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)

The expression of alternatively spliced CD44 adhesion molecules has been implicated in the pathogenesis and metastasis of colorectal cancer. Using a new set of primers for exon-specific reverse transcription-polymerase chain reaction (RT-PCR) we delineated the exact exon composition of CD44 mRNAs in normal colorectal mucosa, including isolated colonic crypts, in colorectal carcinomas and in their hepatic metastases. In addition, the surface expression of CD44 isoforms was analysed by immunohistochemistry. We identified by RT-PCR eight variant transcripts expressed in colorectal carcinomas and their metastases, but also constitutively in normal colorectal epithelia. In the normal colorectal epithelium, the surface expression of CD44 standard and variant molecules was restricted to proliferating cells at the bottom of the crypts. Despite expression of these transcripts in colorectal cancers and their metastases, monoclonal antibodies specific for standard or variant epitopes encoded by exons v5 and v6 stained only a few neoplastic lesions. These data point to a differentiation-specific CD44 expression and splicing pattern in proliferating colorectal epithelia. However, they do not support a cancer- or metastasis-specific CD44 splicing pattern. Instead, cell surface availability of CD44 epitopes was reduced rather than increased in primary tumours and particularly in liver metastases.
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PMID:No evidence for cancer-related CD44 splice variants in primary and metastatic colorectal cancer. 984 61

CD44 splice variants, especially those containing the v6 domain, are assumed to play a critical role in the malignant progression of many human tumors. This concept was based on (i) the aberrant expression of CD44v6 in malignant cells, often encoded by alternatively spliced transcripts, and (ii) the absence of CD44v6 expression in corresponding normal tissues. Remarkably, data on CD44v6 expression in squamous cells do not support this hypothesis: the v6 domain is highly expressed in normal squamous tissues and down-regulation has been described in the majority of squamous-cell carcinomas of the head and neck (HNSCC). In this study, we have compared the expression of v6 in normal oral mucosa and HNSCC in a qualitative and quantitative way. Immuno-histochemistry was performed with 3 different anti-v6 antibodies (U36, U39 and VFF18) on a large panel of HNSCC cell lines and tumors. The v6-encoding splice variants were characterized by screening a cDNA library of a human HNSCC cell line and by RT-PCR on HNSCC cell lines, microdissected normal mucosa and primary as well as metastatic HNSCC tissue. The results revealed that there is no, or only marginal, down-regulation of CD44v6 in HNSCC. About 97% of the primary HNSCC tumors exhibited a high and homogeneous staining pattern (U36, 270/277; U39, 268/277 tumors with more than 50% positive cells). Furthermore, the v6-containing CD44 splice variants present in HNSCC primary tumors and metastases were identical to those expressed in normal mucosa. Our data indicate that v6-containing CD44 splice variants do not play a role in the malignant progression of HNSCC.
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PMID:Characterization of CD44v6 isoforms in head-and-neck squamous-cell carcinoma. 1044 51

Estrogen receptor (ER)3 gene expression in breast epithelium is an intricately regulated event. The human ER gene is transcribed from at least three different promoters which are expressed in a cell- and tissue-specific manner, and result in mRNA isoforms with unique 5'-untranslated exons. The ER is overexpressed in about two thirds of breast tumors, and even in early premalignant breast lesions compared with adjacent normal breast epithelium. Furthermore, normal breast epithelium as well as breast cancer tissue contains alternatively spliced ER mRNA variants where single or multiple exons are skipped. It is still unclear if any or all of the ER mRNA splicing variants are translated in vivo, and if a change in the balance of ER variants could effect tumor development and progression to hormone-independent growth. Although infrequent in primary breast cancer, single amino acid changes within the ER in metastatic disease which might influence cell proliferation may also contribute to neoplastic progression of the mammary epithelium.
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PMID:Estrogen receptor variants. 1081 6

The HMG-I gene family encodes high mobility group proteins originally identified as nonhistone chromosomal binding proteins. HMG-I and -Y proteins are alternatively spliced products of the same mRNA; HMG-C is encoded by a separate gene. The HMG-I proteins function as architectural chromatin-binding proteins that bind to the narrow groove of AT-rich regions in double-stranded DNA. Recent studies indicate an important role for HMG-I proteins in regulating gene expression. Moreover, increased expression of the HMG-I, -Y, and -C proteins correlates with cellular proliferation and neoplastic transformation in several cell types and human cancers. Previous work from our laboratory has shown that HMG-I is a direct c-Myc target gene that is involved in Myc-mediated neoplastic transformation. In this report, we show that increased expression of HMG-Y or -C leads to transformation with anchorage-independent cell growth in two experimental cell lines in a manner similar to that of HMG-I or c-Myc. Moreover, Rat la cells overexpressing HMG-Y or -C form tumors in nude mice analogous to Rat 1a cells overexpressing HMG-I or c-Myc. Distant metastases developed in animals injected with cells overexpressing HMG-I or -C. Our findings suggest that the HMG-I gene family is involved in neoplastic transformation and may represent a new family of oncogenes important in the pathogenesis of several human cancers.
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PMID:The oncogenic properties of the HMG-I gene family. 1094 39

