Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The receptor tyrosine kinase MET has been studied of a large variety of human cancers, including lung and mesothelioma. The MET receptor and its ligand HGF (hepatocyte growth factor) play important roles in cell growth, survival and migration, and dysregulation of the HGF-MET pathway leads to oncogenic changes including tumor proliferation, angiogenesis and metastasis. In small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), and malignant pleural mesothelioma (MPM), MET is dysregulated via overexpression, constitutive activation, gene amplification, ligand-dependent activation, mutation or epigenetic mechanisms. New drugs targeted against MET and HGF are currently being investigated in vitro and in vivo, with promising results. These drugs function at a variety of steps within the HGF-MET pathway, including MET expression at the RNA or protein level, the ligand-receptor interaction, and tyrosine kinase function. This paper will review the structure, function, mechanisms of tumorigenesis, and potential for therapeutic inhibition of the MET receptor in lung cancer and mesothelioma.
Lung Cancer 2009 Feb
PMID:MET as a target for treatment of chest tumors. 1867 14

The vascular endothelial growth factor (VEGF) receptor 2 (VEGFR-2), also called fetal liver kinase 1 (FLK1) in mice and kinase insert domain receptor (KDR) in humans, is an endothelial cell specific receptor tyrosine kinase that mediates lung cancer angiogenesis. We hypothesized that an active immunotherapy approach targeting FLK1 may inhibit lung cancer growth and metastasis. To test this hypothesis, we evaluated whether immune responses to FLK1 could be elicited in mice by immunization with an orally administered DNA vaccine encoding the extracellular domain (ECD) of FLK1 (pcDNA3.1-FLK1(ECD)) carried by attenuated Salmonella typhimurium. We found that the vaccine was effective at protective antitumor immunity in Lewis lung carcinoma models in mice by breaking immune tolerance to FLK1 self-antigen. Both FLK1-specific humoral and cellular immune responses against endothelial cells can be induced in mice by immunization with pcDNA3.1-FLK1(ECD). Immunization with pcDNA3.1-FLK1(ECD) resulted in tumor suppression and prolonged survival in mice challenged with Lewis lung carcinomas cells. Experimental pulmonary metastases were strongly inhibited in pcDNA3.1-FLK1(ECD) immunized mice challenged with Lewis lung carcinoma cells. Thus, we conclude that the plasmid DNA vaccine encoding the extracellular domain of FLK1 could be an important component of FLK1 DNA vaccine to prevent lung carcinoma recurrence and metastasis after surgery.
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PMID:Orally administered DNA vaccine delivery by attenuated Salmonella typhimurium targeting fetal liver kinase 1 inhibits murine Lewis lung carcinoma growth and metastasis. 2011 36

Endothelial cells are potent regulators of immune cell functions and have therefore been examined to determine their role in tumor-induced immune suppression. Previous studies by our laboratory showed that exposure to Lewis lung carcinoma (LLC)-secreted products induced endothelial cells to suppress T-cell functions in vitro. The current studies examined in vitro and in vivo the mechanism by which tumors induce the formation of suppressor endothelial cells and the means by which suppressor endothelial cells disrupt T-cell functions. In vitro studies demonstrated that inhibition of tumor-derived VEGF with neutralizing antibodies or treatment of endothelial cells with the VEGF receptor tyrosine kinase inhibitor, SU5416, prevented endothelial cells from being induced to suppress T-cell functions. Treatment of tumor-bearing mice with SU5416 blocked the development of endothelial cells that are suppressive to CD4 and CD8 T-cell functions. We next examined the role of suppressor endothelial cell-derived PGE2 in the inhibition of T-cell functions. Abrogation of endothelial cell PGE2 production in vitro with indomethacin prevented tumor-conditioned media from stimulating endothelial cell production of immune inhibitory activity toward T-cell functions. Similar treatment of endothelial cells from lungs of tumor-bearing mice blocked their capacity to produce T-cell-inhibitory mediators. These studies demonstrate that tumor-derived VEGF induces endothelial cells to upregulate production of PGE2 which, in turn, leads to suppression of T-cell functions.
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PMID:Tumor secretion of VEGF induces endothelial cells to suppress T cell functions through the production of PGE2. 2014 50

