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)

Urinary bladder cancer is a heterogeneous disease with tumors ranging from papillary non-invasive to solid muscle infiltrating high grade tumors. There are mainly three problems after initial management: recurrence, progression to higher stage and metastases. The respective risk is well known for each of the stages of the disease but not sufficiently for individual optimal risk assessments. The clinical need is initially to establish the correct risk irrespective of later treatment that is to find prognostic factors. Secondarily it is important to develop predictive factors for each specific therapy. With the advent of array-based molecular profiling it is possible to obtain a more complete picture of the cancer biology and thus hope to improve the prediction of risk. Today the microarray approach is implemented at DNA, RNA and protein level. Reported chromosomal alterations in low-grade papillary tumors are few and the most common are 9q and 9p deletions. Activation of the MAPK pathway through mutations of FGFR3, RAS or PI3K seems to be crucial in the genesis of these low malignant tumors. Muscle infiltrating bladder tumors typically have more genetic aberrations than non-muscle invasive cancers. Key genes are related to the p53 and RB pathways. Gene-expression signatures correlated to stage, CIS, progression and recurrence have been proposed but require further validation.
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PMID:Molecular genetics of bladder cancer: an update. 1892 58

Osteopontin (OPN) is a secreted phosphoprotein which mediates tumorigenesis, local growth, and metastasis in a variety of cancers. It is a potential therapeutic target for the regulation of cancer metastasis. RNA aptamer technology targeting OPN may represent a clinically viable therapy. In this study, we characterize the critical sequence of an RNA aptamer, termed OPN-R3, directed against human OPN. It has a K(d) of 18 nmol/l and binds specifically to human OPN as determined by RNA electrophoretic mobility assays. In MDA-MB231 human breast cancer cells examined under fluorescence microscopy, OPN-R3 ablates cell surface binding of OPN to its cell surface CD44 and alpha(v)beta(3) integrin receptors. Critical enzymatic components of the OPN signal transduction pathways, PI3K, JNK1/2, Src and Akt, and mediators of extracellular matrix degradation, matrix metalloproteinase 2 (MMP2) and uroplasminogen activator (uPA), are significantly decreased following exposure to OPN-R3. OPN-R3 inhibits MDA-MB231 in vitro adhesion, migration, and invasion characteristics by 60, 50, and 65%, respectively. In an in vivo xenograft model of breast cancer, OPN-R3 significantly decreases local progression and distant metastases. On the basis of this "proof-of-concept" study, we conclude that RNA aptamer targeting of OPN has biologically relevance for modifying tumor growth and metastasis.
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PMID:RNA aptamer blockade of osteopontin inhibits growth and metastasis of MDA-MB231 breast cancer cells. 1898 31

Chondrosarcoma is a low-grade sarcoma characterized by developing metastases and high local recurrence rate. Bone morphogenetic protein-2 (BMP-2) plays an essential role in tumor progression and metastasis. Here we found that BMP-2 induced the migration of human chondrosarcoma cells (JJ012 cells). BMP-2 also increased the secretion of metalloproteinase-13 (MMP-13) in JJ012 cells, as shown by reverse transcriptase-polymerase chain reaction, western blot and zymographic analysis. The MMP-13 small interfering RNA inhibited the BMP-2-induced MMP-13 expression and thereby significantly inhibited the BMP-2-induced cell migration. Furthermore, phosphatidylinositol 3-kinase inhibitor (PI3K; Ly294002) or Akt inhibitor suppressed BMP-2-induced MMP-13 mRNA expression. Transient transfection with dominant negative p85 and Akt mutant also showed that the PI3K/Akt signaling pathway was involved in BMP-2-induced MMP-13 expression. In addition, AP-1 decoy oligodeoxynucleotide also suppressed the MMP-13 promoter activity enhanced by BMP-2. Moreover, BMP-2 increased the binding of c-Fos and c-Jun to the AP-1 element on the MMP-13 promoter. Taken together, our results indicated that BMP-2 enhanced the invasiveness of chondrosarcoma cells by increasing MMP-13 expression through the PI3K, Akt, c-Fos/c-Jun and AP-1 signal transduction pathway.
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PMID:Bone morphogenetic protein-2 enhances the motility of chondrosarcoma cells via activation of matrix metalloproteinase-13. 1903 72

Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Understanding the distinct genetic and epigenetic changes contributing to the establishment and growth of metastatic lesions is crucial for the development of novel therapeutic strategies. In a search for key regulators of colorectal cancer metastasis establishment, we have found that the serine/threonine kinase Akt2, a known proto-oncogene, is highly expressed in late-stage colorectal cancer and metastatic tumors. Suppression of Akt2 expression in highly metastatic colorectal carcinoma cells inhibits their ability to metastasize in an experimental liver metastasis model. Overexpression of wild-type Akt1 did not restore metastatic potential in cells with downregulated Akt2, thus suggesting non-redundant roles for the individual Akt isoforms. In contrast, Akt2 overexpression in wild-type PTEN expressing SW480 colorectal cancer cells led to the formation of micrometastases; however, loss of PTEN is required for sustained formation of overt metastasis. Finally, we found that the consequence of PTEN loss and Akt2 overexpression function synergistically to promote metastasis. These results support a role for Akt2 overexpression in metastatic colorectal cancer and establish a mechanistic link between Akt2 overexpression and PTEN mutation in metastatic tumor establishment and growth. Taken together, these data suggest that Akt family members have distinct functional roles in tumor progression and that selective targeting of the PI3K/Akt2 pathway may provide a novel treatment strategy for colorectal cancer metastasis.
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PMID:Akt2 overexpression plays a critical role in the establishment of colorectal cancer metastasis. 1907 30

The transforming growth factor beta, Hedgehog, Notch, and Wnt signaling pathways all play critical roles in the development and progression of prostate cancer. It is becoming increasingly apparent that these pathways may intersect with developmentally important transcription factors such as the sex-determining region Y-box 4 (SOX4), homeobox C6, enhancer of zeste 2, and ETS-related gene, which are up-regulated in prostate cancers. For example, identification of the downstream targets of SOX4 and homeobox C6 suggests that these factors may cooperate to activate the Notch pathway and the PI3K/AKT pathway, possibly in response to Wnt signals. PI3K/AKT activation likely occurs indirectly via up-regulation of growth factor receptors, while Notch activation is secondary to up-regulation of Notch pathway components. In addition, SOX4 may affect terminal differentiation via regulation of other transcription factors such as NKX3.1 and MLL, and regulation of components of the microRNA pathway such as Dicer and Argonaute 1. The evidence supporting activation of these pathways in prostate cancer progression suggests that combinations of compounds targeting them may be of benefit to patients with aggressive, metastatic disease.
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PMID:The Sex-determining region Y-box 4 and homeobox C6 transcriptional networks in prostate cancer progression: crosstalk with the Wnt, Notch, and PI3K pathways. 2001 90

Immunodeficient animal models are invaluable tools to investigate the metastatic propensity of human tumours. However residual immune responses, in particular natural killer (NK) cells, severely hamper the traffic and growth of human tumour cells. We studied whether a genetically modified mouse host lacking T, B and NK immunity allowed an improved expression of the metastatic phenotype of malignant human tumours. Metastatic spread of a panel of human sarcoma cell lines was studied in double knockout Rag2(-/-);gammac(-/-) mice in comparison with NK-depleted nude mice. Rag2(-/-);gammac(-/-) mice receiving intravenous (i.v.) or subcutaneous (s.c.) human sarcoma cell lines developed extensive multiorgan metastases. Metastatic efficiency in Rag2(-/-);gammac(-/-) was superior than in nude mice in terms of both metastatic sites and metastasis number. Metastatic growth in Rag2(-/-);gammac(-/-) mice was faster than that in nude mice, thus allowing an earlier metastasis evaluation. Most human sarcomas metastasised in the liver of Rag2(-/-);gammac(-/-) mice, a kind of organ preference undetectable in nude mice and specific of sarcomas, as several carcinoma cell lines failed to colonise the liver of Rag2(-/-);gammac(-/-) mice, independently of their metastatic spread to other sites. In vitro analysis of the molecular mechanisms of liver metastasis of sarcomas implicated liver-produced growth and motility factors, in particular the insulin-like growth factor (IGF) axis. NVP-BEZ235, a specific inhibitor of downstream signal transduction targeting PI3K and mTOR, strongly inhibited liver metastasis of human sarcoma cells. In conclusion, the Rag2(-/-);gammac(-/-) mouse model allowed the expression of human metastatic phenotypes inapparent in conventional immunodeficient mice and the preclinical testing of appropriate targeted therapies.
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PMID:High metastatic efficiency of human sarcoma cells in Rag2/gammac double knockout mice provides a powerful test system for antimetastatic targeted therapy. 2003 88

Wild-type KRAS status is required but not sufficient to confer sensitivity to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAbs) in colorectal cancer patients. As a consequence, one of the major challenges is to identify, in non-mutant KRAS patients, other markers that can predict lack of response to this therapy. Small series have investigated the clinical effect of PIK3CA mutations on resistance to anti-EGFR mAbs and discrepant results have been observed. Furthermore, PTEN loss in metastases may be predictive of resistance to anti-EGFR mAbs, even if PTEN determination is far from an immediate clinical application. The introduction of modulators of the PI3K/AKT/mTOR pathway as potential targeted anticancer drugs is encouraging, but this attractive therapy option is still at an early stage of development.
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PMID:The dark side of the moon: the PI3K/PTEN/AKT pathway in colorectal carcinoma. 2013 Apr 34

