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

Background: Myxoid chondrosarcoma (MCS) is a rare, low-grade, indolent tumor that can occur in soft tissue and bone. It is, however, capable of distant metastases. Previous cytogenetic data include a translocation, t(9;22)(q22-31;q12), occurring in 6 of 14 cases of the extraskeletal variant of the disease. Recently, rearrangement of the EWS gene has been reported in MCS. Methods and Results: Three cases of MCS, two skeletal and one extraskeletal, were examined to identify primary cytogenetic changes and correlate these with immunohistochemical, ultrastructural, and flow-cytometric analysis. The extraskeletal variant of MCS revealed a clonal translocation, t(9;22)(q22;q12), and trisomy for chromosomes 5, 7, 8, 12, 18, and 19. Our two cases of skeletal MCS showed complex karyotypes. In one skeletal tumor, a cryptic translocation involving chromosome 6p21.3 was identified by fluorescence in situ hybridization analysis, using chromosome-specific libraries. Conclusions: Thus far, 50% of cases of extraskeletal MCS, including our cases, have demonstrated a specific translocation, t(9;22)(q22-31;q12). Identifying this translocation is useful in confirming the diagnosis of MCS. Additional cytogenetic and molecular analysis is useful for detecting this translocation, and is also essential to determine other regions of possible diagnostic importance, such as the 6p21.3 breakpoint demonstrated in the present study. These techniques may be most useful for the skeletal lesions, in light of their heterogeneous cell populations and karyotypic variability.
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PMID:Extraskeletal and Skeletal Myxoid Chondrosarcoma: A Multiparameter Analysis of Three Cases Including Cytogenetic Analysis and Fluorescence In Situ Hybridization. 1033 Feb 5

Serous effusions are a frequently encountered clinical manifestation of metastatic disease, with breast, ovarian, and lung carcinomas and malignant mesothelioma (MM) leading the list. Recently, extensive research has resulted in expansion of the antibody panel that is available for effusion diagnosis, thereby reducing the risk for error. Despite this progress, relatively little has been done in way of understanding the biology of cancer cells in effusions, especially those of nonovarian origin. The diagnosis of a malignant effusion signifies disease progression and is associated with a worse prognosis regardless of the tumor site of origin. However, survival is much more variable with ovarian cancer compared with other tumors. Furthermore, cancer cells of different origins differ considerably in their biology and have unique phenotypic and genotypic characteristics. This review summarizes the current knowledge in this field and presents a model for the study of tumor metastasis and disease progression, through large comparative studies of malignant cells in effusions, primary tumors, and solid metastases. The case also is made for potential applications of this rapidly evolving body of knowledge in the diagnosis, classification, and prediction of biological behavior of processes resulting in cryptic effusions at the clinical level.
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PMID:Malignant effusions: from diagnosis to biology. 1545 97

Mucoepidermoid carcinomas (MECs) of the salivary and bronchial glands are characterized by a recurrent t(11;19)(q21;p13) translocation resulting in a MECT1-MAML2 fusion in which the CREB-binding domain of the CREB coactivator MECT1 (also known as CRTC1, TORC1 or WAMTP1) is fused to the transactivation domain of the Notch coactivator MAML2. To gain further insights into the molecular pathogenesis of MECs, we cytogenetically and molecularly characterized a series of 29 MECs. A t(11;19) and/or an MECT1-MAML2 fusion was detected in more than 55% of the tumors. Several cases with cryptic rearrangements that resulted in gene fusions were detected. In fusion-negative MECs, the most common aberration was a single or multiple trisomies. Western blot and immunohistochemical studies demonstrated that the MECT1-MAML2 fusion protein was expressed in all MEC-specific cell types. In addition, cotransfection experiments showed that the fusion protein colocalized with CREB in homogeneously distributed nuclear granules. Analyses of potential downstream targets of the fusion revealed differential expression of the cAMP/CREB (FLT1 and NR4A2) and Notch (HES1 and HES5) target genes in fusion-positive and fusion-negative MECs. Moreover, clinical follow-up studies revealed that fusion-positive patients had a significantly lower risk of local recurrence, metastases, or tumor-related death compared to fusion-negative patients (P = 0.0012). When considering tumor-related deaths only, the estimated median survival for fusion-positive patients was greater than 10 years compared to 1.6 years for fusion-negative patients. These findings suggest that molecularly classifying MECs on the basis of an MECT1-MAML2 fusion is histopathologically and clinically relevant and that the fusion is a useful marker in predicting the biological behavior of MECs.
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PMID:Molecular classification of mucoepidermoid carcinomas-prognostic significance of the MECT1-MAML2 fusion oncogene. 1644 49

