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

Many genes originally identified because of their role in embryonic development are also important in postnatal control of cell growth and differentiation. Mutations in some of these genes have been shown to cause cancer. Basal cell carcinoma (BCC) of the skin is the most common cancer in humans. More than 750000 new cases are diagnosed annually, and the incidence is rising. BCCs are slow-growing, locally invasive tumors that rarely metastasize but can result in extensive morbidity through local recurrence and tissue destruction. Epidemiologic studies suggest that sunlight (particularly UVB radiation) is a strong risk factor for BCC formation, although other factors are also involved. The nevoid basal cell carcinoma syndrome (NBCCS), a rare genetic disorder, is characterized by predisposition to BCCs and other tumors as well as to a wide range of developmental defects. NBCCS maps to chromosome 9q22.3, and loss of heterozygosity at this site in both sporadic and hereditary BCCs suggests that it functions as a tumor suppressor. The gene for NBCCS was recently cloned and is the human homologue of the Drosophila gene "patched." Genetic studies in Drosophila show that patched is part of the hedgehog signaling pathway, which is important in determining embryonic patterning and cell fate in multiple structures of the developing embryo. Human patched is mutated in both hereditary and sporadic BCCs, and inactivation of this gene is probably a necessary, if not sufficient, step for BCC formation. Delineation of the biochemical pathway in which patched functions may lead to rational medical therapy for BCCs and possibly for other tumors associated with NBCCS.
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PMID:Developmental genes and cancer: role of patched in basal cell carcinoma of the skin. 926 47

An increase in the incidence of papillary thyroid cancer has been documented in individuals exposed to Chernobyl fallout in 1986. Experiments using cultured human cells have suggested that radiation can induce the ret/PTC1 rearrangement involving the ret proto-oncogene. To test the hypothesis that the ret/PTC1 rearrangement is involved in the pathogenesis of Chernobyl-associated papillary thyroid carcinomas, we studied a panel of 31 cases from Belarus. All individuals lived in fallout-contaminated oblasts (regions) of Belarus at the time of the accident: Gomel (n = 13), Brest (n = 12), Minsk (n = 4), and Grodno (n = 2). All were under age 20 at the time of the accident; 20 were born between 1982 and 1986. Individual thyroid radiation doses were estimated at 1.1 to 110 rem. Patients underwent surgery in Minsk in 1996. Fifteen patients had locally advanced disease (stage T4). The majority had regional lymph node involvement (stage N1, n = 27). There were no distant metastases. Surgical specimens were frozen at -80 degrees C, RNA was extracted and cDNA prepared. The polymerase chain reaction (PCR) was performed with specific primers for ret/PTC1, and c-ret and GAPDH as controls. Controls were positive in all 31 cases. Nine cases yielded a positive PCR product for the ret/PTC1 rearrangement (29%). Thus, the ret/PTC1 rearrangement is a feature of some Chernobyl-associated papillary thyroid cancers, and is one possible mechanism involved in the pathogenesis of these cancers.
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PMID:The ret/PTC1 rearrangement is a common feature of Chernobyl-associated papillary thyroid carcinomas from Belarus. 951 Jan 21

Our research goal is to better understand the mechanisms controlling the initiation and progression of thyroid diseases. One such disease, papillary thyroid carcinoma (PTC), is the leading endocrine malignancy in the United States. Recently, a family of related fusion proteins, RET/PTC1-5, has been implicated in the early stages of PTC. Although all five members of this family have the c-RET proto-oncogene kinase domain in their COOH terminus, little is known about how these genes alter follicular cell biology. Consequently, to answer questions related to the mechanism of the RET/PTC fusion protein action, we have devised a molecular genetic strategy to study PTC using a mouse model of thyroid disease. A new member of this fusion oncogene family, RET/PTC3, which has been implicated in more cases of solid tumor carcinoma (79%) than PTC1 or PTC2 and predominates (80%) in radiation-induced thyroid cancer of children, was investigated in our study. We have generated transgenic mice expressing human RET/PTC3 exclusively in the thyroid. These mice develop thyroid hyperplasia, solid tumor variants of papillary carcinoma and metastatic cancer. This new transgenic line will be useful in deciphering the molecular and biological mechanisms that cause PTC and histological variations in humans.
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PMID:The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids. 985 89

