Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neoplastic progression is a prolonged and stepwise process, while tumor growth occurs after a series of molecular alterations that culminate in tumorigenesis. The phenotypic changes of transformation in breast carcinogenesis were studied through the use of scanning and transmission electron microscopy. MCF 10F, a spontaneously immortalized human breast epithelial cell line (Soule et al., 1990), was treated with 7,12 dimethylbenz(a)anthracene (DMBA) (Calaf and Russo, 1993) and then transfected with the c-Ha-ras oncogene (Calaf et al., 1995). Treated cells showed a progression in altered morphology, anchorage independency, invasiveness and tumorigenicity in the SCID. Scanning and transmission electron microscopy illustrated that the transformed cells could be distinguished from control cells by the expression of morphological characteristics such as loss of contact inhibition, irregular size and shape, emission of long filopodia and formation of stratified layers. In contrast, control cells showed uniform, flattened and polyhedrical cells, well closely juxtaposed to each other and joined by cytoplasmic interdigitations. Control cells also did not form colonies in agar-methocel, and were not invasive or tumorigenic in SCID mice. These studies showed the progression of breast carcinogenesis by phenotypical changes induced by the carcinogen and the insertion of the c-Ha-ras oncogene.
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PMID:Morphological phenotypes in neoplastic progression of human breast epithelial cells. 1087 6

Epstein-Barr virus (EBV)-induced lymphoproliferative disease (lpd) is a B cell neoplasm that affects patients who are immunosuppressed in the context of organ transplantation or HIV infection. A model for the aggressive form of this entity was generated by xenotransplantation of SCID mice with human peripheral blood leukocytes from individuals with prior contact with EBV. This model, where large B cell lymphoma occurs, was used to test the hypothesis that IL-6 has a major role in EBV-induced B cell tumorigenesis. IL-6 is known to differentiate B cells into immunoglobulin-secreting plasma cells and induce EBV replication, and xenochimeric animals have detectable serum levels of human IL-6. Human IL-6 inhibition with a neutralizing monoclonal antibody decreased tumor incidence from 62 % to 27 %. In addition, anti-IL-6 treatment significantly improved xenotransplanted animal survival, with median survival at > 245 days when compared to that of controls at 132 days. In conclusion, IL-6 plays a critical role in the pathogenesis of EBV-induced human lpd, and IL-6 inhibition may represent a new and promising preventive or therapeutic approach against this malignancy.
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PMID:Epstein-Barr virus-dependent lymphoproliferative disease: critical role of IL-6. 1094 Aug 96

Both the sulfide and sulfone metabolites of sulindac, a nonsteroidal anti-inflammatory drug, display anticarcinogenic effects in experimental models. Sulindac sulfide inhibits cyclooxygenase (COX) enzyme activities and has been reported to suppress ras-dependent signaling. However, the mechanisms by which sulindac sulfone suppresses cancer growth are not as defined. We studied the effects of these sulindac metabolites in human colon cancer-derived Caco-2 cells that have been transfected with an activated K-ras oncogene. Stable transfected clones expressed high levels of COX-2 mRNA and protein, compared with parental cells. K-ras-transfected cells formed tumors more quickly when injected into severe combined immunodeficiency disease mice than parental cells, and this tumorigenesis was suppressed by treatment with sulindac. Sulindac sulfone inhibited COX-2 protein expression, which resulted in a decrease in prostaglandin synthase E2 production. Sulindac sulfide had little effect on COX-2 in this model, but did suppress prostaglandin synthase E2 production, presumably by inhibiting COX enzyme activity. These data indicate that the sulfide and sulfone derivatives of sulindac exert COX-dependent effects by distinct mechanisms.
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PMID:Sulindac sulfone inhibits K-ras-dependent cyclooxygenase-2 expression in human colon cancer cells. 1111 42

We have demonstrated that Epstein-Barr virus (EBV) confers enhanced growth capability in soft agarose, tumorigenesis in the SCID mouse, and resistance to apoptosis in the Burkitt's lymphoma cell line Akata. Subsequently, we have shown that EBV-encoded small RNAs (EBERs) are responsible for these phenotypes. We constantly observed the upregulation of bcl-2 oncoprotein expression upon EBV infection and expression of EBERs. To test whether these phenotypes were due to the upregulation of bcl-2 expression, we introduced bcl-2 into EBV-negative Akata cells at various levels encompassing the range at which EBV-positive cells expressed it. As cells expressed bcl-2 at higher levels, they became more capable of growing in soft agarose and became resistant to apoptosis. However, clones expressing bcl-2 at a higher level than EBV-positive Akata cells were negative in the tumorigenesis assay in the SCID mouse. On the other hand, introduction of bax into EBV-positive Akata cells reduced the resistance to apoptosis; however, it failed to reduce the growth capability in soft agarose. These data indicate that EBV targets not only bcl-2, but also an unknown pathway(s) to enhance the oncogenic potential of Akata cells.
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PMID:Role of bcl-2 in Epstein-Barr virus-induced malignant conversion of Burkitt's lymphoma cell line Akata. 1115 30

