VEGF-D frequently generated pleural dissemination (11/14 and 9/11, respectively). Although both VEGF-C and VEGF-D generated LN metastasis (6/10 and 8/11, respectively), the locations of the metastasized LNs were quite different. TKB5/VEGF-C metastasized on the same side of axillary LNs as i.t. (right axillary LNs), whereas TKB5/VEGF-D metastasized to the mediastinal and left axillary and/or cervical LNs. Since the TKB5/VEGF-A/C or TKB5/VEGF-A/D co-transfectants revealed overlapping tumor progression patterns of VEGF-A and VEGF-C or VEGF-D, the metastatic LNs had abundant new capillaries and were larger than those of TKB5/VEGF-C or TKB5/VEGF-D-inoculated mice. Our results clearly demonstrate that VEGF-A secreted from intrathoracic lung cancer cells plays important roles in producing pleural effusion, dissemination, and capillary neogenesis, that VEGF-C is involved in LN metastasis, and VEGF-D in pleural dissemination and LN metastasis. It is most likely, however, that the mechanisms by which VEGF-C promotes LN metastasis are different from those of VEGF-D. The regulation of the expression of VEGFs in intrathoracic lung cancer cells might be a useful therapeutic approach to inhibiting tumor development and improving patient prognosis.
 ...
PMID:Enhancement of pleural dissemination and lymph node metastasis of intrathoracic lung cancer cells by vascular endothelial growth factors (VEGFs). 1530 73

Vascular endothelial growth factors (VEGF)-A, -C and -D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma (EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma (SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and -D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending.
 ...
PMID:Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies. 1586 86

The angiogenic factor called vascular endothelial growth factor (VEGF)-D is a ligand for VEGF receptor-2 (VEGFR-2/KDR) and receptor-3 (VEGFR-3/Flt-4). It is implicated in the development of lymphatic vessels and promotion of lymphatic metastasis. The purpose of this study was to investigate the prognostic significance of VEGF-D expression in patients with gastric carcinoma. We assessed the expression of VEGF-D in gastric carcinoma by immunohistochemistry on 143 consecutive patients' stored sections and evaluated the lymphatic vessel count (LVC) in tumors using the novel selective lymphatic endothelium marker D2-40. VEGF-D expression was observed in 55 (39%) tumor sections. The expression of VEGF-D correlated significantly with tumor size, T of the TNM classification, lymphatic and venous system invasion, LVC, lymph node metastasis, M of TNM, and pTNM stage. Multivariate analysis indicated that VEGF-D expression was an independent prognostic factor for both relapse-free survival (RFS) and overall survival (OS). Our data indicate the involvement of VEGF-D in tumor progression via lymphoangiogenic pathways. Practically, VEGF-D expression can be useful for predicting RFS and OS in patients with gastric carcinoma.
 ...
PMID:Prognostic significance of vascular endothelial growth factor D in gastric carcinoma. 1631 50

Recent advances in understanding the biology of lymphangiogenesis, the new growth of lymphatic vessels, have cast new light on the molecular basis of metastasis to regional lymph nodes. The receptor tyrosine kinase VEGFR-3 is virtually exclusively expressed on lymphatic but not blood endothelium in the adult, and activation of VEGFR-3 by its ligands VEGF-C and VEGF-D is sufficient to induce lymphangiogenesis. Correlative studies with human tumors and functional studies using animal tumor models show that increased levels of VEGF-C or VEGF-D in tumors lead to enhanced numbers of lymphatic vessels in the vicinity of tumors, which in turn promotes metastasis to regional lymph nodes by providing a greater number of entry sites into the lymphatic system for invading tumor cells. These findings have prompted studies to investigate whether inhibitors of VEGFR-3 activation might represent novel therapeutic agents for the suppression of metastasis. However, a number of points regarding the therapeutic potential of anti-lymphangiogenic treatments in the context of cancer remain to be addressed. The spectrum and relative importance of molecules that induce lymphangiogenesis and the regulation of their expression during tumor progression, the reversibility of tumor-induced lymphangiogenesis, and possible side-effects of anti-lymphangiogenesis-based therapies all need to be investigated. Most importantly, the extent to which lymph node metastases contribute to the formation of metastases in other organs remains to be elucidated. These aspects are the focus of this review, and their investigation should serve as a roadmap to possible translational application.
 ...
PMID:Tumor-induced lymphangiogenesis: a target for cancer therapy? 1649 4

Vascular endothelial growth factor receptor 3 (VEGFR-3) binds VEGF-C and VEGF-D and is essential for the development of the lymphatic vasculature. Experimental tumors that overexpress VEGFR-3 ligands induce lymphatic vessel sprouting and enlargement and show enhanced metastasis to regional lymph nodes and beyond, whereas a soluble form of VEGFR-3 that blocks receptor signaling inhibits these changes and metastasis. Because VEGFR-3 is also essential for the early blood vessel development in embryos and is up-regulated in tumor angiogenesis, we wanted to determine if an antibody targeting the receptor that interferes with VEGFR-3 ligand binding can inhibit primary tumor growth. Our results show that antibody interference with VEGFR-3 function can inhibit the growth of several human tumor xenografts in immunocompromised mice. Immunohistochemical analysis showed that the blood vessel density of anti-VEGFR-3-treated tumors was significantly decreased and hypoxic and necrotic tumor tissue was increased when compared with tumors treated with control antibody, indicating that blocking of the VEGFR-3 pathway inhibits angiogenesis in these tumors. As expected, the anti-VEGFR-3-treated tumors also lacked lymphatic vessels. These results suggest that the VEGFR-3 pathway contributes to tumor angiogenesis and that effective inhibition of tumor progression may require the inhibition of multiple angiogenic targets.
 ...
PMID:Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. 1723 68

Vascular endothelial growth factor (VEGF)-D is a secreted glycoprotein that induces angiogenesis and lymphangiogenesis. It consists of a central domain, containing binding sites for VEGF receptor-2 (VEGFR-2) and VEGFR-3, and N- and C-terminal propeptides. It is secreted from the cell as homodimers of the full-length form that can be proteolytically processed to remove the propeptides. It was recently shown, using adenoviral gene delivery, that fully processed VEGF-D induces angiogenesis in vivo, whereas full-length VEGF-D does not. To better understand these observations, we monitored the effect of VEGF-D processing on receptor binding using a full-length VEGF-D mutant that cannot be processed. This mutant binds VEGFR-2, the receptor signaling for angiogenesis, with approximately 17,000-fold lower affinity than mature VEGF-D, indicating the importance of processing for interaction with this receptor. Further, we show that members of the proprotein convertase (PC) family of proteases promote VEGF-D processing, which facilitates the VEGF-D/VEGFR-2 interaction. The PCs furin and PC5 promote cleavage of both propeptides, whereas PC7 promotes cleavage of the C-terminal propeptide only. The finding that PCs promote activation of VEGF-D and other proteins with roles in cancer such as matrix metalloproteinases, emphasizes the importance of these enzymes as potential regulators of tumor progression and metastasis.
 ...
PMID:Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2. 1724 58


1 2 3 4 Next >>