Recent progress with therapies targeting endothelial cells has drawn attention also to the pericytes as potential target cells for antiangiogenic therapy. Published data suggest that pericytes might confer resistance to vascular endothelial growth factor (VEGF) withdrawal in tumors. This hypothesis has been supported by experiments using tumors with reversible transgenic expression of VEGF-A as well as by individual pharmacologically targeting VEGF and platelet-derived growth factor receptor signaling in endothelial cells and pericytes using receptor tyrosine kinase (RTK) inhibitors with different specificities. However, the RTK inhibitors applied thus far are not entirely specific to the mentioned pathways, and therefore, the effects putatively attributed to pericyte targeting might reflect other antitumor effects. Here, we have reinvestigated the putative benefits of doubly targeting endothelial cells and pericytes in the treatment of experimental tumors. For this purpose, we used two highly specific tools, the pericyte-deficient pdgfb(ret/ret) mouse and the recently developed specific anti-VEGF-A antibody G6-31, which neutralizes both murine and human VEGF-A. We generated B16, Lewis lung carcinoma, and T241 subcutaneous tumors in both pdgfb(ret/ret) and control mice and treated these mice with G6-31. Our results fail to show any improved effect of VEGF inhibition, as measured by tumor growth or decrease in vascular density, in pericyte-deficient tumors compared with controls. Our observations suggest that additional targeting of pericytes does not increase the antitumor effect already generated by anti-VEGF drugs.
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PMID:The absence of pericytes does not increase the sensitivity of tumor vasculature to vascular endothelial growth factor-A blockade. 2050 41

Angiogenesis is essential for cancer growth and progression. Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis. The addition of bevacizumab, an antibody to vascular endothelial growth factor (VEGF), to paclitaxel and carboplatin improves survival compared with chemotherapy alone in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC). Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) are a new class of drugs that target the TK domain of the VEGF receptors. To evaluate the role of this class of agents in the treatment of NSCLC, some phase II and phase III studies using these agents alone or in combination with other agents have been completed. This review summarizes the currently available data on VEGFR TKIs in the treatment of NSCLC.
Clin Lung Cancer 2010 Sep 01
PMID:Vascular endothelial growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. 2083 56

We previously demonstrated that the receptor for the complement component C1q (gC1qR) is a lipid raft protein that is indispensable for adipogenesis and insulin signaling. Here, we provide the first report that gC1qR is an essential component of lamellipodia in human lung carcinoma A549 cells. Cell-surface gC1qR was concentrated in the lamellipodia along with CD44, monosialoganglioside, actin, and phosphorylated focal adhesion kinase in cells stimulated with insulin, IGF-1, EGF, or serum. The growth factor-induced lamellipodia formation and cell migration were significantly decreased in gC1qR-depleted cells, with a concomitant blunt activation of the focal adhesion kinase and the respective receptor tyrosine kinases. Moreover, the gC1qR-depleted cells exhibited a reduced proliferation rate in culture as well as diminished tumorigenic and metastatic activities in grafted mice. We therefore conclude that cell-surface gC1qR regulates lamellipodia formation and metastasis via receptor tyrosine kinase activation.
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PMID:Cell-surface receptor for complement component C1q (gC1qR) is a key regulator for lamellipodia formation and cancer metastasis. 2153 72