The progression of breast cancer depends on the establishment of a neovasculature, by a process called angiogenesis. Angiogenesis is an invasive cellular event that requires the co-ordination of numerous molecules including growth factors and their receptors, extracellular proteins, adhesion molecules, and proteolytic enzymes. TGFbeta has emerged to be a major modulator of angiogenesis by regulating endothelial cell proliferation, migration, extracellular matrix (ECM) metabolism, and the expression of adhesion molecules. It is a potent growth inhibitor of normal mammary epithelial cells and a number of breast cancer cell lines. It seems that TGFbeta exerts pleiotropic effects in the oncogenesis of breast cancers in a contextual manner, i.e., it suppresses tumourigenesis at an early stage by direct inhibition of angiogenesis and tumour cell growth. However, over-production of TGFbeta by an advanced tumour may accelerate disease progression through indirect stimulation of angiogenesis and immune suppression. The cell membrane antigen CD105 (endoglin) binds TGFbeta1 and TGFbeta3 and is preferentially expressed in angiogenic vascular endothelial cells. The reduction of CD105 levels in HUVEC leads to in vitro angiogenesis inhibition and massive cell mortality in the presence of TGFbeta1. CD105 null mice die in utero with impaired vasculature, indicating the pivotal role of CD105 in vascular development. The administration of an immunotoxin-conjugate, mab to CD105, induces long-term and complete regression of breast cancer growth in SCID mice. Therefore, CD105 is a promising vascular target for antiangiogenic therapy.
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PMID:Angiogenesis in breast cancer: the role of transforming growth factor beta and CD105. 1117 Mar 3

A patient with adrenocortical carcinoma presented with fever, leukocytosis, and increased acute phase reactants. The tumor was infiltrated with neutrophils. Immunohistochemical staining of the tumor showed positive signal for epithelial neutrophil-activating protein-78, an angiogenic and chemotactic CXC chemokine. Conditioned medium from tumor-derived cells (RL-251) showed high concentration of IL-8, epithelial neutrophil-activating protein-78, Gro alpha, and Gro gamma, angiogenic CXC chemokines with a potential role in tumorigenesis. An adrenal cancer/severe combined immunodeficiency mouse chimera was developed. Mice grew tumors rapidly, and circulating levels of IL-8 and epithelial neutrophil-activating protein-78 were detected. In contrast, animals transplanted with NCI-H295 cells, a nonchemokine-secreting cell line, grew tumors more slowly and did not have detectable chemokine levels. Similar to the patient, mice with RL-251 tumors developed marked leukocytosis and neutrophilia, and their tumors were infiltrated with neutrophils. Mice were passively immunized with epithelial neutrophil-activating protein-78 antisera. A marked decrease in tumor growth was observed. Potential for chemokine production by other adrenocortical tumors was investigated by RT-PCR in archival material. Six of seven adrenal carcinomas and one of three adenomas had cDNA for IL-8; six of seven carcinomas and the three adenomas had cDNA for epithelial neutrophil-activating protein-78. We concluded that the clinical presentation of this case resulted from increased tumor production of chemotactic chemokines. Through their angiogenic and chemotactic properties these chemokines may play an important role in adrenal tumorigenesis.
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PMID:Overexpression of CXC chemokines by an adrenocortical carcinoma: a novel clinical syndrome. 1150 40

Occurrence of chromosome 3p deletions in a large number of human tumours suggests the existence of uncharted tumour suppressor gene(s). We previously applied a functional assay, named the Elimination test (Et), for the identification of regions containing tumour growth antagonising genes. This resulted in the definition of chromosome 3 common eliminated region 1 (C3CER1) on 3p21.3, which is regularly eliminated from SCID-derived tumours. Systematic genomic sequencing of 11 PAC clones, combined with comparisons of genomic sequence against EST databases and PCR-based cloning of cDNA sequences allowed us to assemble a comprehensive transcriptional map of 1.4 Mb that includes 19 active genes and three processed pseudogenes. We report four novel genes: FYVE and coiled-coil domain containing 1 (FYCO1), transmembrane protein 7 (TMEM7), leucine-rich repeat-containing 2 (LRRC2) and leucine zipper protein 3 (LUZP3). A striking feature of C3CER1 is a presence of a cluster of eight chemokine receptor genes. Based on a new analysis of the microcell hybrid-derived panel of SCID tumours we also redefined the centromeric border of the C3CER1. It is now located within LRRC2 gene, which is a relative of RSP-1 (Ras Suppressor Protein 1). The detailed knowledge of gene content in C3CER1 is a prerequisite for functional analysis of these genes and understanding of their possible role in tumorigenesis.
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PMID:The transcriptional map of the common eliminated region 1 (C3CER1) in 3p21.3. 1189 56

