Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We have previously reported the development of a transgenic mouse model for prostate cancer derived from PB-Tag transgenic line 8247, henceforth designated the TRAMP (transgenic adenocarcinoma mouse prostate) model. We now describe the temporal and spatial consequences of transgene expression and report the identification and characterization of metastatic disease in the TRAMP model. TRAMP mice characteristically express the T antigen oncoprotein by 8 weeks of age and develop distinct pathology in the epithelium of the dorsolateral prostate by 10 weeks of age. Distant site metastases can be detected as early as 12 weeks of age. The common sites of metastases are the periaortic lymph nodes and lungs, with occasional metastases to the kidney, adrenal gland, and bone. By 28 weeks of age, 100% harbor metastatic prostate cancer in the lymph nodes or lungs. We have also demonstrated the loss of normal E-cadherin expression, as observed in human prostate cancer, as primary tumors become less differentiated and metastasize. The TRAMP model provides a consistent source of primary and metastatic tumors for histopathobiological and molecular analysis to further define the earliest molecular events involved in the genesis, progression, and metastasis of prostate cancer.
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PMID:Metastatic prostate cancer in a transgenic mouse. 879 72

Mature adult mice of the C57BL/6-TgN(Amy1TAg)501Knw transgenic mouse lineage, 501, containing a liver alpha-amylase promoted-SV40 Tag hybrid gene, routinely develop SV40 Tag-induced metastatic osteosarcomas. This form of alpha-amylase was known to be expressed in the liver, salivary glands, pancreas, and fat. Cells in the normal rib adjacent to the periosteum also express alpha-amylase suggesting that transgene expression is correctly targeted to generate osteosarcomas. 501 mice express SV40 Tag in the salivary glands but do not develop abnormalities in these organs by the time of their death from SV40-induced osteosarcomas. Mice of the C57BL/6 strain make a strong and effective anti-tumor immune response to SV40 Tag immunization. However, immunization of 501 mice with SV40 Tag early in life does not alter or prevent SV40 Tag-induced osteosarcomagenesis. 501 mice mount a significantly less effective cytotoxic T-lymphocyte response following SV40 Tag immunization while 501 osteosarcoma-derived cells are fully susceptible to SV40 Tag-specific T-cell lysis. This suggests that partial tolerance, not loss of antigen presentation by tumor cells, characterizes this mouse model of endogenous bone tumor development. To determine whether the immune recognition of endogenous SV40 Tag could influence tumorigenesis, the metastatic potential and time of death from tumor was investigated in CD4-null mutant 501 mice and beta-2 microglobulin-null mutant 501 mice. The size and number of metastases in these strains and longevity of these strains varied. We suggest that components of both the innate and adaptive immune response control tumor appearance and progression.
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PMID:Expression and immune recognition of SV40 Tag in transgenic mice that develop metastatic osteosarcomas. 1095 95

L-selectin mediates homing of lymphocytes to lymph nodes (LN). Transgenic mice that express rat insulin promoter regulated simian virus 40 Tag (RIP-Tag) develop large, local cancers that metastasize to liver but not LN. To test whether this lack of LN metastases reflects their absence from the circulation, transgenic mice were produced that express Tag (T), L-selectin (L), and Escherichia coli LacZ (Z), in pancreatic beta cells. LTZ mice developed insulinomas that specifically had LN metastases; metastasis was blocked by an anti L-selectin mAb. LacZ(+) tumor cells from these LN homed to secondary LN upon transfer. These results suggest that the highly vascularized islet carcinomas are shedding tumor cells into the bloodstream, which is a necessary but insufficient condition for metastasis to occur; L-selectin can facilitate homing of such tumor cells to LN, resulting in metastasis.
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PMID:L-selectin can facilitate metastasis to lymph nodes in a transgenic mouse model of carcinogenesis. 1127 19

