Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of matrix metalloproteinase (MMP)9 in lung cancer progression is controversial. MMP9 promotes local tumor progression and distant metastasis in mouse models by enhancing extracellular matrix degradation, releasing VEGF from extracellular matrix and promoting vascular pericyte recruitment. Furthermore, increased plasma MMP9 expression levels in human subjects with metastatic non-small cell lung cancer (NSCLC) inversely correlates with survival. In contrast, MMP9 can benefit the host by generating inhibitors of endothelial cell proliferation such as angiostatin and NC1 domains of collagen IV. To better understand the role of host MMP9 on the primary growth and metastatic potential of NSCLC, we performed an orthotopic model of NSLC in integrin alpha1-null mice (a genetic model for increased MMP9). In these mice we observed decreased number, size and vascularization of primary NSCLC tumors when compared to wild type controls. In addition, decreased number and size of NSCLC-derived metastases were evident in the alpha1-null mice. Furthermore, pharmacological inhibition of MMPs in the alpha1-null mice at the time of tumor cell injection resulted in an increase in the number of both primary and metastatic lung cancer as compared to untreated mice, suggesting that primary growth and metastases of NSCLC are worsened by the early inhibition of MMPs. In conclusion, although MMP9 may potentially promote tumor growth and metastasis, production of MMP-dependent anti-angiogenic factors seems to override these effects and protects the host from NSCL growth and progression.
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PMID:An orthotopic model of lung cancer to analyze primary and metastatic NSCLC growth in integrin alpha1-null mice. 1608 39

Despite recent advances in current chemotherapy, the prognosis for locally advanced and metastatic nonsmall-cell cancer remains poor, and new approaches are required. An increased understanding of the biology of lung cancer has identified pathways mediated by receptor tyrosine kinases as an important target. The epidermal growth factor receptor (EGFR) is frequently expressed on the surface of the lung cancer cell. EGFR can be targeted by inhibitors of receptor tyrosine kinase activity such as erlotinib and gefitinib and by antibodies specific for the extracellular domain. Subset analysis of responders to the receptor tyrosine kinase inhibitors suggests that clinical benefit may correlate with the presence of EGFR mutations. Other drugs in earlier clinical development include those directed against HER-2, VEGF, farnesyl transferase, COX-2 and retinoid receptor.
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PMID:Targeted therapies for non-small cell lung cancer. 1611 82

Src, a proto-oncogene, has been strongly implicated in the growth, progression and metastasis of a number of human cancers. Its role in lung cancer is, however, still unknown. In the present study, we assessed the expression of Src in three different human lung adenocarcinoma cell lines (PC-9, PC14PE6, A549), and explored the effect of a novel Src kinase inhibitor, M475271, on the behavior of the cell lines. The three cell lines expressed various levels of auto-phosphorylated Src. While M475271 reduced Src-phosphorylation and invasiveness of all three cell lines, it inhibited the proliferation of PC-9 and A549 cells with highly phosphorylated Src, but not PC14PE6 cells. We further examined the effect of M475271 on subcutaneous tumors and lung metastasis caused by PC-9 and/or A549 cells in NK-cell depleted SCID mice. Daily oral treatment with M475271 inhibited the growth of subcutaneous tumors with PC-9 and A549 cells via inhibition of tumor cells proliferation, VEGF production and/or vascularization in the mice in a dose-dependent manner. In the metastasis model with A549 cells, the lung weight in the M475271 (50 mg/kg)-treated group was less than that of the control group, despite no difference in the number of metastatic nodules. Our results suggest that inhibition of tyrosine kinase Src by M475271 could reduce the growth, invasion and VEGF-mediated neovascularization of lung adenocarcinoma cells, resulting in inhibition of growth of subcutaneous tumors and lung metastasis. Therefore, a novel Src tyrosine kinase inhibitor, M475271, might be helpful for controlling the progression of human lung adenocarcinoma.
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PMID:SRC tyrosine kinase inhibitor, m475271, suppresses subcutaneous growth and production of lung metastasis via inhibition of proliferation, invasion, and vascularization of human lung adenocarcinoma cells. 1615 47

