Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The objective of this study was to analyze site-related expression of angiogenic molecules in breast carcinoma, with the aim of characterizing phenotypic alterations along the clinical progression from primary tumor to pleural effusion. A total of 49 malignant pleural effusions and 68 corresponding solid tumors were studied for protein and mRNA expression of vascular endothelial growth factor (VEGF) and its receptor KDR, interleukin-8 (IL-8), basic fibroblast growth factor (bFGF) and the alphaV integrin subunit using immunohistochemistry, mRNA in situ hybridization (ISH) and reverse transcription polymerase chain reaction (RT-PCR). Expression was analyzed for possible association with mRNA expression of the Ets-1 and PEA3 transcription factors. The predictive value of angiogenic molecules, PEA3 and Ets-1, and clinical parameters was analyzed for 18 patients. ISH showed the presence of VEGF, IL-8 and bFGF mRNA in the majority of specimens, irrespective of anatomic site (p > 0.05). However, protein expression of IL-8 and bFGF was lower in effusions compared to primary tumors (p = 0.001 for IL-8, p < 0.001 for bFGF). Expression of alphaV integrin showed an opposite change, with higher level in effusions compared to primary tumors (p = 0.03). bFGF and alphaV integrin expression in effusions was also altered compared to lymph node metastases (p = 0.041 and p = 0.016, respectively). IL-8 and Ets-1 (p = 0.035) and VEGF and PEA3 (p = 0.026) mRNA was co-expressed in effusions. In univariate survival analysis, bFGF protein expression in effusions (p = 0.015), PEA3 mRNA expression in primary tumors (p = 0.02) and previous radiation therapy (p = 0.034) predicted shorter disease-free survival. PEA mRNA expression in primary tumors (p = 0.002) and previous chemotherapy (p = 0.048) predicted poor overall survival, with a similar trend for advanced disease stage at diagnosis (p = 0.05). Our data provide evidence regarding molecular changes that occur along the progression of breast carcinoma from primary tumor to effusion, and suggest altered requirement of angiogenic factors in body cavities. The poor disease-free survival for patients with bFGF-positive effusions suggests a role for this growth factor in mediating tumor survival rather than angiogenesis at this site.
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PMID:Angiogenic molecule expression is downregulated in effusions from breast cancer patients. 1614 38

PTK/ZK is a novel, oral angiogenesis inhibitor that specifically targets all 3 vascular endothelial growth factor (VEGF) receptor tyrosine kinases and is currently in phase III clinical trials. In early clinical trials, PTK/ZK demonstrated a dose-dependent reduction in tumor vascular parameters as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and an acute increase in plasma VEGF levels. The reduction in tumor vascularity was significantly correlated with improved clinical outcome in patients with advanced colorectal cancer and liver metastases. To assess the predictive value of a mouse model of tumor metastases, comparisons were performed for the biological activity of PTK/ZK in the mouse model and in patients with liver metastases in the clinical phase I trials. An orthotopic, syngeneic mouse model was used: C57BL/6 mice injected in the ear with murine B16/BL6 melanoma cells which metastases to the cervical lymph-nodes. The primary tumor and spontaneous metastases express VEGF and VEGF receptors and respond to treatment with VEGFR tyrosine kinase inhibitors. PTK/ZK was administered orally, with assessments by DCE-MRI of the metastases and plasma VEGF taken predose and at 3 days posttreatment and efficacy determined at 7 days posttreatment. Dose-ranging studies in naive mice provided preclinical pharmacokinetic data, while two dose-escalation phase I studies provided clinical pharmacokinetic data. An exposure-response relationship was observed both for mouse metastases (measured as % tumor weight treated/control) and for human liver metastases (measured as % regression). In the B16/BL6 model, the active dose of 50 mg/kg PTK/ZK yielded 62.4 (+/- 16.0) h microM plasma exposure, which is comparable to the plasma area under the concentration time curve (AUC) achieved by the 1000 mg dose of PTK/ZK used in clinical trials. At this exposure level in clinical trials, DCE-MRI showed a reduction in the area under the enhancement curve (IAUC) to 47% of baseline. At a similar exposure in the PTK/ZK-treated mice, a reduction in IAUC to 75% of baseline was observed. Furthermore, at doses of 50 mg/kg PTK/ZK and above, an increase in plasma VEGF level 10 h after drug administration was observed in mice which was consistent with findings from the clinical trials. In conclusion, the preclinical pharmacodynamics of PTK/ZK correlate well with clinical activity in phase I trials over comparable exposures to the drug. Thus, data from this preclinical model proved to be consistent with and thus predictive of the biologic effects of PTK/ZK in phase I/II clinical trials.
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PMID:Biomarkers for assessment of pharmacologic activity for a vascular endothelial growth factor (VEGF) receptor inhibitor, PTK787/ZK 222584 (PTK/ZK): translation of biological activity in a mouse melanoma metastasis model to phase I studies in patients with advanced colorectal cancer with liver metastases. 1617 7

