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

We have summarized the molecular and cellular events involved in nickel (Ni) compound induced carcinogenesis. The major hypothesis for nickel carcinogenic action has involved the ability of the Ni compound to deliver high concentrations of Ni intracellularly, enter the nucleus and interact with chromatin. Ni has been found to selectively damage heterochromatin, and a major action of Ni is its ability to silence the expression of genes located near heterochromatin by inducing a loss of histone H4 and H3 acetylation and DNA hypermethylation. When Ni silences critical genes, such as tumor suppressor genes, the cell is altered to a greater state of neoplastic transformation. The carcinogenic hazard of Ni compounds has been directly related to the ability of that Ni compound to raise the intracellular Ni ions. The mechanisms of Ni-induced gene silencing will be discussed. However, recently it has been found that soluble Ni ions can interact with the cell surface receptors and activate cell signaling resulting in the induction of a variety of cellular genes. In particular, the Ca and hypoxia inducible factor pathway is activated in all cells exposed to soluble Ni ions. In the case of HIF-1 induction, a cell is now equipped with the expression of a variety of genes that will allow the cell to survive the lack of oxygen and thus should enable a previously initiated cancer cell to progress into a full malignant state and metastasize. These new findings support the view that soluble Ni ions exhibit carcinogenic potential by activating cell promotion and lend strength to the epidemiological data showing soluble Ni to be associated with cancer risk in Ni refinery workers.
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PMID:Molecular mechanisms of nickel carcinogenesis: gene silencing by nickel delivery to the nucleus and gene activation/inactivation by nickel-induced cell signaling. 1272 58

The distinction between two primary carcinomas on the one hand and a metastatic disease on the other hand in patients suffering from synchronous endometrioid carcinomas of the uterus and ovary is difficult. Exclusive histopathologic analysis appears to be insufficient and sometimes misleading. The tumor suppressor PTEN was found to be important in early neoplastic transformation in endometrioid carcinomas of the uterus. In this study, we screened synchronous endometrioid carcinomas of the uterus and ovary of 10 patients for loss of heterozygosity using seven different microsatellite markers at 10q23.3 and for mutations in the entire coding region of PTEN. Point mutations or microdeletions/insertions were found in six patients. Allelic loss at 10q23.3 was detected in eight patients. Based on conventional histology, a metastatic disease was diagnosed in seven patients and a concomitant uterine and ovarian carcinoma in three patients. After molecular analysis, the histopathologic diagnosis of three patients had to be revised. Histopathology represents the standard method to process tumor specimens from these patients. Nevertheless, mutation screen for PTEN and LOH analysis at 10q23.3 provide helpful genetic tools to establish a correct final diagnosis, which is important in view of prognosis and therapeutic implications.
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PMID:PTEN as a molecular marker to distinguish metastatic from primary synchronous endometrioid carcinomas of the ovary and uterus. 1276 11

The family of Jak kinases is composed from at least four different tyrosine kinases (Tyk2, Jak1, Jak2, Jak3) that share significant structural homology with each other. The members of this family of kinases associate constitutively with a variety of cytokine and hormone receptors. Upon binding of the specific ligands to their receptors, Jak kinases are rapidly activated and their kinase activities induced, to regulate tyrosine phosphorylation of various effectors and initiate activation of downstream signaling pathways. The discovery of this family of tyrosine kinases dates back in the early 1990s with the cloning of the Tyk-2 tyrosine kinase as a critical element of the Type I interferon signaling pathway. Extensive work over the last few years has provided evidence that Jak kinases play important roles in the generation of responses for interferons, which are cytokines that exhibit important antitumor activities. There is also accumulating evidence that constitutive activation of different Jaks and Stats mediates neoplastic transformation and promotes abnormal cell proliferation in various malignancies. This review summarizes the role of various Jak-kinase dependent pathways in malignancies and discusses the therapeutic implications of the recent advances in the field.
Cancer Metastasis Rev 2003 Dec
PMID:Jak family of kinases in cancer. 1288 16

