Biomedical subjects

Tapio Visakorpi

Publications and source records attributed to Tapio Visakorpi.

32 records · Page 2Linked to original sources

PubMed2004

Molecular mechanisms of prostate cancer.

During the last ten years our knowledge of genetic alterations in prostate cancer has significantly increased. For example, several chromosomal loci possibly harboring predisposing or somatically mutated genes have been suggested. Still, we lack the comprehensive molecular model for the development and progression of prostate cancer. Only a few genes have been found to be aberrant in a significant proportion of prostate cancer. These include GSTP1, PTEN, TP53, and AR. Thus, they are natural targets for new treatment strategies.

Acyltransferases↗

PubMed2004

No amplifications of hypoxia-inducible factor-1alpha gene in invasive breast cancer: a tissue microarray study.

OBJECTIVE: Hypoxia Inducible Factor-1 (HIF-1) is an important transcription factor that stimulates tumour growth and metastases via several pathways, including angiogenesis and altered metabolism. Activation of HIF-1 depends on the levels of its alpha-subunit, which increase during hypoxia. Recent studies showed that the HIF-1alpha gene was amplified in prostate cancer, leading to overexpression of HIF-1alpha at normoxia. The aim of this study was to evaluate the presence of HIF-1alpha gene amplifications in invasive breast cancer as an explanation for HIF-1alpha protein overexpression. METHODS: Protein and gene expression of HIF-1alpha were analyzed on a tissue microarray of 94 breast cancers by immunohistochemistry and fluorescent in situ hybridization (FISH), respectively. RESULTS: Overexpression of HIF-1alpha protein was found in 58/94 (62%) of patients. No amplifications of the HIF-1alpha gene were detected. CONCLUSION: Increased protein levels of HIF-1alpha are not associated with amplification of the HIF-1alpha gene in human breast cancer. Therefore, other mechanisms than gene amplification must be responsible for HIF-alpha overexpression at normoxia.

Breast Neoplasms↗

PubMed2003

Identification of patients with transitional cell carcinoma of the bladder overexpressing ErbB2, ErbB3, or specific ErbB4 isoforms: real-time reverse transcription-PCR analysis in estimation of ErbB receptor status from cancer patients.

PURPOSE: The purpose of this research was to quantitatively analyze tumor-specific overexpression of all ErbB receptors and ErbB4 isoforms in transitional cell carcinoma (TCC) of the bladder. EXPERIMENTAL DESIGN: A real-time reverse transcription-PCR protocol was set up to simultaneously quantitate the mRNA levels of all four of the ErbB receptors and ErbB4 isoforms. Exon-intron structure of the ErbB4 gene was determined for ErbB4 isoform analysis. The assay was validated by analyzing: (a) defined ErbB cDNAs; (b) cell lines transfected with defined ErbB cDNAs; and (c) cancer cell lines with ErbB status controlled by Western blotting. ErbB mRNA expression was quantitated from 29 clinical samples representing TCC, interstitial cystitis, or histologically normal bladder. Cutoff expression levels predicting neoplasia at 95% probability were determined. ErbB expression and amplification was analyzed by immunohistochemistry and chromogenic in situ hybridization. RESULTS: Experiments with control cDNAs and cell lines demonstrated that the assay was both specific and sensitive, and that ErbB mRNA levels closely correlated with protein levels in cancer cell lines. Determination of cutoff expression levels indicated tumor-specific overexpression of ErbB2, ErbB3, and specific ErbB4 isoforms in a subset of TCC patients. Significant overexpression of ErbB mRNAs was also detected in cases without amplification of the respective gene or when the protein product was not localized at the cell membrane. CONCLUSION: Bladder cancer patients with tumor-specific overexpression of ErbB receptors or their isoforms were identified. Real-time reverse transcription-PCR could be used for ErbB receptor status quantitation to produce prognostic and predictive information for cancer therapy.

Animals↗

PubMed2003

Human pHyde is not a classical tumor suppressor gene in prostate cancer.

