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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HER2/neu (HER2) gene is a member of a family of genes which has been implicated in cancer. These four genes, HER1/EGFR, HER2, HER3 and HER4 encode for transmembrane proteins that are involved in the regulation of cell proliferation, differentiation and survival. Amplification of HER2 occurs in 20%-25% of breast cancers and is associated with an aggressive tumor phenotype and poor prognosis. Results from five randomized, phase III clinical trials have recently demonstrated that trastuzumab (Herceptin) significantly improves disease free survival and overall survival when used in conjunction with chemotherapy for early stage HER2-positive breast cancer. Despite adjuvant trastuzumab, approximately 15% of patients with early stage disease recur, and those with metastatic disease eventually become resistant to therapy. Novel treatment approaches are needed for patients who have either intrinsic or acquired resistance to trastuzumab. This article reviews the role of trastuzumab in managing early and advanced stage HER2-positive disease, the role of lapatinib (Tykerb) in trastuzumab resistant disease, and the novel agents in development targeting mechanisms of trastuzumab resistance.
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PMID:Targeting the human epidermal growth factor receptor 2 (HER2) in the treatment of breast cancer: recent advances and future directions. 1847 95

Epidermal growth factor (EGF) receptor (EGFR) is frequently elevated in epithelial ovarian cancer, and E-cadherin expression is often reduced in advanced disease. In this study, we investigated a mechanism by which EGFR activation promotes disruption of adherens junctions through induction of matrix metalloproteinase 9 (MMP-9). We show that EGFR activation down-modulates E-cadherin, and broad spectrum MMP inhibition ameliorates EGF-stimulated junctional disruption and loss of E-cadherin protein. MMP-9 involvement in EGF-dependent down-regulation of E-cadherin was determined by siRNA specifically directed against MMP-9. Furthermore, treatment with recombinant MMP-9 or transient expression of MMP-9 is sufficient to reduce E-cadherin levels in differentiated ovarian tumor cells. Stable overexpression of MMP-9 led to a loss of E-cadherin and junctional integrity, and promoted a migratory and invasive phenotype. Thus, elevated MMP-9 protein expression is sufficient for junctional disruption and loss of E-cadherin in these cells. The associations between EGFR activation, MMP-9 expression, and E-cadherin were investigated in human ovarian tumors and paired peritoneal metastases wherein immunohistochemical staining for activated (phospho) EGFR and MMP-9 colocalized with regions of reduced E-cadherin. These data suggest that regulation of MMP-9 by EGFR may represent a novel mechanism for down-modulation of E-cadherin in ovarian cancer.
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PMID:Matrix metalloproteinase 9 is a mediator of epidermal growth factor-dependent e-cadherin loss in ovarian carcinoma cells. 1855 5

The aim of the study was to identify the impact on prognosis of hypoxia-inducible factor-1 genetic program in colorectal carcinomas and to develop an experimental procedure that would allow a reliable quantitative gene expression analysis in formalin-fixed and paraffin-embedded tissue. The expression of hypoxia-inducible factor-1alpha and 13 hypoxia-inducible factor-1 target genes (AMF, CAIX, VEGF, VEGFR1, VEGFR2, HGF, MET, TGFalpha, EGFR, IGF2, MMP2, PLAUR, NIX) was quantified by real-time polymerase chain reaction in 18 colorectal, poorly differentiated neuroendocrine carcinomas and in 60 invasive colorectal carcinomas. Moreover, hypoxia-inducible factor-1alpha protein expression was evaluated by immunohistochemistry. High levels of hypoxia-inducible factor-1alpha were positively associated with poorly differentiated neuroendocrine carcinoma histology (P < .005), poor differentiation (P < .025), presence of necrosis, and presence of microsatellite instability (P < .05). AMF, TGFalpha, IGF2, NIX, VEGF, and VEGFR2 transcripts were significantly higher in the very aggressive poorly differentiated neuroendocrine carcinomas than in exocrine colorectal carcinomas and TGFalpha expression was significantly associated with presence of lymph nodal metastases (P < .05). High levels of TGFalpha and NIX were significantly associated with decreased overall survival (P < .001; P < .01). The multivariate analysis showed that advanced stage, presence of lymph node metastases, and high TGFalpha expression had an independent effect on survival (P < .006; P < .01; P < .0006). Our study suggests an up-regulation of the hypoxia-inducible factor-1 transcriptional pathway in colorectal carcinomas. hypoxia-inducible factor-1alpha overexpression alone, has no impact on the prognosis of colorectal carcinomas likely because the consequences of hypoxia-inducible factor-1alpha expression/stabilization strongly depend on the genetic background of the transformed cells. Mechanisms leading to increased synthesis of hypoxia-inducible factor-1alpha mRNA via autocrine growth factor loops may play a crucial role in invasive growth in this site.
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PMID:Up-regulation of the hypoxia-inducible factor-1 transcriptional pathway in colorectal carcinomas. 1861 49