In recent years developmental biology has contributed a great deal to cancer research. This is in part because both fields address the question of how genes control the three-dimensional organisation of tissues, and how mutation of genes alters this. But also in recent years, the discovery that signalling pathways are conserved from worms to man, combined with the power of developmental biology's model organisms, principally Drosophila and C. elegans, to reveal signalling pathways that control tissue growth and organisation, has had a huge impact. Examples of this are the subject of the reviews in this issue, including the EGF-receptor, Wnt/APC/catenin, TGF-beta/Smad and hedgehog/patched/smoothened pathways, all of which were discovered and/or pieced together in model organisms, and all of which are disrupted by mutation in human cancer. Other topics considered are the control and execution of apoptosis; the search for tumour-suppressor-like genes in Drosophila; and genes of the Polycomb and Trithorax Groups that regulate the commitment of cells to patterns of differentiation, and that are among the targets for chromosome translocations. These stories illustrate how developmental biology has shown that there are many more signalling pathways relevant to neoplasia than the receptor tyrosine kinase pathways that first dominated the field; and that the signalling is more than just mitogenic or anti-mitogenic, and should be viewed as providing cells with information about their position and neighbours, that determines their role, differentiation and behaviour.
Cancer Metastasis Rev 1999
PMID:The impact of developmental biology on cancer research: an overview. 1072 82

The hedgehog signalling pathway plays a vital role in Drosophila embryonic patterning and development. Hedgehog is a secreted protein, unrelated to classical growth factors, which seems to form concentration gradients across those tissues involved in pattern formation. Cloning of vertebrate homologues of hedgehog and other genes has illustrated the remarkable conservation of function of this pathway throughout evolution. The human homologue of patched, a receptor for the hedgehog protein, was cloned as the gene responsible for naevoid basal cell carcinoma syndrome (NBCCS/'Gorlin Syndrome'), an autosomal dominant condition in which patients suffer from multiple basal cell carcinomas and a wide spectrum of developmental abnormalities. Its role as a tumour suppressor gene in both NBCCS and sporadic basal cell carcinoma led to the suggestion that mutation or inactivation of human patched may be an essential step in development of basal cell carcinomas and other skin tumours. This review describes our current understanding of hedgehog signalling in Drosophila and vertebrates and its relation to the development of human basal cell carcinoma and other skin tumours, together with a discussion of future avenues of research into this critical and intriguing pathway.
Cancer Metastasis Rev 1999
PMID:The hedgehog signalling pathway and its role in basal cell carcinoma. 1072 88

Papillary thyroid carcinomas in humans are associated with the ret/PTC oncogene and, following loss of p53 function, may progress to anaplastic carcinomas. Mice with thyroid-targeted expression of ret/PTC1 developed papillary thyroid carcinomas that were minimally invasive and did not metastasize. These mice were crossed with p53-/- mice to investigate whether loss of p53 would promote anaplasia and metastasis of ret/PTC1-induced thyroid tumors. The majority of p53-/- mice died or were euthanized by 17 weeks of age due to the development of thymic lymphomas, soft tissue sarcomas, and testicular teratomas. All ret/PTC1 mice developed thyroid carcinomas, but tumors in p53-/- mice were more anaplastic, larger in diameter, more invasive, and had a higher mitotic index than tumors in p53+/+ and p53+/- mice. Thyroid tumors did not metastasize in any of the experimental p53+/+ and p53+/- mice </=28 weeks of age or p53-/- mice </= 17 weeks of age; however, an older (170-day-old) male p53-/- mouse used to maintain the colony developed anaplastic thyroid carcinoma with liver metastases. These findings demonstrate that the lack of functional p53 in ret/PTC1 mice promotes anaplasia and invasiveness of thyroid carcinomas.
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PMID:Loss of p53 promotes anaplasia and local invasion in ret/PTC1-induced thyroid carcinomas. 1093 69