A novel putative tumor suppressor gene, pHyde, was recently cloned from rat prostate. The rat gene has been shown to inhibit prostate cancer cell proliferation both in vitro and in vivo. However, the role of human pHyde in prostate cancer has not been studied before. Here, we analyzed human prostate cancer cell lines (LNCaP, DU145, PC-3, 22Rv1), xenografts (LuCaP 23.1, 35, 41, 49, 58, 69, 70 and 73) and clinical prostate carcinomas for genetic alterations and expression of pHyde. The expression of pHyde in normal human tissues as well as in prostate cancer was studied by Northern analysis and real-time quantitative RT-PCR. It was ubiquitously expressed in all normal tissues analyzed. Although, the expression was significantly (p=0.007) lower in poorly differentiated than in well and moderately differentiated carcinomas, there were no differences in the expression levels between benign prostate hyperplasia, untreated primary and recurrent hormone-refractory prostate carcinomas (p=0.607). Altogether, missense mutations were detected in 2 out of 68 samples studied ( approximately 3%) by denaturing high-performance liquid chromatography (DHPLC) and sequencing. One of the samples with the mutation also exhibited a loss of a gene copy by fluorescence in situ hybridization (FISH). This was the only sample that exhibited a genetic alteration in both alleles, suggesting that the human pHyde is not a classical prostate tumor suppressor gene. The reduced expression of the gene found in some tumors warrant further studies.

Animals↗

PubMed2003

Expression of ERalpha and ERbeta in prostate cancer.

BACKGROUND: It has been suggested that estrogens and their receptors (ERs) may be involved in the development and progression of prostate cancer. To elucidate the significance of these receptors, expression of both ERalpha and ERbeta was measured in benign and malignant prostate tumors, as well as in cell lines. METHODS: Expression of ERalpha and ERbeta was measured in prostate hyperplasia (BPH, n = 7), androgen-dependent (n = 30) as well as hormone-refractory (n = 12) prostate carcinomas, and in four prostate cancer cell lines (LNCaP, DU145, PC-3, and 22Rv1) using real-time quantitative RT-PCR. RESULTS: Only low-level expression of ERalpha was found in all tumor types and cell lines. The level of expression was similar to that observed in breast carcinomas found to be negative for ERalpha by immunohistochemistry. All cell lines showed low, but detectable, levels of ERbeta expression. The mean expression of ERbeta in the hormone-refractory carcinomas was about half that seen in BPH or the androgen-dependent carcinomas; however, the difference was not statistically significant. CONCLUSIONS: The data suggest it is unlikely that alterations in the expression of either ER are commonly involved in the progression of prostate cancer.

Breast Neoplasms↗

PubMed2003

The molecular genetics of prostate cancer.

The molecular genetics of prostate cancer, the second most common cause of cancer-related death in men, is poorly understood. Inherited factors are believed to account for 42% of the risk of prostate cancer, and although multiple chromosomal loci of susceptibility have been identified, the target genes for these loci have not been well defined. Its heterogeneous nature suggests that the predisposition to prostate cancer may involve multiple genes and variable phenotypic expression. Genes that have been found to play a role in progression of prostate cancer include GSTP1 and PTEN, as well as the androgen receptor (AR) gene. Evidence suggests that the AR signaling pathway can be activated by other ligands when androgen levels are low. Recent findings have also implicated Kruppel-like factor 6 (KFL6), E-cadherin, the p40 subunit of eukaryotic translation initiation factor (eIF3-p40), and Elongin C, but confirmatory evidence is required to clarify the roles of these factors. Technologic advances, such as complementary DNA and tissue microarrays, have facilitated identification of genetic alterations and investigations of their function, but improved tools for searching and analyzing genes are still needed.

Adenocarcinoma↗

PubMed2002

Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families.

Loss of function mutations in the fumarate hydratase (fumarase, FH) gene were recently identified as the cause for dominantly inherited uterine and cutaneous leiomyomas and renal cell cancer. To further evaluate the role of FH in tumorigenesis, we screened FH mutations from tumor types seen in hereditary leiomyomatosis and renal cell cancer mutation carriers-41 uterine and 10 cutaneous leiomyomas, 52 renal cell carcinomas, 53 sarcomas, 29 prostate carcinomas, and 15 lobular breast carcinomas. Few mutations were detected. Biallelic inactivation of FH was found in one uterine leiomyosarcoma, one cutaneous leiomyoma, and one soft tissue sarcoma. Whereas the two former lesions were shown to originate from a germ-line mutation, the soft tissue sarcoma is to our knowledge the first example of purely somatic inactivation of FH in tumors.

Base Sequence↗

PubMed2002

Refined mapping of allele loss at chromosome 10q23-26 in prostate cancer.