Endocan, previously called endothelial cell specific molecule-1, is a soluble proteoglycan of 50 kDa, constituted of a mature polypeptide of 165 amino acids and a single dermatan sulphate chain covalently linked to the serine residue at position 137. This dermatan sulphate proteoglycan, which is expressed by the vascular endothelium, has been found freely circulating in the bloodstream of healthy subjects. Experimental evidence is accumulating that implicates endocan as a key player in the regulation of major processes such as cell adhesion, in inflammatory disorders and tumor progression. Inflammatory cytokines such as TNF-alpha, and pro-angiogenic growth factors such as VEGF, FGF-2 and HGF/SF, strongly increased the expression, synthesis or the secretion of endocan by human endothelial cells. Endocan is clearly overexpressed in human tumors, with elevated serum levels being observed in late-stage lung cancer patients, as measured by enzyme-linked immunoassay, and with its overexpression in experimental tumors being evident by immunohistochemistry. Recently, the mRNA levels of endocan have also been recognized as being one of the most significant molecular signatures of a bad prognosis in several types of cancer including lung cancer. Overexpression of this dermatan sulphate proteoglycan has also been shown to be directly involved in tumor progression as observed in mouse models of human tumor xenografts. Collectively, these results suggest that endocan could be a biomarker for both inflammatory disorders and tumor progression as well as a validated therapeutic target in cancer. On the basis of the recent successes of immunotherapeutic approaches in cancer, the preclinical data on endocan suggests that an antibody raised against the protein core of endocan could be a promising cancer therapy.
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PMID:Endocan or endothelial cell specific molecule-1 (ESM-1): a potential novel endothelial cell marker and a new target for cancer therapy. 1616 66

The two-kringle domain of tissue-type plasminogen activator (TK1-2) has been identified as a novel angiogenesis inhibitor. In the previous study, purified Pichia-derived TK1-2 has been shown to suppress in vivo growth of human lung and colon cancer cells. Here, we demonstrate that E. coli-derived non-glycosylated TK1-2 suppresses tumor growth more potently than Pichia-derived TK1-2 and prolongs the survival of tumor bearing mice. The recombinant TK1-2 prepared through E. coli expression, His-tag affinity chromatography and in vitro refolding was injected intraperitoneally once daily into nude mice 7 days after subcutaneous implantation with PC14 lung cancer cells (n=10). Measurement of tumor volumes indicated that low-dose TK1-2 treatment (10 mg/kg) suppressed tumor growth by approximately 85.2% (p<0.01), while high-dose TK1-2 treatment (50 mg/kg) even more potently inhibited tumor growth (>93.8%) (p<0.005). Treatment of TK1-2 also prolonged the survival of tumor-bearing mice in a dose-dependent fashion. In an independent HCT116 xenograft model, E. coli-derived TK1-2 was more effective in suppressing tumor growth than Pichia-derived TK1-2. Immunohistochemical analysis of tumor tissue also revealed that the expression of VEGF, SMA-alpha, TNF-alpha and angiogenin was less positive in the E. coli-derived TK1-2-treated group than in the Pichia-derived TK1-2-treated group. These results suggest that E. coli-derived refolded, non-glycosylated TK1-2 can be used more effectively as an anti-cancer agent.
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PMID:Potent anti-tumor and prolonged survival effects of E. coli-derived non-glycosylated kringle domain of tissue-type plasminogen activator. 1639 90

