FGF7 and FGF2 are increased in benign prostatic hyperplasia and are associated with increased proliferation.

Purpose: To determine if overexpression of FGF7 and FGF2 occurs in benign prostatic hyperplasia (BPH) and if so, whether such overexpression is correlated with increased proliferation of epithelial and/or stromal cells.

Materials And Methods: The FGF7 and FGF2 content of protein extracts of normal peripheral zone, normal transition zone and hyperplastic prostatic tissues were determined by enzyme-linked immunoabsorption assay. Proliferation of epithelial and stromal cells was assessed by immunohistochemistry with anti-Ki67 antibodies on frozen sections of the same tissues used for protein extraction.

Common mutations in BRCA1 and BRCA2 do not contribute to early prostate cancer in Jewish men.

Background: Families with a high incidence of hereditary breast cancer, and subsequently shown to have terminating mutations in BRCA1 or BRCA2, appear to have a higher incidence of prostate cancer among male relatives. We aimed to determine whether the common germline mutations of BRCA1 or BRCA2 in Ashkenazi Jewish men predisposed them to prostate cancer.

Methods: We examined genomic DNA from 83 (for BRCA1 185delAG) or 82 (for BRCA2 6174delT) Ashkenazi Jewish prostate cancer patients, most of whom were treated at a relatively young age, for the most common germline mutation in each gene seen in the Ashkenazi population.

Mitogenic activation of human prostate-derived fibromuscular stromal cells by bradykinin.

Biologically active kinin peptides are released from precursor kininogens by kallikreins. Kinins act on kinin receptors to mediate diverse biological functions including smooth muscle contraction, inflammation, pain and mitogenicity. All components of the kallikrein-kinin system exist in human male genital secretions suggesting that these molecules participate in physiological and pathophysiological genitourinary function.

FGF9 is an autocrine and paracrine prostatic growth factor expressed by prostatic stromal cells.

Polypeptide growth factors, including members of the fibroblast growth factor (FGF) family, play an important role in the growth and maintenance of the normal prostate. We have found that FGF9 is expressed at high levels in the normal peripheral and transition zone of the human prostate. Analysis of FGF9 production by primary cultures of prostatic epithelial and stromal cells has shown that FGF9 is produced and secreted by the prostatic stromal cells.

Alterations in expression of basic fibroblast growth factor (FGF) 2 and its receptor FGFR-1 in human prostate cancer.

Fibroblast growth factors (FGFs) play an important role in the growth and maintenance of the normal prostate. There is increasing evidence from both animal models and analysis of human prostate cancer cell lines that alterations of FGFs and/or FGF receptors (FGFRs) may play an important role in prostate cancer progression. To better define the role of FGF2 and FGF7 in human prostate cancer in vivo, we have quantified these two growth factors in clinically localized human prostate cancers and uninvolved prostate by ELISA and Western blotting and determined their localization by immunohistochemistry.

Inactivation of the PTEN tumor suppressor gene is associated with increased angiogenesis in clinically localized prostate carcinoma.

The PTEN tumor suppressor gene encodes a dual-specificity protein phosphatase that may play a key role in modulating integrin-mediated signals. Inactivation of the PTEN gene has been detected in a small percentage of clinically localized prostate cancers but is common in metastatic disease. It has been shown in glioblastoma cell lines that loss of chromosome 10q, where the PTEN gene is located, is associated with increased angiogenic activity in the conditioned medium attributable to downregulation of thrombospondin-1, a negative regulator of angiogenesis.

Allelic loss on chromosome 13q in human prostate carcinoma.

To clarify the role in prostate tumorigenesis played by loss of the three known or putative tumor suppressor loci on the centromeric portion of chromosome 13q, we examined 80 clinically localized and 15 advanced prostate carcinomas for allelic loss at microsatellite markers mapped to this region, including markers tightly linked to the BRCA-2, retinoblastoma (Rb), and DBM (deleted in B-cell malignancy) loci. Among the 80 clinically localized cases, 24 showed allelic loss at one or more 13q loci. In all cases with loss, the Rb and/or DBM loci were lost.

Chromosome 10 alterations in prostate adenocarcinoma (review).

Inactivations of tumor suppressor genes are the most common genetic alterations in prostate adenocarcinoma. Such inactivations are frequently accompanied by loss of portions of the chromosome on which the tumor suppressor gene resides. Loss of portions of both 10p and 10q have been identified in a significant percentage of prostate carcinomas, as well as other malignant neoplasms, and such losses are associated with advanced clinical stage and aggressive behavior in these neoplasms.