The introduction of concepts proposing multiple cellular subgroups in the normal female breast leads to the hypothesis that distinct cellular phenotypes in the female breast give rise to different subtypes of breast carcinomas e.g. expressing ER, HER2 and EGFR differentially. Therefore, origin of breast carcinoma types may be based on the formation of a cancer prone field in which the committed progenitor cells pass mutations to their progenies, glandular as well as myoepithelial cells. The existence of such field within the human breast was inferred from the results on primary breast cancer obtained by PCR-based microsatellite analysis of allelic imbalance (AI) of the EGF receptor gene. Here, normal breast tissue shows egfr AI adjacent to breast cancer tissue also harboring egfr gene AI. The therapeutic implications of such a model are fundamental, as tumors may display different phenotypes which arise from transformation of different progenitor cells as well as from transformation of more differentiated progenies within a cancer prone field. Thereby they may show up with different clinical courses of the disease, higher rates of metastases and responses to therapy. In this review, we discuss this mechanism focusing on the EGF receptor as an example for regulators of progenitor cell growth in many tissues. Phylloides tumors serve as a putative model for embryonic differentiation stage ruled by EGFR signaling and give insights into the tumor-host-interaction. The inhibition of the EGF receptor by specific monoclonal antibodies (e.g. Erbitux) will give an answer in as far EGFR-signaling is decisive for the development of an invasive breast cancer. For this purpose new models have been inaugurated which vary in the EGF receptor gene dosage and protein expression. Moreover, we discuss the EGF receptor as a target for the treatment of pre-malignant lesions with a high risk for malignant growth, e.g. DCIS, which certainly will be detected more frequently by mammography screening programs soon.
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PMID:Allelic imbalances of the egfr gene as key events in breast cancer progression--the concept of committed progenitor cells. 1869 Aug 49

NSCLC cells with a mesenchymal phenotype have shown a marked reduction in sensitivity to EGFR inhibitors, though the molecular rationale has remained obscure. Here we find that in mesenchymal-like tumor cells both tyrosine phosphorylation of EGFR, ErbB2, and ErbB3 signaling networks and expression of EGFR family ligands were decreased. While chronic activation of EGFR can promote an EMT-like transition, once having occurred EGFR family signaling was attenuated. We investigated the mechanisms by which mesenchymal-like cells bypass EGFR signaling and acquire alternative routes of proliferative and survival signaling. Mesenchymal-like NSCLC cells exhibit aberrant PDGFR and FGFR expression and autocrine signaling through these receptors can activate the MEK-ERK and PI3K pathways. Selective pharmacological inhibition of PDGFR or FGFR receptor tyrosine kinases reduced cell proliferation in mesenchymal-like but not epithelial NSCLC cell lines. A metastable, reversible EMT-like transition in the NSCLC line H358 was achieved by exogenous TGFbeta, which served as a model EMT system. The H358/TGFbeta cells showed many of the attributes of established mesenchymal-like NSCLC cells including a loss of cell-cell junctions, a loss of EGF-family ligand expression, a loss of ErbB3 expression, increased EGFR-independent Mek-Erk pathway activation and reduced sensitivity to EGFR inhibition. Notably an EMT-dependent acquisition of PDGFR, FGFR and TGFbeta receptors in H358/TGFbeta cells was also observed. In H358/TGFbeta cells both PDGFR and FGFR showed functional ligand stimulation of their intrinsic tyrosine kinase activities. The findings of kinase switching and acquired PDGFR and FGFR signaling suggest investigation of new inhibitor combinations to target NSCLC metastases.
Clin Exp Metastasis 2008
PMID:Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy. 1869 32

Lapatinib is an oral dual inhibitor of EGFR and HER2, the coexpression of which is associated with metastatic disease in patients with renal cell carcinoma. A recent randomized phase III trial of lapatinib versus hormone therapy was conducted in patients with cytokine-refractory metastatic renal cell carcinoma and tumors overexpressing EGFR and/or HER2. The study included 416 such patients who received either lapatinib (n = 209) or hormone therapy (n = 207). No benefit in time to progression, which was the primary end point of the study, or other clinical outcome measures, could be demonstrated for lapatinib therapy. A nonsignificant numerical advantage in time to progression was observed in patients with EGFR overexpression in the primary tumor (immunohistochemistry score 3+), suggesting that lapatinib could be of benefit in this subset of patients. This commentary emphasizes the need for further prospective studies to demonstrate the benefit of lapatinib therapy in patients with metastatic renal cell carcinoma.
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PMID:Lapatinib therapy for patients with advanced renal cell carcinoma. 1846 19

