Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The activating mutation BRAF(V600E) is a frequent genetic event in papillary thyroid carcinomas (PTC) that predicts a poor prognosis, leading to loss of sodium/iodide symporter (NIS) expression and subsequent radioiodide-refractory metastatic disease. The molecular basis of such an aggressive behavior induced by BRAF remains unclear. Here, we show a mechanism through which BRAF induces NIS repression and promotes epithelial to mesenchimal transition and invasion based on the operation of an autocrine transforming growth factor (TGF)beta loop. BRAF induces secretion of functional TGFbeta and blocking TGFbeta/Smad signaling at multiple levels rescues BRAF-induced NIS repression. Although this mechanism is MAP/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK independent, secreted TGFbeta cooperates with MEK-ERK signaling in BRAF-induced cell migration, Matrigel invasion, and EMT. Consistent with this process, TGFbeta and other key components of TGFbeta signaling, such as TbetaRII and pSmad2, are overexpressed in human PTC, suggesting a widespread activation of this pathway by locally released TGFbeta. Moreover, this high TGFbeta/Smad activity is associated with PTC invasion, nodal metastasis, and BRAF status. Interestingly, TGFbeta is overexpressed in the invasive front, whereas NIS is preferentially expressed in the central regions of the tumors, suggesting that this negative correlation between TGFbeta and NIS occurs locally inside the tumor. Our study describes a novel mechanism of NIS repression in thyroid cancer and provides evidence that TGFbeta may play a key role in promoting radioiodide resistance and tumor invasion during PTC progression.
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PMID:The BRAFV600E oncogene induces transforming growth factor beta secretion leading to sodium iodide symporter repression and increased malignancy in thyroid cancer. 1986 38

Encapsulated thyroid tumors of follicular cell origin with high-grade features (EFHG) are unusual neoplasms. In current classification schemes, they are called atypical adenomas or follicular, papillary, or poorly differentiated carcinoma. When noninvasive, EFHG create a major therapeutic/diagnostic dilemma stemming from their rarity, low-stage, high-grade appearance, and lack of long-term follow-up studies. All cases of EFHG were defined as encapsulated tumors of follicular cell origin with at least 5 mitoses per 10 high-power fields and/or tumor necrosis. Available tissues were subjected to a thyroid carcinoma platform for mass spectrometry high-throughput genotyping, which consisted of 111 known mutations in 16 different genes: BRAF, RET, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes. Twenty-five cases met the selection criteria. Tumor necrosis was present in 56.0% (n = 14). Extensive vascular invasion was identified in 24.0% (n = 6). Eight (32%) of 25 tumors were noninvasive. Twenty-two patients (88%) were free of disease (median follow up: 8.5 years). All 8 noninvasive tumor did not recur despite focal/extensive tumor necrosis in 3 cases and a median follow-up of 11.9 years. EFHG with no vascular invasion did not recur. In patients without distant metastases at presentation (n = 24), 33% (2/6) of patients with extensive angioinvasion relapsed, whereas none of 18 with absent/focal vascular invasion recurred (P = .054). Mutations were found in 10 (45%) of 22 cases tested: 8 had NRAS codon 61, 1 KRAS codon 61, and 1 had coexistent BRAF V600E and AKT1. There was a higher frequency of RAS (9/22, 41%) than BRAF mutations (1/22, 4.5%) (P = .009). Noninvasive EFHG have an indolent behavior even in the presence of extensive tumor necrosis. EFHG with absent vascular invasion have an excellent prognosis despite the frequent occurrence of tumor necrosis. NRAS mutations are the most frequent oncogenic event in EFHG.
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PMID:Encapsulated thyroid tumors of follicular cell origin with high grade features (high mitotic rate/tumor necrosis): a clinicopathologic and molecular study. 1991 80