Neuronal defects and delayed wound healing in mice lacking fibroblast growth factor 2.

Basic fibroblast growth factor (FGF2) is a wide-spectrum mitogenic, angiogenic, and neurotrophic factor that is expressed at low levels in many tissues and cell types and reaches high concentrations in brain and pituitary. FGF2 has been implicated in a multitude of physiological and pathological processes, including limb development, angiogenesis, wound healing, and tumor growth, but its physiological role is still unclear. To determine the function of FGF2 in vivo, we have generated FGF2 knockout mice, lacking all three FGF2 isoforms, by homologous recombination in embryonic stem cells.

Homozygous deletion of the PTEN tumor suppressor gene in a subset of prostate adenocarcinomas.

A novel tumor suppressor gene, PTEN, which encodes a dual-specificity protein phosphatase, has recently been identified on chromosome 10q23. We have previously shown that both alleles of this gene are inactivated in three of four prostate cancer cell lines tested. To evaluate the role of inactivation of this gene in primary stage B prostate cancers, 60 cases were analyzed using Southern blotting with PTEN probes and microsatellites on 10q23.

Endothelin-1 production and agonist activities in cultured prostate-derived cells: implications for regulation of endothelin bioactivity and bioavailability in prostatic hyperplasia.

Background: Endothelin-1 (ET-1) interacts with specific G-protein-coupled receptors to initiate short-term (contraction) and long-term (mitogenesis) events in target cells. ET-1 is an abundant prostate secretory protein that, in its biologically active form, elicits prostatic smooth muscle contraction. The present study was designed to determine the effects of ET-1 on prostate cell growth and to examine the regulation of endogenous ET-1 activity and bioavailability.

Sporadic breast cancers exhibit loss of heterozygosity on chromosome segment 10q23 close to the Cowden disease locus.

Cowden disease, a dominantly inherited syndrome characterized by a variety of proliferative lesions and predisposition to breast and thyroid cancer, has recently been linked to the polymorphic marker D10S215 on chromosome segment 10q23. Loss of heterozygosity in prostate cancer is linked to the same marker, whereas loss of heterozygosity in glioblastoma, endometrial cancer, and other malignancies also localizes to this region. Most recently, a putative tumor suppressor gene (PTEN/MMAC1) has been identified in the region between D10S215 and an adjacent, more telomeric marker (D10S541) and was found to be altered in breast cancers, prostate cancers, and glioblastomas.

Human parvovirus B19 in bone marrows from adults with acquired immunodeficiency syndrome: a comparative study using in situ hybridization and immunohistochemistry.

Human parvovirus B19, which infects and lyses erythroid precursors, can cause severe anemia in patients with immunodeficiency. The incidence of parvovirus infection in adult acquired immunodeficiency syndrome (AIDS) patients is unknown. Eighty-one archival formalin-fixed, paraffin-embedded (FFPE) bone marrow biopsies from 73 AIDS adults were immunostained with monoclonal R92F6 against B19 VP1 and VP2 capsid proteins using streptavidin peroxidase and streptavidin alkaline phosphatase techniques.

PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.

Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions.

Transthyretin Ile 122 and cardiac amyloidosis in African-Americans. 2 case reports.

Two cases of cardiac amyloidosis resulting from deposition of the Ile 122 variant of transthyretin in African-Americans are presented. These cases illustrate several typical features of this disorder, including electrocardiographic abnormalities and digoxin toxicity. Transthyretin Ile 122 is a common amyloidogenic variant in African-Americans (present as a heterozygous variant in 4% of this population); therefore, the diagnosis of transthyretin Ile 122 cardiac amyloidosis should be considered in African-Americans with unexplained restrictive cardiomyopathy or arrhythmias.

Allelic loss on chromosome 10 in prostate adenocarcinoma.

A total of 83 prostate adenocarcinomas was evaluated for allelic loss on chromosome 10 by analysis of loss of polymorphic microsatellite repeats. Initially, 64 stage B carcinomas were analyzed at 12 loci on chromosome 10. Nine cases showed loss of chromosome 10 sequences, with a fractional allelic loss of 20%.

Loss of heterozygosity on chromosomes 10 and 17 in clinically localized prostate carcinoma.