Currently, there is no effective therapy for metastatic breast cancer after surgery, radiation, and chemotherapy have been used against the primary tumor. Because curcumin suppresses nuclear factor-kappaB (NF-kappaB) activation and most chemotherapeutic agents activate NF-kappaB that mediates cell survival, proliferation, invasion, and metastasis, we hypothesized that curcumin would potentiate the effect of chemotherapy in advanced breast cancer and inhibit lung metastasis. We tested this hypothesis using paclitaxel (Taxol)-resistant breast cancer cells and a human breast cancer xenograft model. As examined by electrophoretic mobility gel shift assay, paclitaxel activated NF-kappaB in breast cancer cells and curcumin inhibited it; this inhibition was mediated through inhibition of IkappaBalpha kinase activation and IkappaBalpha phosphorylation and degradation. Curcumin also suppressed the paclitaxel-induced expression of antiapoptotic (XIAP, IAP-1, IAP-2, Bcl-2, and Bcl-xL), proliferative (cyclooxygenase 2, c-Myc, and cyclin D1), and metastatic proteins (vascular endothelial growth factor, matrix metalloproteinase-9, and intercellular adhesion molecule-1). It also enhanced apoptosis. In a human breast cancer xenograft model, dietary administration of curcumin significantly decreased the incidence of breast cancer metastasis to the lung and suppressed the expression of NF-kappaB, cyclooxygenase 2, and matrix metalloproteinase-9. Overall, our results indicate that curcumin, which is a pharmacologically safe compound, has a therapeutic potential in preventing breast cancer metastasis possibly through suppression of NF-kappaB and NF-kappaB-regulated gene products.
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PMID:Curcumin suppresses the paclitaxel-induced nuclear factor-kappaB pathway in breast cancer cells and inhibits lung metastasis of human breast cancer in nude mice. 1624 23

Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in the synthesis of prostaglandins. It is over-expressed in multiple cancers and has been associated with diminished tumor immunity. Dendritic cells (DCs) are considered candidates for cancer immunotherapy due to their ability to process and present antigens to T cells and stimulate immune responses. However, DC-based vaccines have exhibited minimal effectiveness against established tumors. In this study, we evaluated the effect of short-term administration of the selective COX-2 inhibitor celecoxib on the efficacy of DC-based vaccines in preventing and treating established 4T1 murine mammary tumors. We show that dietary celecoxib alone significantly suppresses the growth of primary tumors and the incidence of lung metastases in the prophylactic setting but is less effective against pre-established tumors. However, we demonstrate that celecoxib administered after primary tumor establishment synergizes with tumor lysate-pulsed DC and the adjuvant, GM-CSF, to improve the antitumor immune response by suppressing primary tumor growth and markedly reducing the occurrence of lung metastases. This triple combination therapy elicits a tumor-specific immune response evidenced by elevated IFN-gamma and IL-4 secretion by CD4+ T cells and results in increased infiltration of CD4+ and CD8+ T cells to the tumor site. In addition, dietary celecoxib inhibits angiogenesis evidenced by decreased vascular proliferation within the tumor and serum vascular endothelial growth factor levels. These studies suggest that short-term celecoxib therapy in combination with DC vaccines may be safely used for treating metastatic breast cancer.
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PMID:Short-term dietary administration of celecoxib enhances the efficacy of tumor lysate-pulsed dendritic cell vaccines in treating murine breast cancer. 1633 15

In the United States, non-small cell lung cancer (NSCLC) constitutes 85% of all newly diagnosed lung cancers. Over the past 40 years, the 5-year survival rates in NSCLC have improved from 6% to 15%, with surgery remaining the most curative approach. However, resection is feasible in less than 35% of patients at diagnosis, and 40% to 50% of newly diagnosed patients present with metastatic disease. Platinum-based combination chemotherapy is standard treatment for these patients, but improvement beyond platinum doublets has not been achieved. Therefore, a clear-cut need exists for new treatment approaches for NSCLC. Targeted therapies, particularly angiogenesis inhibitors, are hoped to facilitate therapeutic progress. Neovascularization not only allows for the continued growth of the primary tumor, but also provides migrating tumor cells access to the systemic circulation, facilitating metastasis. A number of studies have shown a clear correlation between vascular endothelial growth factor (VEGF) expression, microvessel density, and impaired prognosis. Monoclonal antibodies directed against the VEGF and VEGF receptor have been studied in depth in advanced NSCLC. A randomized phase III trial evaluated the role of the anti-VEGF-A antibody bevacizumab in combination with paclitaxel and carboplatin versus chemotherapy alone in NSCLC. Based on toxicity observations from a phase II study, this trial excluded patients with squamous histology, brain metastases, or an ongoing need for therapeutic anti-coagulation or non-steroidal anti-inflammatory agents. Preliminary data confirmed a survival advantage of 12.5 months for patients in the bevacizumab arm compared with 10.2 months in the control arm (P = .0075), which showed that antiangiogenic therapies can be effective in NSCLC. Antiangiogenic therapies, including antibodies against VEGF, and, in particular, new small-molecule inhibitors of the VEGF receptor, are reviewed and discussed in detail.
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PMID:The emerging role of vascular endothelial growth factor receptor tyrosine kinase inhibitors. 1645 76

