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PubMed2002

Hyaluronidase gene profiling and role of hyal-1 overexpression in an orthotopic model of prostate cancer.

The mRNA levels of hyal-1, hyal-2, LUCA3 and PH20, the 4 hyaluronidases with demonstrated endoglucosaminidase activity, were extensively profiled in normal and tumor tissues and cell lines, using dot blot analysis and quantitative PCR. In normal tissues, hyal-1, hyal-2 and LUCA3 all showed unique patterns of mRNA expression, but were generally of widespread distribution, whereas PH20 mRNA was restricted to testes. In a small set of breast tumor samples, no elevations in hyal-1, hyal-2 or LUCA3 mRNA were seen. Hyaluronidase activity measured by a novel assay or zymography was also not elevated in sera from a number of breast cancer patients, compared to sera from normal volunteers. In ex vivo xenograft tumor cell lines, however, hyal-1 or hyal-2 mRNA levels were frequently elevated, whereas LUCA3 was only infrequently elevated and PH20 not at all. Two cell lines were engineered to overexpress hyal-1: a breast cancer line (CAL51) and a prostate cancer line (PC3M). Although the in vitro properties of the hyal-1 overexpressing cell lines were indistinguishable from the parental cells, the orthotopic growth of hyal-1 expressing PC3M cells in nu/nu mice resulted in significantly increased numbers of metastases, supportive of a role for hyal-1 in extravasation and metastatic tumor formation in this model of prostate cancer.

Adenocarcinoma↗
PubMed2004

Calcitriol-induced prostate-derived factor: autocrine control of prostate cancer cell growth.

Calcitriol (1alpha,25-dihydroxycholecalciferol) seems to play an important role in the complex control of prostate cell growth. It inhibits proliferation and induces differentiation and apoptosis in prostate cancer cells. However, the molecular mechanisms of the antiproliferative activity of calcitriol are not completely understood. The expression of prostate-derived factor (PDF), a member of the transforming growth factor-beta (TGF-beta) superfamily, has been shown to be associated with proapoptotic and antimitotic activities. We show that calcitriol induces PDF expression in LNCaP human prostate cancer cells in a concentration- and time-dependent manner. In LNCaP cells, the suppression of cell growth by calcitriol is accompanied by stimulation of PDF mRNA and protein synthesis. Human recombinant PDF inhibits LNCaP cell growth. We do not detect any effect of PDF-specific antibody on the basal growth of LNCaP cells, but this antibody partially reverses the suppression of LNCaP cell growth by calcitriol, suggesting that the effect of calcitriol on cell growth is at least partially mediated by PDF. In PC-3 cells, which are less responsive to the growth-inhibitory effect of calcitriol, it has no effect on PDF expression. We do not detect an effect of recombinant PDF on SMAD phosphorylation in LNCaP cells, but ERK1/2 kinases are transiently phosphorylated in response to PDF, which suggests that in LNCaP cells PDF may exert its action through pathway alternative to the classical TGF-beta signaling pathway. The present study describes the regulation of PDF, the proapoptotic protein of the TGF-beta superfamily, by calcitriol in androgen-responsive prostate cancer cells. This is a new link between calcitriol and growth factors of TGF-beta superfamily in the control of prostate cell growth.

Antineoplastic Agents↗
PubMed2005

Differential expression of 37 selected genes in hormone-refractory prostate cancer using quantitative taqman real-time RT-PCR.

Progression of prostate cancer to androgen independence remains the primary obstacle to improved survival. The development of more effective treatments depends on our understanding of the molecular events associated with the hormone-refractory stage. We quantified, among 90 screened genes, the expression of 37 target genes, using real-time quantitative RT-PCR. Gene expression was studied in 13 samples of HPRC compared to 33 clinically localised cancers and normal prostate tissue. We identify 19 genes with significant differential expression in HRPC compared to localised prostate cancer. Genes with decreased expression included receptors for growth factors, MMR genes and the serine protease hepsin. Analysis of increased gene expression confirmed the importance of AR upregulation and highlighted genes not previously linked to HRPC, including enzymes involved in steroid synthesis and the antiapoptotic factor survivin. Progression of prostate cancer to the hormone-refractory state is associated with differential gene expression, which may prove useful for both understanding disease progression and the development of new therapeutic approaches.

Androgens↗
PubMed2007

The effects of aging on tumor growth and angiogenesis are tumor-cell dependent.