Placental site trophoblastic tumour (PSTT) is a very rare and unique form of gestational trophoblastic disease (GTD). This tumour represents a neoplastic transformation of intermediate trophoblastic cells that normally play a critical role in implantation. PSTT can occur after a normal pregnancy, abortion, term delivery, ectopic pregnancy or molar pregnancy. It displays a wide clinical spectrum, and when metastatic, can be difficult to control even with surgery and chemotherapy. Unlike other forms of GTD, PSTT is characterized by low beta-hCG levels because it is a neoplastic proliferation of intermediate trophoblastic cells. Expression, however, of human placental lactogen (hPL) is increased on histologic section as well as in the serum. The most common presenting symptoms of PSTT are vaginal bleeding and amenorrhoea. Diagnosis is confirmed by dilatation and curettage (D and E) and hysterectomy but meticulous evaluation of metastasis is mandatory. Most cases are confined to the uterus but pelvic involvement, lung and other organ metastasis has been reported. Unlike other forms of GTD, the WHO prognostic score is of little help. For the PSTT patient, surgery is the primary treatment of choice. For patients desiring future childbearing, D and C and adjuvant chemotherapy is an option. Because these tumours tend to be less sensitive than other types of GTD to chemotherapy, the most successful regimen to date has been with EMA/CO or EMA/EP. Good prognosis is anticipated in cases localized to the uterus, and when the interval between antecedent pregnancy and treatment is less than 2 years. In cases with distant metastasis or delayed treatment, the outcome is dismal. Advances in chemotherapeutic regimens have improved clinical reponse in metastatic disease.
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PMID:Placental site trophoblastic tumour. 1461 93

Paget's carcinoma (PC) of the breast is characterized by neoplastic cells of "glandular" type located within the epidermis of the nipple-areolar complex, often associated with an underlying ductal carcinoma, either in situ or invasive. At present the origin of PC cells is controversial, although there is a widespread opinion that PC cells are "foreign" elements to the epidermis resulting from an epidermotropic migration of neoplastic elements from an underlying ductal carcinoma. An alternative view is that some cases result from neoplastic transformation of preexisting, innocent intraepidermal clear cells of the nipple-areolar complex (Toker cells) that migrate from nonneoplastic ducts. Consequently, 10 cases were studied using methods for clonality (ie, loss of heterozygosity and mitochondrial DNA displacement loop sequence analysis). Microdissection of intraepidermal neoplastic cells and of cells from underlying duct carcinomas and metastases was performed. In no fewer than 2 cases, PC cells were genetically different from underlying lesions, which showed consistent homology among themselves. Therefore, it is suggested that the rule of epidermotropism by neoplastic cells from an underlying carcinoma is not applicable to all cases, and that in some cases PC cells might be the result of neoplastic transformation of preexisting intraepidermal nonneoplastic cells. Consequently, the underlying tumors are coincidental neoplastic lesions (collision tumors).
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PMID:Intraepidermal cells of Paget's carcinoma of the breast can be genetically different from those of the underlying carcinoma. 1469 19

Head and neck squamous cell carcinomas (HNSCC) are characterized by a marked propensity for local invasion and spread to cervical lymph nodes, with distant metastases developing in 30-40% of cases. HPV-16 is an important risk factor for HNSCC. How HPV enhances susceptibility to HNSCC is not fully understood, but seems to involve cofactors. In this study, we examined the effect of the cooperation between HPV-16 and the tyrosine kinase receptor ErbB-2 on E-cadherin/catenin complex patterns and neoplastic transformation of human normal oral epithelial (NOE) cells. We report that overexpression of ErbB-2 or E6/E7 alone does not affect E-cadherin/catenin complex patterns nor does it induce cell transformation of NOE cells. In contrast, coexpression of E6/E7 and ErbB-2 downregulates E-cadherin and catenin expression. This is accompanied by cytoplasmic localization of E-cadherin, as well as nuclear translocation of alpha, beta, and gamma-catenins. Furthermore, we demonstrate that E6/E7 cooperate with overexpressed ErbB-2 to induce tumor formation in nude mice and to upregulate cyclin D1 and c-myc expression. Our data suggest that E6/E7 cooperate with ErbB-2 in head and neck carcinogenesis, at least in part, via the conversion of beta-catenin from a cell adhesion to a nuclear function, that is, to act as a potential transcriptional regulator. This conversion leads to the upregulation of cyclin D1, c-myc and other oncoproteins necessary for alteration of the E-cadherin/catenin complex and cell transformation of NOE cells.
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PMID:E6/E7 proteins of HPV type 16 and ErbB-2 cooperate to induce neoplastic transformation of primary normal oral epithelial cells. 1472 63