The RET/PTC oncogenes, activated forms of the RET protooncogene, almost exclusively found in papillary thyroid carcinoma (PTC). What is more, the targeted expression of RET/PTC in mice leads to the development of thyroid tumors very similar to human PTCs. In all RET/PTC types the RET tyrosine kinase domain is fused to the N-terminus of ubiquitously expressed genes that is capable of ligand-independent dimerization. The majority of RET/PTC identified consists of two types which results from the inversion of chromosome 10: RET/PTC1 and RET/PTC3. The prevalence of RET/PTC in papillary thyroid carcinomas of thyroid varies widely from a few to about 80% with the highest frequency in tumors arising in children after ionizing radiation. In Polish population the frequency of RET rearrangements in papillary cancers is 27%, although, it was reported to be twice higher in young patients (50% in patients younger than 21 at operation). Correlation with clinical outcome as well as prognostic value of RET/PTC is controversial. Some authors suggest that it predicts metastases, others found rearranged RET in more favourable, slow growing tumors. RET/PTC3 seems to be associated with solid/follicular variant PTC and short latency period (it is found more frequently in children) whereas RET/PTC1--with classic PTC variant and long latency.
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PMID:[Rearrangement of the RET gene in papillary thyroid carcinoma]. 1218 64

Rearrangements of the RET receptor tyrosine kinase gene generating RET/PTC oncogenes are specific to papillary thyroid carcinoma (PTC), the most frequent thyroid tumor. Here, we show that the RET/PTC1 oncogene, when exogenously expressed in primary normal human thyrocytes, induces the expression of a large set of genes involved in inflammation and tumor invasion, including those encoding chemokines (CCL2, CCL20, CXCL8, and CXCL12), chemokine receptors (CXCR4), cytokines (IL1B, CSF-1, GM-CSF, and G-CSF), matrix-degrading enzymes (metalloproteases and urokinase-type plasminogen activator and its receptor), and adhesion molecules (L-selectin). This effect is strictly dependent on the presence of the RET/PTC1 Tyr-451 (corresponding to RET Tyr-1062 multidocking site). Selected relevant genes (CCL20, CCL2, CXCL8, CXCR4, L-selectin, GM-CSF, IL1B, MMP9, UPA, and SPP1/OPN) were found up-regulated also in clinical samples of PTC, particularly those characterized by RET/PTC activation, local extrathyroid spread, and lymph node metastases, when compared with normal thyroid tissue or follicular thyroid carcinoma. These results, demonstrating that the RET/PTC1 oncogene activates a proinflammatory program, provide a direct link between a transforming human oncogene, inflammation, and malignant behavior.
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PMID:Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. 1620 90

RET/PTC rearrangements are initiating events in the development of a significant proportion of papillary thyroid carcinomas. Activated RET/PTC mutations are thought to be restricted to thyroid disease, but this study proposes that these events may also occur in nonthyroid tumors. A total of 57 nonthyroid papillary tumors were examined for RET/PTC rearrangements using interphase fluorescence in situ hybridization, Taqman reverse transcriptase polymerase chain reaction, and immunohistochemistry. Taqman single nucleotide polymorphism detection was used to analyze for expression of mutated BRAF T1799A. In all, 20% (3/15) of primary peritoneal carcinoma had detectable RET/PTC1 rearrangements by all 3 methodologies. A further case of similar histotype had an alternate RET/ PTC rearrangement. No RET/PTC1 rearrangements were detected in the remaining tumor cohort. All 57 tumors were homozygous for wild-type BRAF. The results indicate that RET/PTC rearrangements occur in a small subset of nonthyroid papillary tumors. These rearrangements may not be directly implicated in tumor growth; rather representing "passenger" mutations reflecting RET instability in secondary tumor subclones.
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PMID:RET/PTC rearrangement occurring in primary peritoneal carcinoma. 1914 13

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


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