Hedgehog, FGF, VEGF, and Notch signaling pathways network together for vascular remodeling during embryogenesis and carcinogenesis. HHIP1 (HHIP) is an endogenous antagonist for SHH, IHH, and DHH. Here, comparative integromics analyses on HHIP family members were performed by using bioinformatics and human intelligence. HHIP1, HHIP2 (HHIPL1 or KIAA1822) and HHIP3 (HHIPL2 or KIAA1822L) constitute human HHIP gene family. Rat Hhip1, Hhip2, and Hhip3 genes were identified within AC107504.4, AC094820.6, and AC134264.2 genome sequences, respectively. HHIP-homologous (HIPH) domain with conserved 18 Cys residues was identified as the novel domain conserved among mammalian HHIP1, HHIP2, and HHIP3 orthologs. HHIP1 mRNA was expressed in coronary artery endothelial cells, prostate, and rhabdomyosarcoma. HHIP2 mRNA was expressed in trabecular bone cells. HHIP3 mRNA was expressed in testis, thyroid gland, osteoarthritic cartilarge, pancreatic cancer, and lung cancer. Promoters of HHIP family genes were not well conserved between human and rodents. Although GLI-, CSL-, and HES/HEY-binding sites were not identified, eleven bHLH-binding sites were identified within human HHIP1 promoter. Expression of HES/HEY family members, including HES1, HES2, HES3, HES4, HES5, HES6, HES7, HEY1, HEY2 and HEYL, in coronary artery endothelial cells was not detected in silico. Up-regulation of HHIP1 due to down-regulation of Notch-CSL-HES/HEY signaling cascade repressing bHLH transcription factors results in down-regulation of the Hedgehog-VEGF-Notch signaling cascade. On the other hand, down-regulation of HHIP1 due to up-regulation of Notch signaling in vascular endothelial cells during angiogenesis results in up-regulation of the Hedgehog-VEGF-Notch signaling cascade. Because HHIP1 is the key molecule for vascular remodeling, HHIP1 is the pharmacogenomics target in the fields of oncology and vascular medicine.
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PMID:Comparative genomics on HHIP family orthologs. 1639 42

Hypoxia is associated with malignant progression and poor outcome in human cancers. The effects of hypoxia are mediated by a series of genomic changes that enable tumor cells to survive or escape their oxygen deficient environment. Recent studies indicated that carbonic anhydrase IX (CA IX) is an intrinsic marker of hypoxia. In the present study we investigated with quantitative RT-PCR the expression of CA IX mRNA in 93 non-small cell lung carcinomas (NSCLC) and in their paired not affected tissues. CA IX mRNA was expressed in 100% NSCLC and in 76% of paired not affected tissues, even if tumoral CA IX expression was found constantly higher (p < 0.02) than that found in normal tissues. The increase of CA IX mRNA expression in cancer tissues was significantly correlated to the increase of corresponding protein, as determined with conventional immunoblotting (p = 0.027). In addition the expression of CA IX mRNA in NSCLC samples was significantly correlated to VEGF (p = 0.002) and MMP-9 (p = 0.002) mRNAs. Whereas CA IX mRNA expression was not associated to any clinical-pathological parameters in our patients, global survival analysis of cancer-related death revealed that high expression of CA IX mRNA predicted unfavorable outcome (p = 0.001) and shorter disease free survival interval (p = 0.004). A multivariate analysis showed that CA IX expression was the strongest prognostic parameter (p = 0.000) in comparison to other conventional predictive markers. In addition, differences emerged on the basis of clinical-pathological parameters: in fact separate Kaplan-Meyer analyses of patients indicated that whereas high levels of CA IX mRNA expression were not predictive of worse prognosis in early NSCLC (G1, T1, Stage 1 and pN- patients), this parameter appeared highly significant in advanced NSCLC (G2-G3, T2-T3, Stage 2-3 and pN+ patients). Finally we demonstrated that CA IX expression was not able to discriminate different survival probability in adenocarcinomas, whereas the same parameter was highly predictive in squamous (p = 0.03) and adenosquamous cell carcinomas (p = 0.001).
Lung Cancer 2006 Apr
PMID:Quantitative analysis of carbonic anhydrase IX mRNA in human non-small cell lung cancer. 1651 6