Epigenetic silencing is now recognized as a 'third pathway' in Knudson's model of tumor-suppressor gene inactivation in cancer and can affect gene function without genetic changes. DNA methylation within gene promoters and alterations in histone modifications appear to be primary mediators of epigenetic inheritance in cancer cells. For selected genes, epigenetic changes are tightly related to neoplastic transformation in colorectal cancers (CRCs). In the colon, aberrant DNA methylation arises very early, initially in normal appearing mucosa, and may be part of the age-related field defect observed in sporadic CRCs. Aberrant methylation also contributes to later stages of colon cancer formation and progression through a hypermethylator phenotype termed CpG Island Methylator Phenotype (CIMP), which appears to be a defining event in about half of all sporadic tumors. CIMP+ CRCs are distinctly characterized by pathology, clinical and molecular genetic features. Histone modifications, recently recognized as a 'histone code' that affects chromatin structure and gene expression also play an important role in the establishment of gene silencing during tumorigenesis. DNA methylation and histone H3 lysine 9 hypoacetylation and methylation appear to form a mutually reinforcing silencing loop that contributes to tumor-suppressor gene inactivation in CRCs. Understanding epigenetic alterations as a driving force in neoplasia opens new fields of research in epidemiology, risk assessment, and treatment in CRCs.
Cancer Metastasis Rev
PMID:Epigenetic changes in colorectal cancer. 1500 Jan 47

The study of radiation-induced transformation in vitro has long been an experimental approach to examine mechanisms underlying radiation carcinogenesis. Even though the major concern of exposure to radiation is the risk of cancer induction at low radiation doses, most laboratory mechanistic studies have focused on high dose effects. This, coupled with the fact that epidemiologic data are rarely powerful enough to accurately discriminate this risk at doses <5 cGy, has led in recent years to an increased effort to study low dose effects using the endpoint of neoplastic transformation in vitro. Since transformation frequencies at low doses are typically low (< 10(-4)), such studies are, by necessity, large and labor intensive. However, they have yielded quantitative dose-response data, as well as insights into underlying cellular and molecular mechanisms. An interesting, and potentially important, finding is that low doses of low LET radiation can suppress neoplastic transformation in vitro to levels below that seen spontaneously. Mechanistic studies have revealed that multiple mechanisms are likely to be involved, and these include both the death of a subpopulation of cells prone to spontaneous neoplastic transformation and the induction of DNA repair. The relative contribution of these mechanisms appears to be dose-dependent. The relevance of in vitro studies to carcinogenesis in vivo is discussed.
Cancer Metastasis Rev
PMID:Radiation-induced neoplastic transformation in vitro: evidence for a protective effect at low doses of low LET radiation. 1519 33

The process of cell loss and cell gain is homeostatically balanced in order to not only generate and maintain the complex dynamic architecture of tissues, but also to allow adaptation to changing circumstances. Tumor cells survive only by virtue of mutations that allow them to proliferate and to evade death signals. In fact, defects in the programd cell death inducing pathways contribute to neoplastic transformation, progression and metastasis by creating a permissive environment for genetic instability and accumulation of gene mutation. Resistance to apoptosis can also enhance the escape to tumor cells from surveillance by the immune system. Moreover, because chemotherapy and irradiation act mostly by inducing apoptosis, dysregulation in the apoptostic pathway can make cancer cells resistant to therapy. This review gives an update on the key players involved in apoptosis as well as how pathologic alterations in each step of apoptotic pathways are involved in the entire progression of neoplastic transformation, how impaired apoptosis affects therapy and how direct targeting vs. the apoptotic regulators could lead to more effective treatment of cancer.
Cancer Metastasis Rev
PMID:Implications of apoptosis regulators in tumorigenesis. 1519 36

We have recently shown that the cancer-associated Sm-like protein (CaSm) is overexpressed in human pancreatic adenocarcinoma (PC). However, the role of CaSm in the process of neoplastic transformation remains unclear. To define further the role of CaSm in PC transformation, we have established a murine model based on the murine pancreatic cancer cell lines Panc02 and Panc03. CaSm is overexpressed in the aggressive Panc02 cells and expressed at much lower levels in the more indolent Panc03 cells. Up-regulation of CaSm in Panc03 cells increased in vitro proliferation and anchorage-independent growth and promoted subcutaneous tumor establishment and growth in syngeneic mice. Conversely, adenoviral down-regulation of CaSm in Panc02 led to significant inhibition of cellular proliferation and anchorage-independent growth in vitro and complete abolition of tumor growth and metastasis in vivo. Up-regulation of CaSm in NIH3T3 resulted in loss of contact inhibition and increased soft agar colony formation in vitro. The requirement for CaSm overexpression for neoplastic transformation confirms the concept that CaSm is a critical oncogene and potential target for molecular intervention. Furthermore, establishment of the murine clinically relevant model of pancreatic metastases provides a framework for the generation of preclinical data to support the development of novel molecular therapies targeting CaSm.
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PMID:Establishing a murine pancreatic cancer CaSm model: up-regulation of CaSm is required for the transformed phenotype of murine pancreatic adenocarcinoma. 1572 32


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