We have analysed the importance of fibroblast growth factor 2 (FGF2) in tumor development. In a transgenic mouse model (Tyrp1-Tag) tumors form in the retinal pigment epithelium (RPE), invade surrounding tissues, and metastasize to lymph node and spleen. To address whether RPE tumor formation is dependent on FGF2, we generated FGF2-deficient mice. Such mice appeared healthy and exhibited no impairment of growth or development. Tyrp1-Tag transgenic mice, which are lacking FGF2 (FGF2-/-) developed RPE tumors that metastasize to spleen and lymph nodes. Tumor growth and survival rate are identical to Tyrp1-Tag transgenic littermates expressing FGF2. Cell lines were isolated from RPE tumors of wild-type and FGF2-deficient mice. They grow in culture, are pigmented and form vascularized tumors, when injected subcutaneously into nude mice of either FGF2-/- or FGF2+/+ genetic background. Kinetics of tumor growth was identical and independent of presence of FGF2. Together, these results demonstrate that FGF2 is not essential for tumor formation of the RPE thus suggesting that tumor growth in general may not be dependent on FGF2.
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PMID:Absence of fibroblast growth factor 2 does not prevent tumor formation originating from the RPE. 1189 16

Changes in expression of arachidonic acid (AA) metabolizing enzymes are implicated in the development and progression of human prostate carcinoma (Pca). Transgenic mouse models of Pca that progress from high-grade prostatic intraepithelial neoplasia (HGPIN) to invasive and metastatic carcinoma could facilitate study of the regulation and function of these genes in Pca progression. Herein we characterize the AA-metabolizing enzymes in transgenic mice established with a prostate epithelial-specific long probasin promoter and the SV40 large T antigen (LPB-Tag mice) that develop extensive HGPIN and invasive and metastatic carcinoma with neuroendocrine (NE) differentiation. Murine 8-lipoxygenase (8-LOX), homologue of the 15-LOX-2 enzyme that is expressed in benign human prostatic epithelium and reduced in Pca, was not detected in wild-type or LPB-Tag prostates as determined by enzyme assay, reverse transcription-PCR, and immunohistochemistry. The most prominent AA metabolite in mouse prostate was 12-HETE. Wild-type prostate (dorsolateral lobe) converted 1.6 +/- 0.5% [(14)C]AA to 12-HETE (n = 7), and this increased to 8.0 +/- 4.4% conversion in LPB-Tag mice with HGPIN (n = 13). Quantitative real-time reverse transcription-PCR and immunostaining correlated the increased 12-HETE synthesis with increased neoplastic epithelial expression of 12/15-LOX, the leukocyte-type (L) of 12-LOX and the murine homologue of human 15-LOX-1. Immunostaining showed increased L12-LOX in invasive carcinoma and approximately one-half of metastatic foci. COX-2 mRNA was detectable in neoplastic prostates with HGPIN but not in wild-type prostate. By immunostaining, COX-2 was increased in the neoplastic epithelium of HGPIN but was absent in foci of invasion and metastases. We conclude that (a) AA metabolism in wild-type mouse prostate differs from humans in the basal expression of LOXs (15-LOX-2 in human, absence of its 8-LOX homologue in mouse prostate); (b) increased expression of 12/15-LOX in HGPIN and invasive carcinoma of the LPB-Tag model is similar to the increased 15-LOX-1 in high-grade human Pca; and (c) the LPB-Tag model shows increased COX-2 in HGPIN, and therefore, it may allow additional definition of the role of this enzyme in the subset of human HGPINs or other precursor lesions that are COX-2 positive, as well as investigation of its contribution to neoplastic cell proliferation and tumor angiogenesis in Pca.
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PMID:Elevated expression of 12/15-lipoxygenase and cyclooxygenase-2 in a transgenic mouse model of prostate carcinoma. 1272 48