Research interest in lymphangioleiomyomatosis (LAM) has grown dramatically in the past decade, particularly among cancer biologists. There are at least two reasons for this: first, the discovery in the year 2000 that LAM cells carry TSC2 gene mutations, linking LAM with cellular pathways including the PI3K/Akt/mTOR axis, and allowing the Tuberous Sclerosis Complex (TSC)-regulated pathways that are believed to underlie LAM pathogenesis to be studied in cells, yeast, Drosophila, and mice. A second reason for the rising interest in LAM is the discovery that LAM cells can travel to the lung, including repopulating a donor lung after lung transplantation, despite the fact that LAM cells are histologically benign. This "benign metastasis" underpinning suggests that elucidating LAM pathogenesis will unlock a set of fundamental mechanisms that underlie metastatic potential in the context of a cell that has not yet undergone malignant transformation. Here, we will outline the data supporting the metastatic model of LAM, consider the biochemical and cellular mechanisms that may enable LAM cells to metastasize, including both cell autonomous and non-cell autonomous factors, and highlight a mouse model in which estrogen promotes the metastasis and survival of TSC2-deficient cells in a MEK-dependent manner. We propose a multistep model of LAM cell metastasis that highlights multiple opportunities for therapeutic intervention. Taken together, the metastatic behavior of LAM cells and the involvement of tumor-related signaling pathways lead to optimism that cancer-related paradigms for diagnosis, staging, and therapy will lead to therapeutic breakthroughs for women living with LAM.
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PMID:mTOR activation, lymphangiogenesis, and estrogen-mediated cell survival: the "perfect storm" of pro-metastatic factors in LAM pathogenesis. 2023 86

Patients with well-differentiated neuroendocrine tumours of the gastrointestinal tract often present with metastases and hormonal symptoms. These patients can be palliated by interventional tumour reduction and medical treatment with somatostatin analogues; no effective chemotherapy is available. Radionuclide therapy via somatostatin receptors is one new therapeutic alternative. The recognition that neuroendocrine tumours express specific receptors for growth factors and chemokines, which are of importance for tumour growth, vascularization, and spread, may open the way for new therapeutic approaches. The signalling pathways in carcinoid tumours are incompletely explored. This review summarizes potential new treatment strategies from clinical and experimental studies, e.g. inhibition of angiogenesis, targeting of growth factors or their receptors by tyrosine kinase inhibitors, interference with specific cellular pathways (mTOR, PI3K, RAS/RAF, Notch), and also inhibition of the proteasome and histone deacetylation. Combining targeted therapy with chemotherapy, or using drugs to sensitize for radionuclide therapy, may enhance the treatment outcome.
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PMID:New medical strategies for midgut carcinoids. 2040 94

To test the hypothesis that herpes viruses may have a role in thyroid neoplasia, we analysed thyroid tissues from patients with benign (44) and malignant (65) lesions for HSV1 and HSV2 DNA. Confirmatory studies included direct sequencing, analysis of viral gene expression, and activation of viral-inducible signalling pathways. Expression of viral entry receptor nectin-1 was examined in human samples and in cancer cell lines. In vitro experiments were performed to explore the molecular mechanisms underlying thyroid cancer cell susceptibility to HSV. HSV DNA was detected in 43/109 (39.4%) examined samples. HSV capsid protein expression correlated with HSV DNA status. HSV-positive tumours were characterized by activation of virus-inducible signalling such as interferon-beta expression and nuclear NFkappaB expression. Lymphocyte infiltration and oncocytic cellular features were common in HSV-positive tumours. HSV1 was detected with the same frequency in benign and malignant thyroid tumours. HSV2 was significantly associated with papillary thyroid cancer and the presence of lymph node metastases. The expression of HSV entry receptor nectin-1 was increased in thyroid tumours compared to normal thyroid tissue and further increased in papillary thyroid cancer. Nectin-1 expression was detected in all examined thyroid cancer cell lines. Nectin-1 expression in cancer cells correlated with their susceptibility to HSV. Inhibition of PI3K/AKT or MAPK/ERK signalling did not affect the level of nectin-1 expression but decreased thyroid cancer cell susceptibility to HSV. These findings showed that HSV is frequently detected in thyroid cancer. During tumour progression, thyroid cells acquire increased susceptibility to HSV due to increased expression of viral entry mediator nectin-1 and activation of mitogenic signalling in cancer cells.
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PMID:Human herpes simplex viruses in benign and malignant thyroid tumours. 2045 54


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