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

The growth of immunogenic tumors in immunocompetent individuals is one of the oldest conundrums in tumor immunology. Although the ability of mouse CD8+ T cells to control transplanted tumors is well documented, little is known about their impact on autochthonous tumors. To gain insight into the role of CD8+ T cells during the course of cancer development, we produced a novel model of spontaneous melanoma. The metallothionein (MT)-ret/AAD mouse is transgenic for the RET oncogene and the chimeric MHC molecule AAD (alpha1-alpha2 domains of HLA-A2 linked to alpha3 domain of H2-Dd). This model recapitulates the natural history of human melanoma, and expression of the AAD molecule makes it suitable for analyzing CD8+ T cell responses directed against peptide Ags that have been previously identified in HLA-A2+ melanoma patients. We found that, as tumors grow, mice develop a broad melanoma-specific CD8+ T cell response. Occurrence of cutaneous nodules is not affected by CD8+ T cell depletion, showing that although CD8+ T cells are functional, they have no effect on established cutaneous tumors. However, depleted mice die from visceral disease much earlier than controls, showing that CD8+ T cells control metastasis spreading and disease progression. Antigenic modulation is observed in visceral metastases, suggesting that visceral nodules may be subject to immunoediting. Our data demonstrate that growth of melanoma in the MT-ret/AAD model involves several tolerance mechanisms sequentially. They also reveal a different role for CD8+ T cells toward early stage of cutaneous tumors and late visceral metastatic stage of the disease.
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PMID:Distinct role for CD8 T cells toward cutaneous tumors and visceral metastases. 1809 12

The RET receptor tyrosine kinase has essential roles in cell survival, differentiation, and proliferation. Oncogenic activation of RET causes the cancer syndrome multiple endocrine neoplasia type 2 (MEN 2) and is a frequent event in sporadic thyroid carcinomas. However, the molecular mechanisms underlying RET's potent transforming and mitogenic signals are still not clear. Here, we show that nuclear localization of beta-catenin is frequent in both thyroid tumors and their metastases from MEN 2 patients, suggesting a novel mechanism of RET-mediated function through the beta-catenin signaling pathway. We show that RET binds to, and tyrosine phosphorylates, beta-catenin and show that the interaction between RET and beta-catenin can be direct and independent of cytoplasmic kinases, such as SRC. As a result of RET-mediated tyrosine phosphorylation, beta-catenin escapes cytosolic down-regulation by the adenomatous polyposis coli/Axin/glycogen synthase kinase-3 complex and accumulates in the nucleus, where it can stimulate beta-catenin-specific transcriptional programs in a RET-dependent fashion. We show that down-regulation of beta-catenin activity decreases RET-mediated cell proliferation, colony formation, and tumor growth in nude mice. Together, our data show that a beta-catenin-RET kinase pathway is a critical contributor to the development and metastasis of human thyroid carcinoma.
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PMID:A novel RET kinase-beta-catenin signaling pathway contributes to tumorigenesis in thyroid carcinoma. 1831 96

Medullary thyroid cancer (MTC) is a highly malignant tumor of the thyroid gland in children, rarely diagnosed and treated by pediatric oncologists. The authors describe a 9-year-old male who presented with facial dysmorphism and history of chronic diarrhea before being diagnosed with advanced MTC. Familiarity with its clinical variants, associated RET protooncogene mutation and its clinical implication, can lead to early identification of this aggressive tumor. To date, surgery remains the only definitive therapy, with continuing dismal prognosis in metastatic disease. However, evolving newer therapeutic strategies like tyrosine kinase inhibitors and pretargeted radioimmunotherapy (pRAIT) may provide hope to children with this aggressive tumor.
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PMID:Chronic diarrhea and facial dysmorphism in children--a clue to men 2B syndrome: a case report. 1836 82

Since the 1980s, cancer cells have been considered to be derived from well-differentiated normal cells via multiple incidents of damage to their genome, especially in oncogenes or tumor suppressor genes, which accelerate proliferation or foster malignant phenotypes, such as the ability to invade the surrounding tissue or metastasize to distant organs. In the thyroid, a novel hypothesis of carcinogenesis, the "fetal cell carcinogenesis" hypothesis, in which thyroid cancer cells are derived from the remnants of fetal cells, instead of well-differentiated somatic cells, such as thyrocytes, by de-differentiation, is proposed. In this hypothesis, thyroid cancer cells are generated from three types of fetal thyroid cells, thyroid stem cells(TSCs), thyroblasts and prothyrocytes by proliferation without differentiation, which results in anaplastic, papillary and follicular carcinoma, respectively. Genomic alternations, such as RET/PTC and PAX8-PPARgamma1 rearrangements and a mutation in the BRAF gene, play an oncogenic role by preventing thyroid fetal cells from differentiating. This hypothesis well explains the clinical and biological features and recent molecular evidence of thyroid cancer. Further, it underscores the importance of identifying stem cells and clarifying the molecular mechanism of organ development. Such data will lead to better understanding of thyroid carcinogenesis and the establishment of more accurate diagnostic methods and more effective therapies. Analysis of molecular behavior in a single tumor cell will be a key technology in the future clinical pathology. Fetal cell science may be the leading research theme in the next few decades.
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PMID:[Fetal cell carcinogenesis hypothesis and its impact on clinical pathology of cancer]. 1854 90

RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3-72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20-72 and distant metastases in 4 subjects aged 28-69. Forty-one subjects had pheochromocytoma detected at age 18-67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26-52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20% by age 30 and 67% by age 50, and for HPT penetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.
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PMID:Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation. 1879 25