Papillary thyroid carcinomas (PTC) are the most common thyroid tumors that usually have a good prognosis. Recurrence, metastases, and cancer death may occur in a few patients and are more commonly associated with more aggressive tumors, such as tall cell, columnar cell, or diffuse sclerosing variants of the PTC. We present the clinicopathologic, immunohistochemical, and molecular features of a rare aggressive variant of the PTC showing prominent hobnail features. The patients included 6 females and 2 males. Ages ranged from 28 to 78 years (mean 57.6). Patients presented with a neck mass and cervical lymphadenopathy. Tumor size ranged from 1.0 cm to 4.0 cm (mean 2.5 cm). The tumors were usually multifocal with variably sized complex papillary structures lined by cells with increased nuclear/cytoplasmatic ratios and apically placed nuclei that produced a surface bulge (hobnail appearance). Thyroglobulin, TTF-1, HBME-1, and p53 were positive in all cases, and there was membrane staining for beta-catenin and E-cadherin. The proliferative index with Ki67 ranged from 2% to 20% with a mean of 10%. BRAF mutation was present in 4/7 (57.1%) cases. Distant metastases to liver, lung, bone, brain, muscle, and pancreas developed in 5 patients. The average follow-up time was 77.2 months. Four patients died of disease after a mean of 42.8 months. Two patients are alive with disease after 4 and 87 months, respectively. Two patients are alive without disease after 120 and 236 months. PTC with a prominent hobnail pattern is a moderately differentiated PTC variant with aggressive clinical behavior and significant mortality.
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PMID:Papillary thyroid carcinoma with prominent hobnail features: a new aggressive variant of moderately differentiated papillary carcinoma. A clinicopathologic, immunohistochemical, and molecular study of eight cases. 2044 47

PURPOSE: Activation of the phosphoinositide 3-kinase (PI3K)-AKT pathway has been implicated in melanoma based primarily on the prevalence of mutations in PTEN and NRAS. To improve our understanding of the regulation and clinical significance of the PI3K-AKT pathway in melanoma, we quantitatively measured the levels of phosphorylated AKT, its substrate GSK3alpha/beta, and its negative regulator PTEN in clinical metastases. Results were compared with mutational status, clinical outcomes, and sites of metastasis. EXPERIMENTAL DESIGN: DNA and protein were isolated from dissected frozen melanoma metastases (n = 96). Activating mutations of BRAF, NRAS, AKT, PIK3CA, and KIT were detected by mass spectroscopy genotyping. Phosphorylated AKT (Ser473 and Thr308), P-GSK3alpha/beta, and PTEN protein expression were measured by reverse-phase protein array. A panel of human melanoma cells lines (n = 58) was analyzed for comparison. RESULTS: BRAF-mutant tumors had higher levels of P-AKT-Ser473 (P = 0.01), P-AKT-Thr308 (P = 0.002), and P-GSK3alpha/beta (P = 0.08) than NRAS-mutant tumors. Analysis of individual tumors showed that almost all tumors with elevated P-AKT had low PTEN levels; NRAS-mutant tumors had normal PTEN and lower P-AKT. Similar results were observed in melanoma cell lines. Stage III melanoma patients did not differ in overall survival based on activation status of the PI3K-AKT pathway. Brain metastases had significantly higher P-AKT and lower PTEN than lung or liver metastases. CONCLUSIONS: Quantitative interrogation of the PI3K-AKT pathway in melanoma reveals unexpected significant differences in AKT activation by NRAS mutation and PTEN loss, and hyperactivation of AKT in brain metastases. These findings have implications for the rational development of targeted therapy for this disease. (Clin Cancer Res 2009;15(24):7538-46).
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PMID:Integrated Molecular and Clinical Analysis of AKT Activation in Metastatic Melanoma. 1999 8