Tumors evolve mechanisms to escape immune control by a process called immune editing, which provides a selective pressure in the tumor microenvironment that could lead to malignant progression. A variety of tumor-derived factors contribute to the emergence of complex local and regional immunosuppressive networks, including vascular endothelial growth factor, interleukin-10, transforming growth factor-beta, prostaglandin E(2), and soluble phosphatidylserine, soluble Fas, soluble Fas ligand, and soluble MHC class I-related chain A proteins. Although deposited at the primary tumor site, these secreted factors could extend immunosuppressive effects into the local lymph nodes and the spleen, promoting invasion and metastasis. Vascular endothelial growth factors play a key role in recruiting immature myeloid cells from the bone marrow to enrich the microenvironment as tumor-associated immature dendritic cells and tumor-associated macrophages. The understanding of the immunosuppressive networks that evolve is incomplete, but several features are emerging. Accumulation of tumor-associated immature dendritic cells may cause roving dendritic cells and T cells to become suppressed by the activation of indoleamine 2,3-dioxygenase and arginase I by tumor-derived growth factors. Soluble phosphatidylserines support tumor-associated macrophages by stimulating the release of anti-inflammatory mediators that block antitumor immune responses. Soluble Fas, soluble FasL, and soluble MHC class I-related chain A proteins may help tumor cells escape cytolysis by cytotoxic T cells and natural killer cells, possibly by counterattacking immune cells and causing their death. In summary, tumor-derived factors drive the evolution of an immunosuppressive network which ultimately extends immune evasion from the primary tumor site to peripheral sites in patients with cancer.
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PMID:Tumor-driven evolution of immunosuppressive networks during malignant progression. 1674 Jun 84

Extracellular pH (pH(e)) is lower in many tumors than in the corresponding normal tissue. The significance of acidic pH(e) in the development of metastatic disease was investigated in the present work. Human melanoma cells (A-07, D-12, and T-22) were cultured in vitro at pH(e) 6.8 or 7.4 (control) before being inoculated into the tail vein of BALB/c nu/nu mice for formation of experimental pulmonary metastases. Cell invasiveness was studied in vitro by using Matrigel invasion chambers and angiogenesis was studied in vivo by using an intradermal assay. Protein secretion was measured by ELISA and immunocapture assays. Cells cultured at acidic pH(e) showed increased secretion of proteinases and proangiogenic factors, enhanced invasive and angiogenic potential, and enhanced potential to develop experimental metastases. Acidity-induced metastasis was inhibited by treatment with the general matrix metalloproteinase (MMP) inhibitor GM6001, the general cysteine proteinase inhibitor E-64, or blocking antibody against vascular endothelial growth factor-A (VEGF-A) or interleukin-8 (IL-8). Our study indicates that acidic pH(e) promotes experimental pulmonary metastasis in A-07, D-12, and T-22 human melanoma cells by a common mechanism involving acidity-induced up-regulation of the proteolytic enzymes MMP-2, MMP-9, cathepsin B, and cathepsin L and acidity-induced up-regulation of the proangiogenic factors VEGF-A and IL-8. One consequence of this observation is that treatment strategies involving deliberate tumor acidification to improve the efficacy of chemotherapy, photodynamic therapy, and hyperthermia should be avoided. Moreover, the possibility that the pH(e) of the primary tumor may be an important prognostic parameter for melanoma patients merits clinical investigation.
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PMID:Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. 1681 44

