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

Colorectal cancer (CRC) represents a major health problem in the Western world. Approximately 60% of patients with CRC require systemic therapy for metastatic disease, either at diagnosis or at disease recurrence. Until recently, classic chemotherapeutic agents have been combined in the treatment of advanced CRC. The recent considerable development of novel monoclonal antibodies that target key components of biological pathways has expanded the options to treat advanced CRC patients. These newer agents more specifically target unique features of the cancer cell and its surroundings and so attempt to exploit the progress that has been made in the understanding of basic cell biology. Two targets in particular--the process of new blood vessel development, or angiogenesis, and the EGF receptor and its signalling pathway--are exploited by the newest monoclonal antibodies available for use in this setting. This clinical review focuses on the defining role of the two most clinically advanced novel agents, bevacizumab and cetuximab in metastatic colorectal cancer.
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PMID:The new era in the treatment of advanced colorectal cancer patients: the role of monoclonal antibodies. 1706 25

YKL-40 is produced by cancer cells and tumour-associated macrophages. YKL-40 may play a role in cancer cell proliferation, differentiation, survival, invasiveness, metastasis, in angiogenesis and the inflammation and remodelling of the extracellular matrix surrounding the tumour. Serum YKL-40 is a biomarker of prognosis, confirmed in 13 different types of cancer including > 2500 patients. Highest serum YKL-40 is found in patients with metastatic cancer with the shortest recurrence-free interval and shortest overall survival. Serum YKL-40 provides independent information compared with clinical characteristics and biomarkers, such as HER2, carcinoembryonic antigen, CA-125, prostate-specific antigen and lactate dehydrogenase. The authors hypothesise that inhibition of YKL-40 by monoclonal antibodies either directly or towards its receptor may be as efficient a cancer therapeutic as the monoclonal antibodies against HER2, HER1, vascular endothelial growth factor and CD20. Drugs inhibiting YKL-40 should be explored as new cancer therapeutics.
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PMID:Is YKL-40 a new therapeutic target in cancer? 1722 36

Molecular requirements for carcinoma cell interactions with the microenvironment are critical for disease progression but are poorly understood. Integrin alpha v beta 5, which senses the extracellular matrix, is important for carcinoma cell dissemination in vivo. alpha v beta 5 signaling induces Mig-7, a novel human gene product that is apparently carcinoma-specific. We hypothesized that Mig-7 expression facilitates tumor cell dissemination by increasing invasion and vasculogenic mimicry. Results show that embryonic cytotrophoblasts up-regulated Mig-7 expression before they acquired an invasive phenotype capable of pseudovasculogenesis. Mig-7 protein primarily co-localized with vasculogenic mimicry markers factor VIII-associated antigen, vascular endothelial-cadherin, and laminin 5 gamma 2 chain domain III fragment in lymph node metastases. Overexpression of Mig-7 increased gamma 2 chain domain III fragments known to contain epidermal growth factor (EGF)-like repeats that can activate EGF receptor. Interestingly, EGF also induced Mig-7 expression. Carcinoma cell adhesion to laminins was significantly reduced by Mig-7 expression. Remarkably, in two-dimensional and three-dimensional Matrigel cultures, Mig-7 expression caused invasion and vessel-like structures. Melanoma cells, which were previously characterized to invade aggressively and to undergo vasculogenic mimicry, expressed Mig-7. Taken together, these data suggest that Mig-7 expression allows cells to sense their environment, to invade, and to form vessel-like structures through a novel relationship with laminin 5 gamma 2 chain domain III fragments.
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PMID:Overexpression of carcinoma and embryonic cytotrophoblast cell-specific Mig-7 induces invasion and vessel-like structure formation. 1745 52

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

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

The occurrence of metastases is a critical determinant of the prognosis for breast cancer patients. Effective treatment of breast cancer metastases is hampered by a poor understanding of the mechanisms involved in the formation of these secondary tumor deposits. To study the processes of metastasis, valid in vivo tumor metastasis models are required. Here, we show that increased expression of the EGF receptor in the MTLn3 rat mammary tumor cell-line is essential for efficient lung metastasis formation in the Rag mouse model. EGFR expression resulted in delayed orthotopic tumor growth but at the same time strongly enhanced intravasation and lung metastasis. Previously, we demonstrated the critical role of NK cells in a lung metastasis model using MTLn3 cells in syngenic F344 rats. However, this model is incompatible with human EGFR. Using the highly metastatic EGFR-overexpressing MTLn3 cell-line, we report that only Rag2(-/-)gammac(-/-) mice, which lack NK cells, allow efficient lung metastasis from primary tumors in the mammary gland. In contrast, in nude and SCID mice, the remaining innate immune cells reduce MTLn3 lung metastasis formation. Furthermore, we confirm this finding with the orthotopic transplantation of the 4T1 mouse mammary tumor cell-line. Thus, we have established an improved in vivo model using a Rag2(-/-) gammac(-/-) mouse strain together with MTLn3 cells that have increased levels of the EGF receptor, which enables us to study EGFR-dependent tumor cell autonomous mechanisms underlying lung metastasis formation. This improved model can be used for drug target validation and development of new therapeutic strategies against breast cancer metastasis formation.
Clin Exp Metastasis 2009
PMID:An improved model to study tumor cell autonomous metastasis programs using MTLn3 cells and the Rag2(-/-) gammac (-/-) mouse. 1946 69