Prostate cancer (CaP) is the most common cancer in adult men in North America. Since there is no naturally occurring prostate cancer in the mouse, preclinical studies stipulate for the establishment of a genetically manipulated mouse CaP model with features close to the human situation. In view of the limitations of transgenic technique-derived CaP models, herein we report the first application of knockin technology to establish a new mouse adenocarcinoma prostate model (PSP-KIMAP) by targeting of SV40 Tag to a prostate tissue-specific gene, PSP94 (prostate secretory protein of 94 amino acids). In order to demonstrate its novelty, we compared KIMAP to a PSP94 gene-directed transgenic mouse adenocarcinoma of the prostate (PSP-TGMAP) model. The CaP development of the PSP-KIMAP mice started almost immediately after puberty at 10 weeks of age from mouse prostatic intraepithelial neoplasia (mPIN) with microinvasion to well-differentiated CaP, and demonstrated a close-to-human kinetics of prolonged tumor growth and a predominance of well and moderately differentiated tumors. The invasive nature of KIMAP model was demonstrated by multitissue metastases (lymph node, lung and liver etc) and also by immunohistochemical study of multiple invasive prostate tumor markers. PSP-KIMAP model is responsive to androgen deprivation (castration). The knockin technology in our KIMAP model demonstrates highly predictive CaP development procedures and many advantageous features, which the traditional transgenic technique-derived CaP models could not reach for both basic and clinical studies. These features include the high stability of both phenotype and genotype, highly synchronous prostate cancer development, high and precise prostate tissue targeting and with no founder line variation. The differences between the two CaP models were attributed to the introduction of a single endogenous knockin mutation, resulting in a CaP model self-regulated and controlled by a prostate gene promoter/enhancer of PSP94.
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PMID:Knockin of SV40 Tag oncogene in a mouse adenocarcinoma of the prostate model demonstrates advantageous features over the transgenic model. 1567 47

Different antiangiogenic and antimetastatic recombinant adenoviruses were tested in a transgenic mouse model of metastatic ocular cancer (TRP1/SV40 Tag transgenic mice), which is a highly aggressive tumor, developed from the pigmented epithelium of the retina. These vectors, encoding amino-terminal fragments of urokinase plasminogen activator (ATF), angiostatin Kringles (K1-3), endostatin (ES) and canstatin (Can) coupled to human serum albumin (HSA) were injected to assess their metastatic and antiangiogenic activities in our model. Compared to AdCO1 control group, AdATF-HSA did not significantly reduce metastatic growth. In contrast, mice treated with AdK1-3-HSA, AdES-HSA and AdCan-HSA displayed significantly smaller metastases (1.19+/-1.19, 0.87+/-1.5, 0.43+/-0.56 vs controls 4.04+/-5.12 mm3). Moreover, a stronger inhibition of metastatic growth was obtained with AdCan-HSA than with AdK1-3-HSA (P=0.04). Median survival was improved by 4 weeks. A close correlation was observed between the effects of these viruses on metastatic growth and their capacity to inhibit tumor angiogenesis. Our study indicates that systemic antiangiogenic factors production by recombinant adenoviruses, particularly Can, might represent an effective way of delaying metastatic growth via inhibition of angiogenesis.
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PMID:A gene transfer comparative study of HSA-conjugated antiangiogenic factors in a transgenic mouse model of metastatic ocular cancer. 1708 95