Loss of heterozygosity (LOH) at chromosomal loci has been associated with the presence of tumor suppressor genes at the deleted loci. Twenty-six clinically localized, Stage B prostate carcinomas were analyzed for LOH on chromosomes 10 and 17 using microsatellite markers. Two of 26 carcinomas showed LOH on 17p while one showed LOH on 17q.

Alterations of the retinoblastoma gene in clinically localized, stage B prostate adenocarcinomas.

Alterations of the retinoblastoma (Rb) tumor suppressor gene and its encoded protein have been detected in a variety of malignant neoplasms. The authors have evaluated a series of 26 clinically localized stage B prostate adenocarcinomas for loss of heterozygosity (LOH) at 13q14 (including the Rb locus), rearrangements or partial deletions of the Rb gene, and alterations of Rb protein level by quantitative immunohistochemistry. LOH at the Rb locus occurred in 35% of the informative specimens.

The BN51 protein is a polymerase (Pol)-specific subunit of RNA Pol III which reveals a link between Pol III transcription and pre-rRNA processing.

The three eukaryotic nuclear RNA polymerase (Pol) contain common and unique subunits. Cloning of the unique Pol III subunit genes in yeast cells has revealed a potential homolog in the mammalian system, the BN51 gene. The human BN51 gene was originally isolated as a suppressor of a temperature-sensitive cell cycle mutant of BHK cells (tsBN51).

Alterations in the p53 and MDM-2 genes are infrequent in clinically localized, stage B prostate adenocarcinomas.

Alterations in the p53 gene have been described in a variety of human malignant neoplasms. We have examined 29 stage B prostate carcinomas for alterations in the p53 gene and for amplification of the MDM-2 gene. No evidence of mutations in the conserved exons 5 to 8 was found by polymerase chain reaction single-stranded conformation polymorphism analysis and no accumulation of p53 protein was found by immunohistochemistry.

Cell cycle control of the BN51 cell cycle gene which encodes a subunit of RNA polymerase III.

The BN51 cell cycle gene complements a temperature-sensitive cell cycle mutation of BHK-21 cells which leads to arrest in G1 at the nonpermissive temperature. Recent evidence indicates it encodes an essential subunit of RNA polymerase III. The BN51 gene is induced 4-fold 4-h after stimulation of quiescent, serum-starved fibroblasts with serum.

The gene complementing a temperature-sensitive cell cycle mutant of BHK cells is the human homologue of the yeast RPC53 gene, which encodes a subunit of RNA polymerase C (III).

The temperature-sensitive BN51 cell cycle mutant of BHK cells arrests in G1 at the nonpermissive temperature (39.5 degrees C). We have previously reported cloning the gene which complements this mutation.

A retrovirus carrying the K-fgf oncogene induces diffuse meningeal tumors and soft-tissue fibrosarcomas.

The K-fgf/hst oncogene encodes a growth factor of the fibroblast growth factor (FGF) family and transforms cells through an autocrine mechanism which requires extracellular activation of its receptor(s). To identify the cell and tissue targets of K-fgf oncogenic potential in vivo, we constructed a recombinant retrovirus carrying the human K-fgf cDNA and injected it, together with helper Moloney murine leukemia virus, into immunocompetent as well as nude mice. The original construct was highly transforming in tissue culture but produced no detectable pathologies in vivo with the exception of a single fibrosarcoma which arose after a long latency.

Protection of mice against tumor growth by immunization with an oncogene-encoded growth factor.

The K-fgf/hst oncogene encodes a growth factor of the fibroblast growth factor (FGF) family that is secreted and transforms cells through a mechanism of autocrine cell proliferation. K-fgf-transformed cells are highly tumorigenic in immunocompetent allogeneic and syngeneic animals. BALB/c mice were immunized with a bacterial fusion protein consisting of a portion of the MS2 polymerase and of the human K-FGF precursor lacking only the first 4 amino acids or with a recombinant protein corresponding to the mature, secreted form of K-FGF (176 amino acids).

Organization and expression of the cell cycle gene, ts11, that encodes asparagine synthetase.

The human ts11 gene was isolated on the basis of its ability to complement the mutation of the BHK cell cycle ts11 mutant, which is blocked in G1 at the nonpermissive temperature. This gene has now been identified as the structural gene for asparagine synthetase (AS) on the bases of sequence homology and the ability of exogenous asparagine to bypass the ts11 block. The ts11 (AS) mRNA has a size of about 2 kilobases and is induced in mid-G1 phase in human, mouse, and hamster cell lines.