Expression of melanoma invasiveness, ultimately leading to the formation of metastases, requires that cancer cells break through the successive skin barriers (dermo-epidermal junction, dermis) constituted of various extracellular matrix constituents. In order to facilitate their progression, melanoma cells express, in concert with stromal cells, a group of proteolytic systems which degrade this extracellular structures. However, proteolysis of basement membrane, collagen or elastic fibers can uncover cryptic sites or/and liberate matrix fragments whose properties appeared distinct from their intact macromolecule counterparts. Those fragments, called matrikines, are able to empede or to accelerate melanoma progression ex vivo and in vivo. Non-collagenous domains of basement membrane collagens, which behave like potent "matstatins", are seen as potential pharmacological agents in melanoma.
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PMID:[Role of matrikins in melanoma progression]. 1656 8

Metastasis from the primary tumor to distant sites involves an array of molecules that function in an integrated manner. Proteolytic remodeling and subsequent tumor cell interactions with the extracellular matrix regulate tumor invasion. In previous studies, we have identified a cryptic epitope (HUIV26) that is specifically exposed after alterations in the triple helical structure of type IV collagen. Exposure of this cryptic epitope plays a fundamental role in the regulation of angiogenesis in vivo. However, little is known concerning the ability of tumor cells to interact with this cryptic site or whether this site regulates tumor cell metastasis in vivo. In this regard, many of the same cellular processes that regulate angiogenesis also contribute to tumor metastasis. Here we provide evidence that tumor cells such as B16F10 melanoma interact with denatured collagen type IV in part by recognizing the HUIV26 cryptic site. Systemic administration of a HUIV26 monoclonal antibody inhibited experimental metastasis of B16F10 melanoma in vivo. Taken together, our findings suggest that tumor cell interactions with the HUIV26 cryptic epitope play an important role in regulating experimental metastasis and that this cryptic element may represent a therapeutic target for controlling the spread of tumor cells to distant sites.
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PMID:Inhibition of experimental metastasis by targeting the HUIV26 cryptic epitope in collagen. 1665 24

The epithelial-mesenchymal transition (EMT) is a critical step for pancreatic cancer cells as an entry of metastatic disease. Wide variety of cytokines and signaling pathways are involved in this complex process while the entire picture is still cryptic. Recently, miRNA was found to regulate cellular function including EMT by targeting multiple mRNAs. We conducted comprehensive analysis of miRNA expression profiles in invasive ductal adenocarcinoma (IDA), intraductal papillary mucinous adenoma, intraductal papillary mucinous carcinoma, and human pancreatic cancer cell line to elucidate essential miRNAs which regulate invasive growth of pancreatic cancer cells. Along with higher expression of miR-21 which has been shown to be highly expressed in IDA, reduced expression of miR-126 in IDA and pancreatic cancer cell line was detected. The miR-126 was found to target ADAM9 (disintegrin and metalloproteinase domain-containing protein 9) which is highly expressed in pancreatic cancer. The direct interaction between miR-126 and ADAM9 mRNA was confirmed by 3' untranslated region assay. Reexpression of miR-126 and siRNA-based knockdown of ADAM9 in pancreatic cancer cells resulted in reduced cellular migration, invasion, and induction of epithelial marker E-cadherin. We showed for the first time that the miR-126/ADAM9 axis plays essential role in the inhibition of invasive growth of pancreatic cancer cells.
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PMID:MiR-126 acts as a tumor suppressor in pancreatic cancer cells via the regulation of ADAM9. 2284 3