In 1987, Carney et al reported 11 thyroid tumors with the following features: circumscription or encapsulation, trabecular architecture with intratrabecular hyalin and colloid, polygonal and spindle cells, nuclei with frequent grooves and cytoplasmic inclusions, occasional psammoma bodies, and a low mitotic rate. The neoplasms did not recur or metastasize during a follow-up period that averaged 10 years, and they were titled hyalinizing trabecular adenomas. Subsequently, the nuclear features of the neoplasm led to the introduction of 2 modified titles for it, hyalinizing trabecular tumor and hyalinizing trabecular neoplasm. Later, discovery of RET/PTC mutations in the tumor resulted in it being designated as a type of papillary thyroid carcinoma. We studied 119 neoplasms of the type outlined, collected over a 20-year period, for invasion, recurrence and metastasis, and obtained follow-up in 96% of the cases. One hundred eighteen tumors showed no evidence of aggressive behavior (capsular, vascular, and parenchymal invasion), local recurrence, or metastasis. One tumor showed vascular and capsular invasion, and pulmonary metastasis. We conclude that the overwhelming majority of hyalinizing trabecular tumors of the thyroid behave as benign neoplasms and that, at this time, hyalinizing trabecular adenoma is the most appropriate title for them.
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PMID:Hyalinizing trabecular tumors of the thyroid gland are almost all benign. 1881 21

'Calcitonin screening' is not accepted as the standard of care in daily practice. The clinical and surgical consequences of 'calcitonin screening' in a series of patients with mildly elevated basal calcitonin and pentagastrin stimulated calcitonin levels are presented. 260 patients with elevated basal (>10 pg/ml) and stimulated calcitonin levels (>100 pg/ml) were enrolled in this prospective study. None of the patients was member of a known medullary thyroid carcinoma family. Thyroidectomy and bilateral central and lateral neck dissections were performed. Testing for the presence of germ-line mutations was performed in all patients. Histological and immunohistochemical findings were compared with basal and stimulated calcitonin levels. All patients were subsequently followed biochemically. C-cell hyperplasia (CCH) was found in 126 (49%) and medullary thyroid cancer was found in 134 (51%) patients. RET proto-oncogen mutations were documented in 22 (8%) patients (medullary thyroid cancer:18, CCH:4). In 56 (46%) of 122 patients, sporadic CCH was classified neoplastic ('carcinoma in situ'). Of 97 (72%; 10 with hereditary medullary thyroid cancer) had pT1 (International Union against Cancer recommendations 2002) and 33 (25%) had pT2 or pT3 and 4 (3%) pT4 tumors. Of 39 (29.1%) had lymph node metastases. 106 (79.1%; 15 (38.5%) with lymph node metastases) patients were cured. Evaluation of basal and stimulated calcitonin levels enables the prediction of medullary thyroid cancer. All patients with basal calcitonin >64 pg/ml and stimulated calcitonin >560 pg/ml have medullary thyroid cancer. Medullary thyroid cancer was documented in 20% of patients with basal calcitonin >10 pg/ml but <64 pg/ml and stimulated calcitonin >100 pg/ml but <560 pg/ml.
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PMID:Sporadic hypercalcitoninemia: clinical and therapeutic consequences. 1898 70

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

In endocrine malignancies (thyroid carcinoma, parathyroid carcinoma, adrenocortical carcinoma, malignant pheochromocytoma) surgery is currently the treatment of choice, in case of differentiated thyroid carcinomas followed by 131-I-radioiodine administration. This approach is often successful in early disease; however, treatment options for advanced endocrine malignancies remain unsatisfactory and prognosis is poor. In particular, cytotoxic chemotherapy and radiation therapy often show only limited and transient efficacy and are associated with significant toxicity. Thus, new treatment options are urgently needed. Advances in the understanding of the molecular pathology of endocrine malignancies has recently led to identification of key events in endocrine oncogenesis (e.g. oncogenic RET mutations in medullary thyroid carcinoma or RET/PTC rearrangements in papillary thyroid carcinoma). These new insights are increasingly matched by new compounds (e.g. tyrosine kinase inhibitors) targeting signaling pathways essential for tumor cell survival, proliferation and metastases. Accordingly, a rapidly growing number of preclinical investigations and early clinical trials in endocrine malignancies have been initiated. First results of "targeted therapies" in medullary and differentiated thyroid carcinoma are impressive: phase II trials targeting RET or VEGF receptor kinases led to objective tumor response in up to 50% of patients. This review covers these recent molecular and clinical advances which most likely will dramatically alter the treatment of endocrine malignancies within the coming decade.
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PMID:New targets and therapeutic approaches for endocrine malignancies. 1937 19

RET codon 609 point mutations are rare and may predispose to aggressive medullary thyroid carcinoma (MTC). In a kindred with 15 carriers of the Cys609Ser RET mutation we observed no MTC before 17 years of age, no lymph node metastases before 30 years and no distant metastases before 60 years. Two patients developed pheochromocytoma and one had primary hyperparathyroidism as the first sign of the syndrome. In conclusion, at variance from what already known, in this large kindred the Cys609Ser RET mutation predispose to a scarcely aggressive, highly penetrant MTC and a low penetrance of pheochromocytoma and primary hyperparathyroidism.
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PMID:Characterization of the largest kindred with MEN2A due to a Cys609Ser RET mutation. 1947 97


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