Differentiated thyroid cancer accounts for >90% of cases of thyroid cancer, with most patients having an excellent prognosis. Distant metastases occur in 10%-15% of patients, decreasing the overall 10-year survival rate in this group to 40%. Radioactive iodine has been the mainstay of treatment for distant metastases, with good results when lesions retain the ability to take up iodine. For patients with metastatic disease resistant to radioactive iodine, treatment options are few and survival is poor. Chemotherapy and external beam radiotherapy have been used in these patients, but with disappointing results. In recent years, our understanding of the molecular pathways involved in thyroid cancer has increased and a number of molecular targets have been identified. These targets include the proto-oncogenes BRAF and RET, known to be common mutations in thyroid cancer; vascular endothelial growth factor receptor and platelet-derived growth factor receptor, associated with angiogenesis; and the sodium-iodide symporter, with the aim of restoring its expression and hence radioactive iodine uptake. There are now multiple trials of tyrosine kinase inhibitors, angiogenesis inhibitors, and other novel agents available to patients with metastatic thyroid cancer. This review discusses both traditional and novel treatments for metastatic differentiated thyroid cancer with a particular focus on emerging treatments for patients with radioactive iodine-refractory disease.
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PMID:Standard and emerging therapies for metastatic differentiated thyroid cancer. 2014 32

Tumor metastasis is a leading cause of cancer-related death. Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase recruited to integrin-mediated matrix attachment sites where FAK activity is implicated in the control of cell survival, migration, and invasion. Although genetic studies support the importance of FAK activity in promoting tumor progression, it remains unclear whether pharmacological FAK inhibition prevents tumor metastasis. Here, we show that the FAK inhibitor PND-1186 blocks FAK Tyr-397 phosphorylation in vivo and exhibits anti-tumor efficacy in orthotopic breast carcinoma mouse tumor models. PND-1186 (100 mg/kg intraperitoneal, i.p.) showed promising pharmacokinetics (PK) and inhibited tumor FAK Tyr-397 phosphorylation for 12 hours. Oral administration of 150 mg/kg PND-1186 gave a more sustained PK profile verses i.p., and when given twice daily, PND-1186 significantly inhibited sygeneic murine 4T1 orthotopic breast carcinoma tumor growth and spontaneous metastasis to lungs. Moreover, low-level 0.5 mg/ml PND-1186 ad libitum administration in drinking water prevented oncogenic KRAS- and BRAF-stimulated MDA-MB-231 breast carcinoma tumor growth and metastasis with inhibition of tumoral FAK and p130Cas phosphorylation. Although PND-1186 was not cytotoxic to cells in adherent culture, tumors from animals receiving PND-1186 exhibited increased TUNEL staining, decreased leukocyte infiltrate and reduced tumor-associated splenomegaly. In vitro, PND-1186 reduced tumor necrosis factor-a triggered interleukin-6 cytokine expression, indicating that FAK inhibition may impact tumor progression via effects on both tumor and stromal cells. As oral administration of PND-1186 also decreased experimental tumor metastasis, PND-1186 may therefore be useful clinically to curb breast tumor progression.
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PMID:Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. 2023 93

Anti-EGFR targeted therapy is a potent strategy in the treatment of metastatic colorectal cancer (mCRC) but activating mutations in the KRAS gene are associated with poor response to this treatment. Therefore, KRAS mutation analysis is employed in the selection of patients for EGFR-targeted therapy and various studies have shown a high concordance between the mutation status in primary CRC and corresponding metastases. However, although development of therapy related resistance occurs also in the context of novel drugs such as tyrosine kinase-inhibitors the effect of the anti-EGFR treatment on the KRAS/BRAF mutation status itself in recurrent mCRC has not yet been clarified. Therefore, we analyzed 21 mCRCs before/after anti-EGFR therapy and found a pre-/posttherapeutic concordance of the KRAS/BRAF mutation status in 20 of the 21 cases examined. In the one discordant case, further analyses revealed that a tumor mosaicism or multiple primary tumors were present, indicating that anti-EGFR therapy has no influence on KRAS/BRAF mutation status in mCRC. Moreover, as the preselection of patients with a KRAS(wt) genotype for anti-EGFR therapy has become a standard procedure, sample sets such ours might be the basis for future studies addressing the identification of potential anti-EGFR therapy induced genetic alterations apart from KRAS/BRAF mutations.
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PMID:Concordance of KRAS/BRAF Mutation Status in Metastatic Colorectal Cancer before and after Anti-EGFR Therapy. 2030 May 83