One hallmark of cancer is the degradation of the extracellular matrix (ECM), which is caused by proteinases. In oral cancers, matrix metalloproteinases (MMPs), especially MMP-9, are associated with this degradation. MMPs break down the ECM allowing cancer to spread; they also release various factors from their cryptic sites, including cytokines. These factors modulate cell behavior and enhance cancer progression by regulating angiogenesis, migration, proliferation, and invasion. The development of early metastases is typical for oral cancer, and increased MMP-9 expression is associated with a poor disease prognosis. However, many studies fail to relate MMP-9 expression with metastasis formation. Contrary to earlier models, recent studies show that MMP-9 plays a protective role in oral cancers. Therefore, the role of MMP-9 is complicated and may fluctuate throughout the different types and stages of oral cancers.
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PMID:Fluctuating roles of matrix metalloproteinase-9 in oral squamous cell carcinoma. 2336 50

Ets-1 overexpression in human breast cancers is associated with invasiveness and poor prognosis. By overexpressing Ets-1 or a dominant negative mutant in MMT breast cancer cells, we previously highlighted the key role of Ets-1 in coordinating multiple invasive features of these cells. Interestingly, we also noticed that Ets-1 decreased the density of breast cancer cells cultured in three-dimensional extracellular matrix gels. The 3D context was instrumental to this phenomenon, as such downregulation was not observed in cells grown on two-dimensional plastic or matrix-coated dishes. Ets-1 overexpression was deleterious to anchorage-independent growth of MMT cells in soft agar, a standard model for in vitro tumorigenicity. The relevance of this mechanism was confirmed in vivo, during primary tumor growth and in a metastatic assay of lung colonization. In these models, Ets-1 was associated with epithelial-to-mesenchymal transition features and modulated the ratio of Ki67-positive cells, while hardly affecting in vivo apoptotic cell death. Finally, siRNA-mediated knockdown of Ets-1 in human breast cancer cell lines also decreased colony growth, both in anchorage-independent assays and 3D extracellular matrix cultures. These in vitro and in vivo observations shed light on an unsuspected facet of Ets-1 in breast tumorigenesis. They show that while promoting malignancy through the acquisition of invasive features, Ets-1 also attenuates breast tumor cell growth and could therefore repress the growth of primary tumors and metastases. This work also demonstrates that 3D models may reveal mechanisms of tumor biology that are cryptic in standard 2D models.
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PMID:Ets-1 controls breast cancer cell balance between invasion and growth. 2470 81

Metastasis is responsible for most cancer-related deaths, and, among common tumor types, melanoma is one with great potential to metastasize. Here we study the contribution of epigenetic changes to the dissemination process by analyzing the changes that occur at the DNA methylation level between primary cancer cells and metastases. We found a hypomethylation event that reactivates a cryptic transcript of the Rab GTPase activating protein TBC1D16 (TBC1D16-47 kDa; referred to hereafter as TBC1D16-47KD) to be a characteristic feature of the metastatic cascade. This short isoform of TBC1D16 exacerbates melanoma growth and metastasis both in vitro and in vivo. By combining immunoprecipitation and mass spectrometry, we identified RAB5C as a new TBC1D16 target and showed that it regulates EGFR in melanoma cells. We also found that epigenetic reactivation of TBC1D16-47KD is associated with poor clinical outcome in melanoma, while conferring greater sensitivity to BRAF and MEK inhibitors.
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PMID:Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. 2622 7

Objective. To show that I-131 false-positive results on whole-body scans (WBSs) after thyroidectomy for thyroid cancer may be a result of inflammation unassociated with the cancer. Methods. We performed a retrospective image analysis of our database of thyroid cancer patients who underwent WBS from January 2008 to January 2012 to identify and stratify false positives. Results. A total of 564 patients underwent WBS during the study period; 96 patients were referred for 99 I-131 single-photon emission computed tomography (SPECT/CT) scans to better interpret cryptic findings. Among them, 73 scans were shown to be falsely positive; 40/73 or 54.7% of false-positive findings were a result of inflammation. Of the findings, 17 were in the head, 1 in the neck, 4 in the chest, 3 in the abdomen, and 14 in the pelvis; 1 had a knee abscess. Conclusions. In our series, inflammation caused the majority of false-positive WBSs. I-131 SPECT/CT is powerful in the differentiation of inflammation from thyroid cancer. By excluding metastatic disease, one can properly prognosticate outcome and avoid unnecessary, potentially harmful treatment of patients with thyroid cancer.
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PMID:In Thyroidectomized Thyroid Cancer Patients, False-Positive I-131 Whole Body Scans Are Often Caused by Inflammation Rather Than Thyroid Cancer. 2697 18


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