BACKGROUND: Allele loss of at least two segments in 10q, one mapping to the PTEN gene and one more distal were described in prostate cancer, with loss more frequent in advanced prostate cancer. METHODS: A 63 cM region from 10q23 to q26 was studied for allele loss (LOH) in 59 prostate cancer samples using a dense map of microsatellite markers. RESULTS: LOH of at least one marker in 10q was observed in 13/59 tumors. LOH increased with grade and stage. Detailed deletion mapping identified three regions of allele loss. The first region mapped to the site of the PTEN gene, the second is defined by loss of one marker, D10S1692, in one tumor, and the third is defined between markers D10S1757 and D10S587, including DMBT, with a subregion of approximately 1.2 Mb mapping between markers D10S209 and D10S1679, lost in one tumor. CONCLUSIONS: LOH at the PTEN gene is frequent but mutations in the remaining allele were not detected by SSCP-screening. There may be more than two tumor suppressor (TS) genes mapping more distal of PTEN. The site for these putative TS genes can now be mapped with a dense set of precisely localized markers in a larger series of advanced tumors.

Chromosome Mapping↗

PubMed2002

Genomewide DNA hypomethylation is associated with alterations on chromosome 8 in prostate carcinoma.

To elucidate the relationship between genomewide DNA hypomethylation and chromosome instability, 55 prostate carcinoma specimens were analyzed for extent of hypomethylation by Southern blot analysis of LINE-1 sequence methylation and for loss or gain of chromosomal material by comparative genomic hybridization. Seventeen (31%) tumors showed strong hypomethylation of DNA, whereas four (7%) displayed slight hypomethylation and the rest of the tumors normal-level methylation. Chromosomal aberrations were observed in 34 carcinomas. The most frequent chromosomal alterations were loss of 13q in 18 cases and aberrations in 8p (loss) or 8q (gain) in 16 cases. The presence of chromosomal loss or gain was significantly associated with the presence of strong hypomethylation. A striking correlation (P = 0.00001) was observed between aberrations on chromosome 8 and hypomethylation, whereas no association was seen between DNA hypomethylation and loss of 13q. The association between DNA hypomethylation and the presence of metastases was statistically significant (P = 0.044), and both chromosomal alterations and DNA hypomethylation tended to be more frequent in higher-stage tumors. In conclusion, the data indicate that hypomethylation is associated with chromosomal instability in prostate cancer. Specifically, a surprisingly strong association between alterations on chromosome 8 and genomewide hypomethylation was found. This association suggests that DNA hypomethylation and alterations in chromosome 8 may be mechanistically linked to each other in prostate carcinoma.

Aged↗

PubMed2002

Chromosomal aberrations in prostate cancer xenografts detected by comparative genomic hybridization.

A major problem in studying prostate cancer has been the lack of model systems because of the difficulties in growing prostate cancer cells in vitro. Recently, however, several human prostate cancer xenografts, grown in immune-deficient mice, have been established. Here, we characterized 13 such xenografts (LuCaP 23.8, 23.12, 35, 41, 49, 58, 69, 70, 73, LAPC-4AD, LAPC-4AI, LAPC-9AD, and LAPC-9AI) as well as one prostate cancer cell line (22Rv1) derived from a xenograft for chromosomal alterations by comparative genomic hybridization and a modification of multicolor fluorescence in situ hybridization. On average, the xenografts contained 13 (range 5-28) aberrations, 5 (1-13) gains, and 8 (1-15) losses, per case. The chromosome arms that most often contained losses were 2q, 5q, 6q, 8p, 13q, and 18q, and gains were 7q, 8q, and Xq. The same regions were previously shown to be often altered in advanced prostate carcinomas in patients. The androgen-dependent and corresponding androgen-independent sublines of LAPC-4 and LAPC-9 shared all genetic alterations, suggesting that the transition of the growth from androgen dependency to independence does not involve major chromosomal aberrations in these two models. In conclusion, the identified genetic aberrations lay the groundwork for further detailed genetic analyses of these xenografts.

Animals↗

PubMed2002

Expression and gene copy number analysis of ERBB2 oncogene in prostate cancer.

An anti-ERBB2 antibody, trastuzumab, has been shown to be highly efficient in the treatment of metastatic breast cancers overexpressing the ERBB2 gene. It has been suggested that overexpression and even amplification of ERBB2 may play a role in the development of prostate cancer. Here, we have analyzed gene copy number and expression of the ERBB2 gene in both androgen-dependent primary and metastatic tumors, as well as recurrent hormone-refractory tumors. The expression levels were compared to the expression of ERBB2 in breast cancers with or without ERBB2 gene amplification. Of 126 prostate tumors, chromogenic in situ hybridization (CISH) revealed only 1 case containing borderline (six to eight copies) amplifications of ERBB2. This hormone-refractory tumor, however, did not express ERBB2 protein. Immunohistochemical staining of ERBB2 protein was negative (0 or 1+ intensity) in all prostate samples (n = 124) analyzed. To quantitate the level of ERBB2 mRNA expression in prostate tumors (n = 34) and cell lines (n = 3), as well as in breast tumors (n = 30) and cell lines (n = 16), real-time reverse transcriptase-polymerase chain reaction (LightCycler) methodology was used. The expression level was similar in all prostate tumor types and corresponded to the level of expression in breast carcinomas without ERBB2 amplification. Breast tumors with ERBB2 amplification expressed, on average, approximately 20 times (P < 0.001) higher mRNA levels than prostate tumors or breast carcinomas without the gene amplification. In conclusion, the expression of ERBB2 in prostate cancer is relatively low, and is not altered during disease progression. Thus, it is unlikely that treatment modalities relying on the overexpression of ERBB2 gene will be useful in treating prostate cancer.

