Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Impact of nodal involvement in papillary thyroid cancer remains controversial. The incidence of nodal metastases is high and the presence of involved nodes has a negative impact on recurrence and possibly on survival as well, particularly in older patients. The risk of nodal disease increases with age, tumor size, and BRAF oncogene expression. Most thyroid surgeons sample the ipsilateral central nodes as a minimum and clear the central compartment if there is gross adenopathy present. Lateral compartment neck dissection is reserved for patients with known metastatic disease. This article attempts to review the literature on surgery of lymph nodes in papillary thyroid cancer.
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PMID:The role of lymphadenectomy in the management of papillary carcinoma of the thyroid. 1917 45

Mutational activation of BRAF is the earliest and most common genetic alteration in human melanoma. To build a model of human melanoma, we generated mice with conditional melanocyte-specific expression of BRaf(V600E). Upon induction of BRaf(V600E) expression, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRaf(V600E) combined with Pten tumor suppressor gene silencing elicited development of melanoma with 100% penetrance, short latency and with metastases observed in lymph nodes and lungs. Melanoma was prevented by inhibitors of mTorc1 (rapamycin) or MEK1/2 (PD325901) but, upon cessation of drug administration, mice developed melanoma, indicating the presence of long-lived melanoma-initiating cells in this system. Notably, combined treatment with rapamycin and PD325901 led to shrinkage of established melanomas. These mice, engineered with a common genetic profile to human melanoma, provide a system to study melanoma's cardinal feature of metastasis and for preclinical evaluation of agents designed to prevent or treat metastatic disease.
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PMID:Braf(V600E) cooperates with Pten loss to induce metastatic melanoma. 1928 48

Cetuximab and panitumumab efficacy in metastatic colorectal cancer (mCRC) may be influenced by EGFR gene status and/or deregulation of its downstream signalling proteins detected in primary tumour. However, metastasis might have different molecular patterns with respect to primary tumour, possibly affecting the prediction of EGFR-targeted therapy efficacy. We analysed primary tumour and metastasis in 38 mCRC patients. Twelve cases were cetuximab/panitumumab treated. EGFR gene status and protein expression were investigated through fluorescent in situ hybridisation and immunohistochemistry (IHC), K-Ras/BRAF mutations by sequencing and PTEN expression by IHC. We observed EGFR gene deregulation in 25 out of 36 primary tumours and 29 out of 36 metastases, K-Ras mutations in 16 out of 37 cancers and in 15 out of 37 metastases, BRAF mutations in 2 out of 36 cancers and 2 out of 36 metastases and PTEN loss in 8 out of 38 cancers and 12 out of 38 metastases. For the first time in literature, we show that primary colorectal cancer and paired metastasis may exhibit difference with respect to EGFR pathway deregulation mechanisms possibly implying a different response to cetuximab or panitumumab treatment. The investigation of treated patients confirms this hypothesis. We therefore suggest that the analysis of metastatic lesion should be considered in patient management as well as in designing future clinical trials aimed to investigate the effect of anti-EGFR monoclonal antibodies in the treatment of mCRC.
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PMID:Differing deregulation of EGFR and downstream proteins in primary colorectal cancer and related metastatic sites may be clinically relevant. 1958 70

B-Raf(V600E), an oncogenic protein kinase, is the most frequent genetic alteration in papillary thyroid carcinomas (PTC). PTC represents 80-90% of all thyroid cancers and over the past five years, more than 200 manuscripts have been published about the relationship between "B-Raf(V600E) and thyroid cancer". B-Raf(V600E) genetically arises from a transversion point mutation (valine-to-glutamate substitution at amino acid residue-600, V600E) and leads to over activation of the mitogen-activated protein kinases (MAPK) signaling pathway. The MAPK pathway is essential for transmitting proliferation signals generated by cell surface receptors and cytoplasmic signaling elements to the nucleus. In many cancers, including thyroid cancer, B-Raf(V600E) appears to play a crucial role in cell proliferation, survival and de-differentiation. In thyroid cancer, the V600E mutation occurs with greater frequently in aggressive subtypes of PTC, and in individuals that present at advanced stages of disease with extra-thyroidal extension and/or lymph node metastases. B-Raf(V600E) is considered a marker of aggressive disease in both PTC (>1 cm) and micro-PTC (</=1 cm), and interestingly, is associated with both loss of I-131 avidity and PTC recurrence. Though treatment of patients with thyroid cancer is usually successful and most patients are rendered disease-free, to date there are no effective therapies for patients with invasive, non-radioiodine sensitive tumors or metastatic disease. In this article we will review the relation between B-Raf(V600E) and PTC, as well as both non-selective and selective pharmacological agents currently under investigation for treatment of B-Raf(V600E) positive PTC.
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PMID:Role of B-Raf(V600E) in differentiated thyroid cancer and preclinical validation of compounds against B-Raf(V600E). 1935 76

Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1_G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET-positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors.
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PMID:Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. 1948 99

Rapidly growing insight into the molecular biology of colorectal cancer has led to high hopes for the identification of molecular markers to be used in optimized and tailored treatment regimens. However, many of the published data on gene-specific biomarkers are contradictory in their findings, and no tests are currently used in clinical practice, with the exception of microsatellite instability (MSI) and guanylyl cyclase C (GCC) testing in the adjuvant setting, and in Europe KRAS mutation testing is used in the setting of epidermal growth factor receptor (EGFR)-targeted therapy for metastatic disease. There are many reasons for the failure of the initial marker hypothesis-driven approach. Although supported by a good biologic rationale, single markers such as tumor protein p53 (TP53) gene mutations, when applied to a complex tumor type containing many synchronous alterations, do not perform well in predicting outcome. Many markers also suffer from technical shortcomings, resulting from the lack of quantitative techniques to capture the impact of the molecular alteration. The impact of markers obtained from microarray expression profiling needs to be further investigated in studies based on much larger cohorts, and cross-validation studies will be essential. Recently, mutations in the KRAS gene were shown to be strong negative predictors of response to EGFR inhibitors in metastatic disease. It has also been suggested that BRAF gene mutations may be predictive of EGFR inhibitor resistance, and there are some conflicting data regarding the role of the PIK3CA gene. Further studies are needed to help integrate the latest findings into clinically useful tools for personalized medicine.
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PMID:Clinical biomarkers in oncology: focus on colorectal cancer. 1953 45

Multifocal sporadic gastrointestinal stromal tumours (GISTs) may be misinterpreted as recurrent or metastatic disease, leading to inappropriate treatment. As molecular analysis is generally not available in routine practise, histological criteria that would facilitate diagnosis of multiple primary GISTs in routine slides are needed. We studied 14 GISTs (mean size, 2.7 cm) from six men and one woman (mean age, 70 years) applying morphological features and direct sequencing of KIT, PDGFRA, BRAF, and KRAS. Diagnosis was synchronous in five and metachronous in two patients. Paired tumours originated in stomach/small bowel (n = 5), duodenum/jejunum (n = 1), and stomach/oesophagus (n = 1) and revealed spindle (n = 10) and mixed spindle and epithelioid (n = 4) phenotype. Tumours were well circumscribed and have involved the muscularis propria in a pattern typical of primary GISTs. Different somatic KIT mutations were found in tumours from four patients. One patient had a KIT-mutated and a BRAF-mutated (V600E) tumour. Two patients had wild-type tumours. No PDGFRA or KRAS mutations were detected. Our results underscore the molecular heterogeneity of sporadic multifocal GISTs. The characteristic involvement of the muscularis propria and the site-typical morphology and immunophenotype facilitated the diagnosis of primary GISTs in all cases and correlated with molecular findings, emphasising the value of conventional histology in recognising independent primary GISTs.
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PMID:Multiple sporadic gastrointestinal stromal tumours arising at different gastrointestinal sites: pattern of involvement of the muscularis propria as a clue to independent primary GISTs. 1957 46