In the treatment of lung cancers, a local cryotherapy can be proposed as a palliative option for bronchial clearance. But this therapy can also be used as an adjuvant treatment, for instance in association with chemotherapy. We have already demonstrated differential biological effects of these therapies and the benefit to combine them. The aim of this study was to determine if this benefit observed at a molecular level was correlated with tumour growth. As vascular changes occur after cryotherapy, intratumoral angiogenesis was also studied. Cells from the A549 cell line were inoculated into SCID mice. Tumours were treated by cryotherapy (nitrous oxide cryoprobe), chemotherapy (injection of Vinorelbine) or both. Tumour growth was studied in each group and the T/C ratios were compared. Tumours treated by cryochemotherapy presented a significantly reduced volume and the lower T/C ratio, confirming the benefit of a combined treatment. Angiogenesis was assessed at variable time points after cryotherapy by immunohistochemical staining of VEGF and western blot analysis. A late cryo-induced angiogenesis was observed 8-15 days after treatment (expression of VEGF increased from 13% in untreated tumours to 77 and 70%, respectively). To determine if this hypervascularization could enhance the efficiency of chemotherapy, the drug was injected 15 days after cryotherapy and the induction of cell death was investigated (morphological study, immunohistochemical staining of cleaved caspase-3, TUNEL). Necrosis was increased but not apoptosis, suggesting that though a crucial parameter, intratumoral microvessel density is not the only factor to consider to reach an optimal efficiency of a combined treatment.
Lung Cancer 2006 Oct
PMID:Benefit of a combined treatment of cryotherapy and chemotherapy on tumour growth and late cryo-induced angiogenesis in a non-small-cell lung cancer model. 1688 70

Although Fas (APO-1/CD95) is well known as a death receptor, its stimulation occasionally fails to induce apoptosis in malignant cells. On the contrary, Fas is reported to advance the cell cycle in cancer cells. Therefore, we investigated roles of Fas in cell growth and apoptosis using human lung cancer cell lines. Fas was localized in the cytoplasm in exponentially growing cells, whereas only confluent cells expressed Fas on the cell membrane. A stimulation of confluent cells by either of EGF, IGF-I or VEGF induced once a decrease in Fas expression level and its sequential recovery. Fas expression levels in confluent cells were negatively correlated with cell doubling times (r=0.757, p=0.0088). Fas remained on the cell membrane of IgM-treated cells even after the growth factor stimulation, leading to apoptosis with abnormal mitosis, whereas the same stimulation induced Fas internalization in IgG(1)-treated cells. From these results, we suggest that Fas remaining on the cell membrane amplifies to induce apoptosis. Conversely, Fas internalization may enable cancer cells to escape from apoptosis. Our results suggest that growth factor may contribute to the resistance of cancer cells to Fas-mediated apoptosis in an autocrine or paracrine fashion.
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PMID:The variation in Fas localization and the changes in Fas expression level upon stimulation with growth factors. 1717 68

An increasing knowledge of cell signal transduction pathways has led to a better understanding of multi-step bronchial carcinogenesis. This new data has been used to design new drugs targeting specific proteins involved in epithelial cell transformation. New biotherapies are a major part of the evolving strategies to fight lung cancer and actually represent a true revolution for subsets of patients. Future treatments in lung cancer patients will be tailored on the basis of routine molecular analysis of surgical and bronchoscopic biopsy specimens. Tyrosine-kinase EGFR inhibitors and VEGF inhibitors are the first molecules in this new class of therapies for lung cancer. Their mechanism of action and the resistance mechanisms that occur with these new drugs continue to be analysed, and this knowledge will help to improve the targeting of therapeutic regimes. In the same way, a better knowledge of the molecular resistance mechanisms to classical chemotherapy agents (platinum compounds, anti-metabolite agents or tubulin-interacting agents) will lead to a tailored use of these drugs, based again on the molecular characteristics of tumor specimens. The surprisingly long survivals observed among subsets of 'molecular-selected' patients, treated with frontline EGFR tyrosine-kinase inhibitors (TKIs) in still limited prospective clinical trials, could herald significant improvement in the global efficacy of lung cancer therapeutics.
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PMID:[The place of targeted therapies in the management of non-small cell bronchial carcinoma. Biological mechanisms of bronchial carcinogenesis: towards a better understanding and the development of new therapies]. 1726 49


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