MET, a receptor tyrosine kinase for hepatocyte growth factor, is associated with tumor progression and acquired resistance to epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI). Therefore, MET gene alterations could be both prognostic and predictive. Fluorescence in situ hybridization (FISH) is one method for assessing gene alteration, but the frequency of positive cases varies due to a lack of standardized criteria. We evaluated MET gene copy number in lung adenocarcinoma and its association with clinicopathological characteristics. FISH was applied to evaluate high MET gene copy number and true amplification in 138 lung adenocarcinoma patients using two criteria: the Cappuzzo scoring system and PathVysion. MET positive cases according to the Cappuzzo scoring system evidenced both aneuploidy and true amplification, whereas PathVysion revealed only amplification. Proportion of MET FISH positive cases was 15% and 4% determined by the Cappuzzo system and PathVysion, respectively. PathVysion demonstrated higher frequencies of MET FISH positives among men and smokers and evidenced no MET FISH positives in patients with bronchioloalveolar carcinoma. Prognosis was significantly associated with MET FISH positive only as defined by the PathVysion system (gene amplification), not by the Cappuzzo system. However, progression-free survival time of patients with both EGFR mutations and MET FISH positive defined by the Cappuzzo scoring system was significantly shorter than with EGFR mutations alone. These results suggest that MET FISH is a potential prognostic factor and coexistence of MET FISH with EGFR mutations signifies worse prognosis.
Lung Cancer 2012 Jan
PMID:Co-existence of positive MET FISH status with EGFR mutations signifies poor prognosis in lung adenocarcinoma patients. 2173 94

The receptor tyrosine kinase c-MET and its ligand, hepatocyte growth factor (HGF), regulate multiple cellular processes that stimulate cell proliferation, invasion and angiogenesis. This review provides an overview of the evidence to support c-MET or the HGF/c-MET signaling pathway as relevant targets for personalized cancer treatment based on high frequencies of c-MET and/or HGF overexpression, activation, amplification in non-small cell lung carcinoma (NSCLC), gastric, ovarian, pancreatic, thyroid, breast, head and neck, colon and kidney carcinomas. Additionally, the current knowledge of small molecule inhibitors (tivantinib [ARQ 197]), c-MET/HGF antibodies (rilotumumab and MetMAb) and mechanisms of resistance to c-MET-targeted therapies are discussed.
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PMID:c-MET as a potential therapeutic target and biomarker in cancer. 2212 85

Angiogenesis is a rational target for the treatment of patients with non-small-cell lung cancer (NSCLC). In the E4599 trial, the vascular endothelial growth factor (VEGF)-targeted antibody bevacizumab combined with carboplatin/paclitaxel improved both progression-free survival (PFS) and overall survival (OS) compared with chemotherapy alone. However responses to bevacizumab are usually transient and resistance inevitably develops. Thus other targets should be considered for future antiangiogenic strategies. A number of antiangiogenic agents with a variety of targets are in clinical development for NSCLC. Several multitargeted receptor tyrosine kinase inhibitors (TKIs) such as sorafenib, cediranib, and BIBF 1120, with activity against vascular endothelial growth factor receptor (VEGFR) and other proangiogenic pathways (eg, fibroblast growth factor [FGF] and platelet-derived growth factor [PDGF] pathways) are in clinical development for NSCLC. Many of these TKIs have shown clinical activity in early trials, both alone and in combination with chemotherapy. Other promising agents in development include inhibitors of the angiopoietin/TIE2 pathway, integrin-targeted agents, vascular disrupting agents, and delta-like ligand-4/Notch pathway inhibitors.
Clin Lung Cancer 2012 Sep
PMID:Beyond bevacizumab: antiangiogenic agents. 2229 7

In recent years, better understanding of the molecular biology of non-small-cell lung carcinoma (nsclc) has led to a revolution in the work-up of these neoplasms. As a pathology diagnosis, "nsclc" without further attempt at subclassification is no longer accepted as a standard of care; separating squamous cell carcinoma from adenocarcinoma and large-cell carcinoma carries implications for prognosis and treatment decisions. Currently, detection of the presence in nsclc of mutations involving the epidermal growth factor receptor (EGFR) gene and fusion of the N-terminal portion of the protein encoded by EML4 (echinoderm microtubule-associated protein-like 4 gene) with the intracellular signaling portion of the receptor tyrosine kinase encoded by ALK (anaplastic lymphoma kinase gene)-that is, EML4-ALK-and variants has become routine in many centres because patients having tumours harbouring such alterations might benefit from tyrosine kinase inhibitors as part of their treatment regimen.The purpose of the present review is to highlight important aspects of the screening for molecular derangements in nsclc and to briefly discuss the emergence of possible future biomarkers.
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PMID:The role of molecular pathology in non-small-cell lung carcinoma-now and in the future. 2278 8


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