Breast Neoplasms↗

PubMed2002

Gonadoblastoma and dysgerminoma associated with XY gonadal dysgenesis in an adolescent with chronic renal failure: a case of Frasier syndrome.

STUDY OBJECTIVES: To report a rare reason for primary amenorrhea, a Frasier syndrome, XY gonadal dysgenesis associated with renal failure with eventual development of gonadoblastoma. To study immunohistochemical analysis of gonadoblastoma and dysgerminoma. To analyze the possibility of androgen receptor mutation in this rare syndrome. METHODS: We report a case of a 16-yr-old female with this syndrome. She underwent a laparoscopic bilateral gonadectomy and salpingectomy. A histopathological examination revealed gonadoblastoma with focal malignant dysgerminoma in the left dysgenetic gonad and an immunohistochemical of these fairly rare, malignant tumors. An androgen receptor was coded. Analysis was done. RESULTS: Immunohistochemical analysis showed that inhibin was strongly positive in gonadoblastoma but negative in dysgerminoma. No mutations of the androgen receptor gene were found. CONCLUSIONS: Inhibin positivity in gonadal stroma and in gonadoblastoma may indicate hormonal activity causing advanced puberty in patients with XY gonadal dysgenesis.

Adolescent↗

PubMed2002

Amplification and overexpression of Elongin C gene discovered in prostate cancer by cDNA microarrays.

Functional significance of several oncogenes is mediated by overexpression. To identify overexpressed genes in prostate cancer, we analyzed expression of 1081 transcripts in three prostate cancer cell lines (PC-3, DU145, and LNCaP) using cDNA microarray hybridization. The cDNA microarray analyses were validated by quantitative real-time RT-PCR. On average, 64% of the genes were expressed at detectable levels in the cell lines. Next, the expression profiles were combined with the data on DNA sequence copy number alterations in the cell lines obtained by comparative genomic hybridization. The genes for Elongin C and urokinase type plasminogen-activator, both located in the regions of amplification in the PC-3 cell line (8q21 and 10q22, respectively), were found to be overexpressed in the PC-3. Amplification and overexpression of urokinase type plasminogen-activator in prostate cancer has previously been reported. Here, fluorescence in situ hybridization on tissue microarray showed high-level amplification of the Elongin C gene in 8 (23%) of 35 hormone-refractory carcinomas but in none of the untreated prostate carcinomas (n = 35). Finally, it was shown that the Elongin C gene was overexpressed and amplified also in breast cancer cell line SK-Br-3. The results indicate that Elongin C is a putative target gene for 8q amplification.

Breast Neoplasms↗

PubMed2002

Cloning and characterization of a novel six-transmembrane protein STEAP2, expressed in normal and malignant prostate.

By using subtraction and cDNA array hybridizations, we recently identified an anonymous transcript that was differentially expressed in benign prostate hyperplasia and prostate cancer cell line PC-3. Here, we report the cloning of the full-length cDNA of the gene, designated STEAP2 (six-transmembrane epithelial antigen of the prostate 2). The gene is located at the chromosomal region 7q21 and encodes for a 490-amino acid protein with six predicted transmembrane domains and is predominantly expressed in prostate epithelial cells. Green fluorescent protein fusion construct indicated that the STEAP2 protein is localized mainly in the plasma membrane. Real-time quantitative RT-PCR showed that the gene is expressed at levels more than 10 times higher in normal prostate than in other tissues studied. Of the prostate cancer cell lines, STEAP2 was expressed in significant levels only in androgen-responsive LNCaP. The expression of STEAP2 was significantly higher (p = 0.002) in both untreated primary and hormone-refractory prostate carcinomas than in benign prostate hyperplasias, suggesting that it may be involved in the development of prostate cancer. As a cell-surface antigen, STEAP2 is a potential diagnostic or therapeutic target in prostate cancer.

Amino Acid Sequence↗