Melanoma is one of the fastest growing tumor types in the United States. Immunotherapy and chemotherapy benefit only a few patients with metastatic disease. Therapy targeting a signaling pathway critical to the cancer's growth can provide dramatic benefit in several other malignancies and may be a valuable strategy for advanced melanoma, if drugs with a favorable therapeutic index are effective against essential molecular pathways. One such target is the V600E "gain-of-function" BRAF mutation found in 60% of melanomas; other mutations or molecular alterations cooperate with V600E BRAF, particularly those that cause loss of function of PTEN, upstream of Akt and mammalian target of rapamycin. Rapid development of new agents, a better understanding of the target pathways and mechanisms of resistance, and carefully designed strategies to optimize combinations and sequences of these agents, potentially with chemotherapy or immunotherapy, may ultimately have the potential to overcome the previously insurmountable obstacle of therapy resistance in melanoma.
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PMID:Inside life of melanoma cell signaling, molecular insights, and therapeutic targets. 1967 16

Attachment of tumor cells to the endothelium (EC) under flow conditions is critical for migration of tumor cells out of the vascular system to establish metastases. We found that neutrophils (PMN) increased melanoma cell extravasation. Endogenous IL-8 liberated from melanoma cells or from PMN induced by melanoma cells contributed to PMN-facilitated melanoma cell arrest on the EC in the microcirculation. Functional blocking of IL-8 receptors on PMN or neutralizing soluble IL-8 in the tumor circulation decreased the level of CD11b/CD18 up-regulation on PMN and subsequently reduced melanoma cell extravasation. We also found that targeting mutant V600EB-Raf interrupted melanoma cell extravasation in vitro and subsequent lung metastasis development in vivo. B-Raf encodes a RAS-regulated kinase that mediates cell growth and malignant transformation kinase pathway activation. Results showed that inhibition of V600EB-Raf reduced IL-8 secretion from melanoma cells and reduced the capacity of IL-8 production from the tumor microenvironment involving PMN. Furthermore, reduction in intercellular adhesion molecule-1 (ICAM-1) expression on melanoma cells was found after V600EB-Raf knockdown. These results provide new evidence for the complex role of secreted chemokine and PMN-melanoma adhesion in the recruitment of metastatic cancer cells to the EC, which are significant in fostering new approaches to cancer treatment through anti-inflammatory therapeutics.
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PMID:Immunoediting of leukocyte functions within the tumor microenvironment promotes cancer metastasis development. 1972 Nov 89

We recently identified the secreted protein IGFBP7 as a factor required for an activated BRAF oncogene to induce senescence or apoptosis in primary human cells. In human melanomas containing an activating BRAF mutation (BRAF-positive melanomas), IGFBP7 is epigenetically silenced, which seems to be a critical step in melanoma genesis. Restoration of IGFBP7 function by the addition of recombinant IGFBP7 (rIGFBP7) induces apoptosis in BRAF-positive human melanoma cell lines, and systemically administered rIGFBP7 markedly suppresses the growth of BRAF-positive primary tumors in xenografted mice. Here we further evaluate the role of IGFBP7 in the treatment of BRAF-positive melanoma and other malignancies. We find that in human metastatic melanoma samples IGFBP7 is epigenetically silenced and at an even higher frequency than that found in primary melanomas. Using a murine experimental metastasis assay, we show that systemic administration of rIGFBP7 markedly suppresses the growth of metastatic disease and prolongs survival. An analysis of the NCI60 panel of human cancer cell lines reveals that in addition to melanoma, IGFBP7 induces apoptosis in several other cancer types, in particular colorectal cancer cell lines. In general, IGFBP7 induces apoptosis in human cancer cell lines that have an activating mutation in BRAF or RAS, and that are sensitive to chemical inhibition of BRAF-MEK-ERK signaling. Significantly, systemically administered rIGFBP7 blocks the growth of colorectal tumors containing an activating RAS or BRAF mutation in mouse xenografts. The results presented here, in conjunction with those from previous studies, justify the further development of IGFBP7 as an anticancer agent.
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PMID:Efficacy of IGFBP7 for treatment of metastatic melanoma and other cancers in mouse models and human cell lines. 1986 8


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