Preclinical and clinical studies positively correlate the expression of vascular endothelial growth factor (VEGF)-C in tumors and the incidence of lymph node metastases. However, how VEGF-C regulates individual steps in the transport of tumor cells from the primary tumor to the draining lymph nodes is poorly understood. Here, we image and quantify these steps in tumors growing in the tip of the mouse ear using intravital microscopy of the draining lymphatic vessels and lymph node, which receives spontaneously shed tumor cells. We show that VEGF-C overexpression in cancer cells induces hyperplasia in peritumor lymphatic vessels and increases the volumetric flow rate in lymphatics at the base of the ear by 40%. The increases in lymph flow rate and peritumor lymphatic surface area enhance the rate of tumor cell delivery to lymph nodes, leading to a 200-fold increase in cancer cell accumulation in the lymph node and a 4-fold increase in lymph node metastasis. In our model, VEGF-C overexpression does not confer any survival or growth advantage on cancer cells. We also show that an anti-VEGF receptor (VEGFR)-3 antibody reduces both lymphatic hyperplasia and the delivery of tumor cells to the draining lymph node, leading to a reduction in lymph node metastasis. However, this treatment is unable to prevent the growth of tumor cells already seeded in lymph nodes. Collectively, our results indicate that VEGF-C facilitates lymphatic metastasis by increasing the delivery of cancer cells to lymph nodes and therapies directed against VEGF-C/VEGFR-3 signaling target the initial steps of lymphatic metastasis.
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PMID:Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. 1691 83

Uveal melanoma develops in one of the most capillary-rich tissues of the body and is disseminated hematogenously. Knowledge of the nature and the spatiotemporal expression of angiogenic factors in uveal melanoma is essential to the development of new treatment strategies, especially with regard to improving survival. In this study, we measured the angiogenic potential of several angiogenic factors in different uveal melanoma cell lines, in an in vivo model, and in primary tumor material from patients with melanoma. Most uveal melanoma cell lines expressed vascular endothelial growth factor (VEGF)-A (isoforms 121, 165, 189), VEGF-B, VEGF-C, VEGF-D, and basic fibroblastic growth factor (b-FGF) to various extents. The expression of VEGF-A 121 was always higher than that of the other VEGF-A isoforms, suggesting that VEGF-A 121 is the most abundant VEGF-A isoform. All experimentally induced tumors expressed VEGF-A, VEGF-B, VEGF-C, VEGF-D, and basic fibroblastic growth factor (b-FGF). Similarly, significant amounts of mRNA for VEGF-B, VEGF-C, VEGF-D, and b-FGF were detected in uveal melanoma material from patients. In contrast, VEGF-A mRNA (121, 165, 189) was low (9/28) or not detectable in the tumor samples. The synthesis of VEGF-A 165 and b-FGF protein by various cell lines was measured by enzyme-linked immunosorbent assay (ELISA). Most uveal melanoma cell lines, but not normal melanocytes, strongly synthesized and secreted VEGF-A 165 and b-FGF during cell culture. Our data suggest that the expression of (lymph) angiogenic factors may play a causal role in the angiogenesis and progression of uveal melanoma and distant metastasis.
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PMID:Angiogenic profile of uveal melanoma. 1696 50

The ability of neoplastic cells to dissemination from a primary tumor to lymphatic nodes and to adjacent and distant tissues and organs is an inseparable feature of malignant tumors and the main cause of failure in their treatment. Metastasis formation is a multistage process which includes proteolysis, the motility and migration of cells, proliferation, and neoangiogenesis. In the first step, the cells released from the primary tumor have to penetrate to the blood or lymphatic vessels (intravasation), the road which dissemination follows. Circulating cells can then migrate through the walls of vessels to surrounding tissues (extravasation) where they settle, proliferate, and induce angiogenesis, creating metastases. Indispensable in the process of intra- and extravasation is the activation of proteolytic enzymes capable of degrading the extracellular matrix (ECM) surrounding the endothelium or creating the basement membrane of epithelial tissue in different organs. In this stage, the activation of proteolytic enzymes, such as proteinases of the plasmin system, serine proteinases, and matrix metalloproteinases (MMPs), is necessary. Simultaneously, changes occur in the expression of many superficial glycoproteins and factors responsible for cell adhesion (integrins) and intercellular communication (cadherins). Neoangiogenesis is connected with the expression of many markers of this process, among them vascular endothelial growth factor (VEGF), endoglin (CD105), a transmembranous glycoprotein which is a component of the receptor for transforming growth factor beta (TGFbeta), as well as neuropilin (NRP), the co-receptor for VEGF. Conventionally, the prognosis of neoplastic disease and its treatment are based mainly on exact clinical and histopathological staging. This prognosis could, however, be improved by measuring the molecular and cellular markers which play key roles in tumor progression. Understanding the cellular processes responsible for tumor dissemination can be useful not only in the diagnosis and prognosis of treatment results, but also in developing targeted drugs, selectively directed towards those factors responsible for tumor invasiveness, as well as in creating new therapeutic strategies permitting the use of such drugs. In the present review the authors concentrate mainly on one tumor type, colorectal carcinoma, in which distant metastases, predominantly to the liver, are the main cause of failure, in spite of surgical curing of the primary tumor.
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PMID:[Mechanisms of metastasis and molecular markers of malignant tumor progression. I. Colorectal cancer]. 1701 65


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