Recent advances of molecular genetics have made a noticeable impact in some areas of clinical medicine. Almost comprehensive understanding of the nature of hereditary tumors is frequently heralded as the most substantial practical achievement of molecular oncology. Proper diagnostic algorithms have already been developed for the vast majority of known familial cancer syndromes. Interestingly, an unexpectedly strong "founder" effect has been documented at least for some hereditary cancers occurring in Russia, that significantly simplifies the detection of the corresponding disease-associated gene variants. The number of tests aimed to customize cancer treatment continues to grow every year. EGFR mutation test appears to be the most impressive, as it allows to predict lung cancer response or non-response to gefitinib or erlotinib with indeed unique level of accuracy. The approaches helping to determine individual efficacy and safety profiles for fluoropyrimidines, platinum compounds, irinotecan etc. are currently under development Methods aiming to detect residual amounts of disseminated cancer cells represent another popular avenue of the research. It is expected that these technologies will improve the quality of prediction of local and distant metastases, facilitate monitoring of the minimal residual disease and, in the long perspective, provide the tool for early cancer diagnosis. One has to remember that the molecular detection of disseminated tumor cells is currently used mainly in research settings and is not yet incorporated into routine clinical practice.
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PMID:[Molecular diagnosis in oncology]. 1898 27

Several drugs have been developed and demonstrated similar efficacy in colorectal cancer treatment therefore with choice, time comes for decision. The biologist will have to provide the tools allowing to clarify this choice. Among the tools available, those of pharmacogenetics and pharmacogenomics appear most promising and recent examples allow to illustrate their clinical interest. The pharmacogenetics of anti-cancer agents presents a clinical characteristic, which requires to hold into account the genetic variations not only of host cells but also of those of the tumor cells. Among the most conclusive examples one is that of the prediction of severe neutropenia induced by the irinotecan among patients homozygous for * 28 allele of UGT1A1 enzyme which conjugates SN38 active compound of irinotecan, the other one is the presence of a KRAS mutated allele in tumor cell to predict resistance to anti EGFR antibodies in the treatment of colorectal metastatic cancer.
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PMID:[The biological point of view on pharmacogenetics of anticancer agents in colorectal cancer]. 1900 23

Since 2004 and the first improvement in overall survival in hormone refractory prostate cancer patients (HRPC) brought about by docetaxel, numerous phase II and III studies have been initiated. Considering the lack of efficacy in terms of overall survival, hormonal manipulations such as antiandrogen withdrawal, di-ethylstilbesterol or dexamethason are only indicated in "rising PSA" patients without clinical or radiological evidence of metastases. As first line treatment, the optimal chemotherapy regimen is docetaxel (75 mg/m(2) every 3 weeks) in association with prednisone (5 mg twice daily). Second line chemotherapies (mitoxantron, ixabepilon, docetaxel as a re-treatment, vinorelbin, doxorubicin...) provide modest results only in terms of progression-free survival. A phase III study of Straplatin has been prematurely interrupted. Targeted anti-angiogenic therapies have shown encouraging results in patients with metastatic localizations, and underline the need to identify target patients early through cellular markers (mTOR or EGFR overexpression) as well as the uselessness of PSA dosage to monitor efficacy. An ongoing phase III study is evaluating bevacizumab in association with docetaxel to improve overall survival. Both the Provenge vaccine and DN 101 (calcitriol) showed a survival gain of a few months in phase III studies. An ongoing EORTC phase II trial is evaluating antisense oligonucleotids in HRPC. Early introduction of docetaxel raises the issue of when to start chemotherapy as it may be relevant to initiate this treatment before the onset of hormone independence. GETUG 15 trial will try to answer this question.
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PMID:[Chemotherapy of hormonorefractory and hormonoresistant metastatic prostate cancer]. 1907 Aug 17

The significant advance in the development of molecular-targeting drugs has made an evaluation of Her-2, EGFR, and cyclin D1 an important clinical issue in breast cancer patients. This study compared the Her-2, EGFR, and cyclin D1 status of primary tumors as well as their matching lymph node metastases using immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) in 73 breast cancer patients. Her-2, EGFR, and cyclin D1 protein showed a concordance between the primary lesion and the metastatic regional lymph nodes in 82%, 90%, and 63%, respectively. CISH also revealed 92%, 93%, and 85% concordance in the gene amplification status of Her-2, EGFR, and cyclin D1, showing a reasonable agreement between primary tumors and metastatic regional lymph nodes. Although a statistically significant agreement was found in Her-2 expression, a relatively high discordance rate (18%) raises a little concern. Our findings suggest that the Her-2 status can be reliably assessed on primary tumor but a possible difference can be found in Her-2, EGFR, and cyclin D1 status between the primary and the metastatic sites and this possibility should be concerned in patients considering molecular targeted therapy or patients with progress of disease.
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PMID:Comparison of Her-2, EGFR and cyclin D1 in primary breast cancer and paired metastatic lymph nodes: an immunohistochemical and chromogenic in situ hybridization study. 1911 52


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