Soft-tissue sarcomas (STSs) are a heterogeneous group of rare malignant tumors predominantly arising from the embryonic mesoderm. The mainstay of curative therapy is the complete surgical resection of all tumor manifestations with negative histological margins. However, up to 50% of patients will develop distant metastases during the course of their disease. The prognosis for those patients is grim with a 5-year overall survival of less than 10%. First-line systemic therapy with ifosfamide and doxorubicin results in overall response rates of only 20% by conventional response evaluation criteria in solid tumors (RECIST). However, stabilization of disease can be seen in a greater proportion. Therefore, the role of the RECIST criteria has been questioned and the implementation of new imaging studies (e.g., FDG-PET) has shown promising results in assessing early tumor response to therapy. Furthermore, a broader insight into the molecular pathways of sarcomagenesis has been gained in recent years, revealing intriguing targets for new therapeutic approaches (e.g., VEGF, VEGF receptor, IGF receptor, EGF receptor, mTOR and cyclin-dependent kinases). In addition, a growing body of evidence is linking specific genetic aberrations with clinical outcome (e.g., SYT-SXX translocation in synovial sarcoma). With further insight into the biology of STS and the combination of new treatment options with modern imaging techniques, we will most certainly be able to improve clinical outcome in patients with STS in the upcoming years.
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PMID:New medical treatment options and strategies to assess clinical outcome in soft-tissue sarcoma. 1967 Oct 35

Colorectal cancer (CRC) is frequently complicated by metastatic disease, with the liver being the most common site of metastasis. Surgical resection is the only realistic cure for colorectal liver metastases; however only 10-25% of cases are initially resectable. The introduction of combination chemotherapy has improved survival rates by enabling 10-20% cases with previously unresectable hepatic metastases to become amenable to surgery. Recent results with the biologic agent bevacizumab, a chimeric human-mouse monoclonal antibody against VEGF, and cetuximab, a chimeric human-mouse monoclonal antibody against EGF receptor, have shown that they improve clinical surgical outcomes when added to current first-line regimens in patients with metastatic colorectal cancer. Dual biologic therapy in combination with chemotherapy has, however, yielded disappointing results. Identification of biological markers is expected to help determine which patients are most likely to respond to these newer agents and thus improve targeted therapy.
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PMID:Metastatic colorectal cancer: recent advances in its clinical management. 1995 94

The epidermal growth factor (EGF) receptor is a receptor tyrosine kinase involved in the control of cell proliferation, and its overexpression is strongly associated with a variety of aggressive cancers. For example, 70-80% of metaplastic (cancer cells of mixed type) breast carcinomas overexpress EGF receptors. In addition, the EGF receptor is a highly significant contributor to common brain tumors (glioblastoma multiforme), both in initiation and progression (Huang P.H., Xu A.M., White F.M. (2009) Oncogenic EGFR signaling networks in glioma. Sci Signal;2:re6.). Brain metastases, an unmet medical need, are also common in metastatic cancer associated with overexpression of EGF receptors. Formation of EGF receptor homodimers is essential for kinase activation and was the basis for exploring direct inhibition of EGF receptor activation by blocking dimerization with small molecules. While inhibitors of protein/protein interactions are often considered difficult therapeutic targets, NSC56452, initially identified by virtual screening, was shown experimentally to inhibit EGF receptor kinase activation in a dose-dependent manner. This compound blocked EGF-stimulated dimer formation as measured by chemical cross-linking and luciferase fragment complementation. The compound was further shown to inhibit the growth of HeLa cells. This first-generation lead compound represents the first drug-like, small-molecule inhibitor of EGF receptor activation that is not directed against the intracellular kinase domain.
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PMID:Targeting the dimerization of epidermal growth factor receptors with small-molecule inhibitors. 2045 71

Lapatinib is an orally active, low molecular weight, reversible inhibitor of the intracellular tyrosine kinase domains of both human epidermal growth factor receptor (HER) type 1 (HER1) and type 2 (HER2). In a large phase III trial (EGF30008) in 1286 postmenopausal women with hormone receptor (HR)-positive, metastatic breast cancer who had not received previous therapy for advanced or metastatic disease, the primary endpoint of median progression-free survival in a HER2-positive population of 219 women was significantly longer with lapatinib plus letrozole than with letrozole plus placebo (8.2 vs 3.0 months). Overall response rates (28% vs 15%) and clinical benefit rates (responsive or stable disease for >or=6 months; 48% vs 29%) were also significantly higher with lapatinib plus letrozole than with letrozole plus placebo. Most adverse events associated with lapatinib when administered in combination with letrozole were mild to moderate in severity in the EGF30008 phase III trial.
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PMID:Lapatinib: in postmenopausal women with hormone receptor-positive, HER2-positive metastatic breast cancer. 2122 96


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