Malignant cutaneous melanoma is a highly aggressive form of skin cancer. Despite improvements in early melanoma diagnosis, the 5-year survival rate remains low in advanced disease. Therefore, novel biomarkers are urgently needed to devise new means of detection and treatment. In this study, we aimed to improve our understanding of microRNA (miRNA) deregulation in melanoma development and their impact on patient survival. Global miRNA expression profiles of a set of melanoma lymph node metastases, melanoma cell lines, and melanocyte cultures were determined using Agilent array. Deregulated miRNAs were evaluated in relation with clinical characteristics, patient survival, and mutational status for BRAF and NRAS. Several miRNAs were differentially expressed between melanocytes and melanomas as well as melanoma cell lines. In melanomas, miR-193a, miR-338, and miR-565 were underexpressed in cases with a BRAF mutation. Furthermore, low expression of miR-191 and high expression of miR-193b were associated with poor melanoma-specific survival. In conclusion, our findings show miRNA dysregulation in malignant melanoma and its relation to established molecular backgrounds of BRAF and NRAS oncogenic mutations. The identification of an miRNA classifier for poor survival may lead to the development of miRNA detection as a complementary prognostic tool in clinical practice.
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PMID:MicroRNA expression profiles associated with mutational status and survival in malignant melanoma. 2035 17

The occurrence of medullary thyroid carcinoma (MTC) in patients with germline RET mutation is well established, but the occasional occurrence of papillary thyroid carcinoma (PTC) in this setting remains unexplained. We report a case of synchronous MTC and PTC in a patient with germline RET mutation, and investigate the molecular pathogenesis of these two tumors. A 48-year-old man presented with cervical lymphadenopathy and was found to have metastatic MTC involving cervical and mediastinal lymph nodes. He underwent thyroidectomy and debulking of metastatic disease. The resected thyroid showed bilateral MTC and a 1-cm PTC. His lymph node metastases were predominantly MTC along with a small focus of metastatic PTC. Molecular testing using peripheral blood revealed a germline RET point mutation (Val804Met). Both tumors were analyzed for the BRAF (Val600Glu) mutation and the RET/PTC1 translocation. The PTC was positive for the BRAF mutation but negative for RET/PTC1. The MTC was negative for both abnormalities. We conclude that the MTC was caused by the germline RET mutation, while the PTC was caused by a somatic BRAF mutation. The occurrence of PTC in patients with germline RET mutations appears to be purely coincidental.
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PMID:Synchronous metastatic medullary and papillary thyroid carcinomas in a patient with germline RET mutation: case report, molecular analysis, and implications for pathogenesis. 2036 7

In 2006 there were 60,000 new cases of cutaneous melanoma in the European Union and 13,000 deaths (www.europeancancerleagues. org). Currently available systemic treatment options for metastatic melanoma, including both cytotoxic and immunologic therapies, produce low rates of response and have modest survival impact. Therefore, there is an urgent need for effective novel therapies. Molecularly targeted treatments have demonstrated efficacy in certain cancers e.g. in HER2- positive breast cancer and in chronic myeloid leukaemia. Several pathways are currently being investigated as potential molecular targets in melanoma. The best studied is BRAF which is frequently mutated in melanoma. A multi tyrosine kinase inhibitor, sorafenib, which targets BRAF, has shown promising activity in preclinical studies and is currently being tested in combination with chemotherapy in patients with metastatic disease. In addition to BRAF, therapies which target other components of the Raf/Ras/MAPK pathway are being investigated. Other novel targets currently being investigated include the PI3/AKT pathway, tyrosine kinases, angiogenesis, poly (ADP ribose) polymerases, survivin and heat shock protein 90. Progress on preclinical and clinical evaluation of these novel targets in melanoma will be reviewed.
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PMID:Prospects for non-immunological molecular therapeutics in melanoma. 2041 21


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