CD44 is a group of cell surface molecules involved in cell-cell and cell-matrix interactions. CD44 spliced variants (CD44V) have been found to enhance the metastatic potential of rat tumors. Tumors from the breast, colon, and thyroid express many alternatively spliced products; nonneoplastic tissues do not. Some authors suggest that CD44V5 and V6 may play a role in gastric carcinoma. The aim of the current study was to investigate the role of CD44V6 as a prognostic marker and predictor of metastatic potential in gastric carcinomas. One hundred fifty-five cases of gastric adenocarcinomas were studied: 36 cases of early (EGC), 19 cases of intermediate (MGC), and 100 cases of advanced gastric adenocarcinomas (AGC). A monoclonal antibody against CD44V6 (R&D) was used. CD44V6 expression was positively correlated with advanced stage (P = 0.05). Strong positivity was only detected in those cases of AGC with metastases. Patients with CD44V6 positive tumors revealed a lower 3- and 5-year survival rate (P = 0.0002). Immunohistochemical detection of CD44V6 could now be used as an indicator of tumor progression in biopsies of patients with gastric carcinoma.
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PMID:CD44V6 in gastric carcinoma: a marker of tumor progression. 1139 31

Tumor growth and metastasis require concomitant growth of new blood vessels, which are stimulated by angiogenic factors, including vascular endothelial growth factor (VEGF), secreted by most tumors. Whereas the angiogenic property and molecular mechanisms of VEGF have been well studied, the biological function of its related homolog, placenta growth factor (PlGF), is poorly understood. Here we demonstrate that PlGF-1, an alternatively spliced isoform of the PlGF gene, antagonizes VEGF-induced angiogenesis when both factors are coexpressed in murine fibrosarcoma cells. Overexpression of PlGF-1 in VEGF-producing tumor cells results in the formation of PlGF-1/VEGF heterodimers and depletion of the majority of mouse VEGF homodimers. The heterodimeric form of PlGF-1/VEGF lacks the ability to induce angiogenesis in vitro and in vivo. Similarly, PlGF-1/VEGF fails to activate the VEGFR-2-mediated signaling pathways. Further, PlGF-1 inhibits the growth of a murine fibrosarcoma by approximately 90% when PlGF-1-expressing tumor cells are implanted in syngeneic mice. In contrast, overexpression of human VEGF in murine tumor cells causes accelerated and exponential growth of primary fibrosarcomas and early hepatic metastases. Our data demonstrate that PlGF-1, a member of the VEGF family, acts as a natural antagonist of VEGF when both factors are synthesized in the same population of cells. The underlying mechanism is due to the formation of functionally inactive heterodimers.
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PMID:Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PlGF-1/VEGF heterodimers. 1208 92

Prostate specific membrane antigen (PSMA) is a folate gamma glutamyl carboxypeptidase that is oriented on the plasma membrane of normal and prostate cancer cells. A cytosolic version of PSMA, PSM', results from alternative splicing of the PSMA gene. Two additional alternatively spliced variants of PSMA, PSM-C and PSM-D, have been described recently. The ratio of PSMA to PSM' mRNA was higher in a small number of prostate cancer specimens compared to normal prostate cancer and benign prostatic hypertrophy (Su et al. Cancer Res 1995;55:1441). The intent of our study was to measure the gene expression of PSMA and the 3 PSMA splice variants in a large number of patient's tissues. A real-time, quantitative PCR assay was developed to quantify PSMA, PSM', PSM-C and PSM-D. Discrimination among the variants was achieved by designing unique primers and TaqMan probes for each gene. Amplification and detection was specific for the desired splice variant and was sensitive to one gene copy per reaction. The assay was used to quantify the gene expression in specimens of normal, benign, primary and metastatic prostate cancer from 72 patients. The mean PSMA expression (relative to 18S rRNA) was 2- to 3-fold lower in normal prostate (n = 4) compared to primary (n = 55, p = 0.31) and metastatic (n = 20, p = 0.33) prostate cancer. There was no difference in the PSMA expression between benign and cancerous prostate tissue from the same patients (n = 35). The ratio of PSMA to PSM' was lowest in the normal prostate and increased with increasing Gleason score (p < 0.001). The increased ratio in these tissues was a reflection of both increasing PSMA levels and decreasing PSM' mRNA. The expression of PSM-C did not differ in any of the tissue categories studied. The expression of PSM-D was similar in normal and primary prostate cancer but was 2-fold higher in lymph node (p < 0.005) and bone metastases (p < 0.05) compared to the primary tumors. Our results of the first detailed quantitative analysis of PSMA mRNA expression in patient's tissues demonstrate that PSMA and the 3 PSMA splice variants are expressed in normal, benign, cancerous and metastatic prostate cancer. We note increased PSMA expression in some malignant tissues, however, these increases are modest in magnitude. We also report that the expression of a novel splice variant, PSM-D, is elevated in prostate cancer metastases.
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PMID:Expression of prostate specific membrane antigen and three alternatively spliced variants of PSMA in prostate cancer patients. 1294 15