Human T cell leukemia/lymphoma virus type-1 (HTLV-1) is recognized as the etiological agent of adult T cell leukemia (ATL). Although HTLV-1 can immortalize human lymphocytes in culture, identification of molecular events leading to tumorigenesis after HTLV-1 infection remain elusive. SCID/bg and NOD/SCID mice have reduced natural killer (NK) cell activity and were inoculated intraperitoneally with HTLV-1 transformed cells to refine and characterize the SCID mouse as a small animal model for investigation of HTLV-1 tumorigenesis. HTLV-1 transformed cell lines originally derived by cocultivation of uninfected peripheral blood mononuclear cells (PBMC) with lethally irradiated leukemic cells from patient samples (SLB-1, MT-2 and HT-1-RV) were lymphomagenic when inoculated into NOD/SCID mice. In contrast, immortalized cell lines generated by transfection PBMC with an infectious molecular clone of HTLV-1 (ACH or ACH.p12) were not tumorigenic. The differing behaviors of HTLV-1 infected cell lines in NOD/SCID mice indicates that viral infection and immortalization of human PBMC for growth in culture is not sufficient for induction of a tumorigenic phenotype. The higher level of engraftment of HTLV-1 transformed cell lines in NOD/SCID mice suggests that this is an effective animal model to investigate molecular determinants of HTLV-1 lymphomagenesis.
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PMID:Engraftment and tumorigenesis of HTLV-1 transformed T cell lines in SCID/bg and NOD/SCID mice. 1200 4

We have studied the effect of a newly identified tumor suppressor tissue inhibitor of metalloproteinases- 3 (TIMP-3) on the growth of human melanoma and squamous-cell carcinoma (SCC). Adenoviral delivery of the TIMP-3 gene to human melanoma (A2058) and SCC (UT-SCC-7) cells ex vivo inhibited tumorigenesis after subcutaneous (s.c.) injection of the infected cells into SCID/SCID mice. Three daily consecutive intratumoral injections of 1.4x10(9) plaque-forming units (pfu) of TIMP-3 adenovirus (RAdTIMP-3) inhibited the growth of preestablished melanoma and SCC xenografts in SCID/SCID mice, whereas growth of control virus-injected tumors was not affected. The antitumor effect of RAdTIMP-3 was obtained with in vivo adenoviral transduction efficiency of 8-10%, and it was more potent than that of adenovirally delivered p53. Adenovirusmediated expression of TIMP-3 potently reduced gelatinolytic activity, increased the number of apoptotic cells, and inhibited vascularization of melanomas. Escalation of the adenoviral dose to three rounds of three daily consecutive injections with 1.4x10(9) pfu of RAdTIMP-3 every 6 days entirely inhibited growth of injected melanomas for 32 days. Mixing RAdTIMP-3-infected A2058 cells with uninfected cells in 1:1 ratio in culture resulted in death of all cells in 96 hours. Adenovirally delivered TIMP-3 was also expressed by A2058 cells in soluble form into the culture medium, where it exerted a cytotoxic effect on uninfected A2058 cell cultures after relocating to the cell layer. These results identify TIMP-3 as a novel type of secreted tumor suppressor, which has antiinvasive, antiangiogenic, and proapoptotic effects in vivo, and which displays a potent bystander effect validating further exploration of its applicability in human cancer gene therapy.
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PMID:Antitumor activity and bystander effect of adenovirally delivered tissue inhibitor of metalloproteinases-3. 1202 54

It is well accepted that an increase in the expression of cyclooxygenase-2 (COX-2), a key inducible enzyme involved in the production of prostaglandins and other eicosanoids, may play a significant role in carcinogenesis in addition to its well-known role in inflammatory reactions. Whereas previous studies were largely confined to colorectal tumorigenesis, we have shown that a significantly increased expression of COX-2 may also play a role in the development of lung cancer. COX-2 expression was found to be frequently elevated in lung cancer, especially in adenocarcinoma, and the proportion of lung cancer cells with marked COX-2 expression was much higher in lymph node metastases than in the corresponding primary tumors. It was also shown that early stage adenocarcinoma patients with increased COX-2 expression who were surgically treated had a shorter survival. Our studies, which used high- and low-metastatic human lung cancer cell sublines established in our laboratory, revealed an association between metastatic capabilities and COX-2 expression levels: COX-2-specific inhibitors could inhibit in vitro the invasion of the highly metastatic NCI-H460-LNM35 clone through Matrigel-containing basement membrane components as well as the spontaneous in vivo metastasis in SCID mice. Taken together, these findings suggest that an increase in COX-2 expression maybe associated with the development of lung cancer and possibly with the acquisition of an invasive and metastatic phenotype.
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PMID:Increased expression of COX-2 in the development of human lung cancers. 1208 4


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