Expression of calcitonin (CT) and its receptor (CTR) is elevated in advanced prostate cancer (PC). Although the significance of CT-CTR axis in PC cell growth, invasion, and epithelial to mesenchymal transition has been established, its role in tumor metastasis has not been examined. To examine the role of CT-CTR axis in tumor metastasis, we employed stable CT-CTR activated and silenced system of three PC cell lines, LNCaP cells that lack endogenous CT, PC-3 cells that lack endogenous CTR, and PC-3M cells that co-express CT and CTR. Enforced expression of CT in LNCaP cells and CTR in PC-3 cells increased their ability to form orthotopic tumors and distant metastases in multiple organs. By contrast, silencing of CT expression in PC-3M cells not only reduced their tumorigenicity, but also completely abrogated their metastatic potential. To investigate the effect of in vivo silencing of CT expression on tumor growth, we employed recombinant adeno-associated virus (rAAV) to deliver anti-CT ribozymes in preexisting tumors of nude mice and large probasin promoter (LPB)-Tag transgenic mice. rAAV-CT(-) treatment not only abrogated the growth of pre-implanted tumors in nude mice, but also significantly reduced the growth of spontaneous tumors in LPB-Tag mice. Analysis of CT upregulated and silenced PC-3M transcriptomes revealed 105 genes affected by the modulation of CT expression. These CT signature genes generated survival, adhesion, pro-inflammatory, and pro-metastatic pathways. Added together, these data indicate a pivotal role for CT-CTR axis in PC metastasis and may serve as a potential therapeutic target for advanced PC.
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PMID:Calcitonin promotes in vivo metastasis of prostate cancer cells by altering cell signaling, adhesion, and inflammatory pathways. 1878 82

Liposarcomas are extremely rare in the skin. When they involve the skin, it is usually by upward spread from a subcutaneous or deeper seated liposarcoma. Very rarely, liposarcoma metastasize to the skin or arise as a primary dermal lesion. We describe 2 cases of atypical lipomatous tumor "well-differentiated liposarcoma" located in dermis. Both presented clinically as a skin tag. The neoplasms arose in a 56-year-old female and a 69-year-old male patient. Both lesions were treated by excision and reexcision. In addition to classical morphology of atypical lipomatous tumor with evidence of lipoblasts and atypical adipocytes, immunohistochemistry with nuclear murine double-minute type 2 protein and cyclin-dependent kinase-4 expression as well as fluorescence in situ hybridization analysis showing an amplification of murine double-minute type 2 protein and cyclin-dependent kinase-4 were helpful to establish the diagnosis. None of the cases recurred after surgical treatment. These 2 cases show the importance of not to misdiagnose lesions which clinically may appear to be benign.
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PMID:Atypical lipomatous tumor/"well-differentiated liposarcoma" of the skin clinically presenting as a skin tag: clinicopathologic, immunohistochemical, and molecular analysis of 2 cases. 2135 83

Increased expression of P-glycoprotein, encoded by the MDR1 gene, is considered to be responsible for chemotherapy failure in a number of human cancers. Although it is clear that mutations in the MDR1 gene affect substrate specificity of the transporter in multidrug-resistant cell lines, scant interest has been directed at whether mutations have a unique clinical presentation. To address this question, we studied exon 2 of the MDR1 gene in 9 patients with primary breast carcinoma and 9 healthy controls using PCR and DNA sequence analysis. In order to reduce the possibility of nucleotide misincorporations introduced by Tag polymerase, sequencing of six subclones of each DNA specimen was performed. A mutation was seen as a substitution from G to A at position -1 in two patients and one control. An A to G nucleotide substitution giving rise to an amino acid substitution (Asn-->Asp) in codon 21 at the first potential N-glycosylation site of the P-glycoprotein was seen in primary tumors from four patients and in an axillar lymph node metastases from one of these patients. This mutation was also seen in two healthy individuals, which similar to the patients, both seem to be heterozygous for this MDR1 exon 2 allele. Three other mutations were also found in the patients; a substitution of A to G at position 23 and A to G at position 52 in the same patient and in another patient, G at position 42 was changed to A. However, the last three mutations were not confirmed by repeating analysis of the original genomic sample. The results revealed different distribution of a point mutation between various parts of the same primary tumor and between a lymph node metastasis and the primary tumor tissue. Thus, demonstrating both intra-and inter-tumor heterogeneity. The results also emphasized constitutional allelic variation in the MDR1 gene. Whether this might affect sensitivity to chemotherapy has to be further evaluated.
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PMID:Intra-and inter-individual heterogeneity in exon 2 of the MDR1 gene in primary breast carcinoma and healthy individuals. 2152 63


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