Genetic inactivation of key components of the Wnt signal transduction system is a frequent event in colorectal cancer. These genetic mutations lead to stabilization of beta-catenin, a cytoplasmic-nuclear shuttling protein with a potent transcription activation domain. Stabilization and subsequent nuclear localization of beta-catenin produces aberrant, Wnt-independent signals to target genes, an activity tightly linked to the genesis of colon cancers. In the nucleus, the transcription factor family of LEF/TCF proteins transmits Wnt signals by binding to beta-catenin and recruiting it to target genes for activation. Such activities are carried out by full-length LEF/TCFs that are thought to be mostly interchangeable and redundant. However, truncated forms of LEF-1 and TCF-1 that do not bind to beta-catenin function as dominant negatives and an alternatively spliced TCF isoform with a unique activation function has recently been discovered. The dominant negative forms block Wnt signals because they occupy Wnt target genes and limit beta-catenin access; the alternatively spliced TCF isoform activates certain Wnt target promoters whereas other TCF isoforms and LEF-1 do not. A study of LEF/TCF expression and activity in normal intestine and colon carcinomas suggests that the relative amounts of LEF/TCF isoforms may change as tumors progress and this may influence the strength and specificity of Wnt signals in the nucleus. While the underlying mechanism for a change in the LEF/TCF isoform expression is not yet known, recent evidence implicates the Wnt signaling pathway itself as a potential modulator.
Cancer Metastasis Rev
PMID:Lymphoid enhancer factor/T cell factor expression in colorectal cancer. 1500 Jan 48

Prostate cancer is a leading cause of cancer death in men. Risk prognostication, treatment stratification, and the development of rational therapeutic strategies lag because the molecular mechanisms underlying the initiation and progression from primary to metastatic disease are unknown. Multiple lines of evidence now suggest that KLF6 is a key prostate cancer tumor suppressor gene including loss and/or mutation in prostate cancer tumors and cell lines and decreased KLF6 expression levels in recurrent prostate cancer samples. Most recently, we identified a common KLF6 germ line single nucleotide polymorphism that is associated with an increased relative risk of prostate cancer and the increased production of three alternatively spliced, dominant-negative KLF6 isoforms. Here we show that although wild-type KLF6 (wtKLF6) acts as a classic tumor suppressor, the single nucleotide polymorphism-increased splice isoform, KLF6 SV1, displays a markedly opposite effect on cell proliferation, colony formation, and invasion. In addition, whereas wtKLF6 knockdown increases tumor growth in nude mice >2-fold, short interfering RNA-mediated KLF6 SV1 inhibition reduces growth by approximately 50% and decreases the expression of a number of growth- and angiogenesis-related proteins. Together, these findings begin to highlight a dynamic and functional antagonism between wtKLF6 and its splice variant KLF6 SV1 in tumor growth and dissemination.
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PMID:Targeted inhibition of the KLF6 splice variant, KLF6 SV1, suppresses prostate cancer cell growth and spread. 1599 51

Tumors arise initially as avascular masses in which central hypoxia induces expression of vascular endothelial growth factor-A (VEGF-A) and subsequently tumor vascularization. However, VEGF-A can also be constitutively expressed as a result of genetic events. VEGF-A is alternatively spliced to yield at least 6 different isoforms. Of these, VEGF-A(121) is freely diffusible whereas basically charged domains in the larger isoforms confer affinity for cell surface or extracellular matrix components. We previously reported that in a mouse brain metastasis model of human melanoma, VEGF-A(121) induced a qualitatively different tumor vascular phenotype than VEGF-A(165) and VEGF-A(189): in contrast to the latter ones, and VEGF-A(121) did not induce a neovascular bed but rather led to leakage and dilatation of preexistent brain vessels. Here, we correlate vascular phenotypes with spatial VEGF-A expression profiles in clinical brain tumors (low grade gliomas; n = 6, melanoma metastases; n = 4, adenocarcinoma metastases; n = 4, glioblastoma multiforme; n = 3, sarcoma metastasis; n = 1, renal cell carcinoma metastasis; n = 1). We show that tumors that constitutively express VEGF-A present with different vascular beds than tumors in which VEGF-A is expressed as a response to central hypoxia. This phenotypic difference is consistent with a model where in tumors with constitutive VEGF-A expression, all isoforms exert their effects on vasculature, resulting in a classical angiogenic phenotype. In tumors where only central parts express hypoxia-induced VEGF-A, the larger angiogenic isoforms are retained by extracellular matrix, leaving only freely diffusible VEGF-A(121) to exert its dilatation effects on distant vessels.
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PMID:Development of the tumor vascular bed in response to hypoxia-induced VEGF-A differs from that in tumors with constitutive VEGF-A expression. 1680 7


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