It is generally accepted that histologically similar tumors grow more slowly, with less angiogenesis, in aged mice relative to young mice. We subcutaneously implanted TRAMP-C2 tumor cells, a prostate cancer cell line not previously examined in aging, into syngeneic C57/Bl6 young (4 month) and aged (20 month) mice and compared tumor growth and angiogenesis. Unexpectedly, the prostate tumors grew as fast in aged as in young mice. Angiogenesis in TRAMP-C2 tumors was robust, with no differences between the young and aged mice in the number of vessels, distribution of vessel sizes or features of vessel maturation. Aged mice had lower levels of serum testosterone than the young mice. VEGF levels were similar in the tumors and sera of the young and aged mice. Comparison with B16/F10 melanoma, a cancer cell line that is representative of previous studies in aged mice, showed that B16/F10 tumors grew minimally in the aged mice. In contrast to the B16/F10, TRAMP-C2 tumors had an extracellular matrix with significantly higher levels of MMP2 and MMP9 expression and activity. These unique results demonstrate that tumor progression can be as robust in aged tissues as young tissues. The ability of aged mice to grow large, vascularized prostate tumors is associated with high levels of MMP2/9 activity that may produce a permissive environment for tumor growth and angiogenesis. These data demonstrate that tumor-cell specific features determine the effect of aging on tumor growth and angiogenesis.

Aging↗
PubMed1978

Mechanism of sensitivity of cultured pancreatic carcinoma to asparaginase.

The effects of E. coli L-asparaginase on cultured human pancreatic carcinoma (MIA PaCa-2) have been studied. The enzyme (1 U/ml) inhibited growth and protein synthesis in both MIA PaCa-2 and PANC-1, another pancreatic carcinoma cell line, but had little or no effect on human breast carcinoma or melanoma cells. The inhibition of protein synthesis by E. coli L-asparaginase was largely reversed by L-glutamine but not by L-asparagine. The growth of both MIA PaCa-2 and PANC-1 showed absolute dependence on L-glutamine. These results indicate that the effect of E. coli L-asparaginase on cultured pancreatic carcinoma cells is exerted at least in part through its L-glutaminase activity. Although the addition of L-glutamine to the culture appeared to prevent cell death caused by L-asparaginase, it did not restore the ability of the cells to proliferate. Asparaginase derived from vibrio succinogenes, which is virtually free of L-glutaminase activity, was equally inhibitory to MIA PaCa-2 cell growth but did not affect protein synthesis. It is concluded that the inhibition of growth of cultured pancreatic carcinoma cells by E. coli asparaginase is a combined function of both its L-asparaginase and L-glutaminase activity.

Amino Acids↗
PubMed1990

Metallothionein gene expression and resistance to cisplatin in human ovarian cancer.

Intracellular thiols have been proposed as mediators of resistance to alkylating agents and cisplatin. As metallothionein is the predominant protein thiol, we examined its relationship to cisplatin resistance in human ovarian cancer cell lines. A human ovarian carcinoma cell line, A2780, derived from an untreated patient, was treated with cisplatin in several ways and the induced resistance to cisplatin ranged from 13- to 68-fold. The degree of resistance was dependent upon the method of selection. The drug-resistant cell lines also developed low levels of cross-resistance to cadmium. Additional cell lines established from untreated patients or ovarian cancer patients refractory to cisplatin- and/or carboplatin-containing combination chemotherapy were studied. The most cisplatin-resistant cell lines, OVCAR-8 and -10, were from patients previously treated with intensive chemotherapy. OVCAR-8 was relatively cross-resistant to cadmium while OVCAR-10 appeared relatively sensitive. Cell lines were examined for expression of metallothionein mRNA to evaluate the relationship between cisplatin resistance, cadmium cross-resistance and metallothionein expression. Only two of the cell lines with in vitro-induced resistance to cisplatin, 2780E80 and 2780CP70B3, had detectable metallothionein mRNA. The other cell lines selected in vitro for cisplatin resistance, as well as the parental A2780 ovarian cancer cell line, showed no expression at our level of detection. There was variable expression of metallothionein among the OVCAR cell lines. Cell lines from untreated patients, OVCAR-5 and -7, did express metallothionein, while the most cisplatin-resistant cell lines, OVCAR-8 and -10, did not. We also examined cisplatin induction of metallothionein mRNA in the cell lines. Only 2780CP70B3 among the cell lines with in vitro-induced cisplatin resistance showed increased expression after short-term exposure to cisplatin. OVCAR-4 also had a slight increase in expression after exposure to cisplatin. Mouse C127 cells transfected with a bovine papilloma virus-metallothionein gene construct were compared for cisplatin sensitivity to the same cell type transfected with bovine papilloma virus alone. In this model system, metallothionein expression did not influence cisplatin cytotoxicity. On the basis of these studies, we conclude that there is no causal relationship between metallothionein expression and cisplatin resistance.

Cadmium↗
PubMed1990

Expression of the gene coding for human prostate-specific antigen and related hGK-1 in benign and malignant tumors of the human prostate.

Human glandular kallikrein-1 gene (hGK-1) is closely related to the gene of human prostate-specific antigen (PSA) and both genes are expressed in the human prostate. We have studied PSA and hGK-1 mRNAs in human prostatic tissue samples from patients with benign prostatic hyperplasia (BPH) or adenocarcinoma (CA), using Northern and slot-blot analysis in order to gain insight into the expression of these highly similar genes. Multiple mRNAs were found to originate from both genes. The major mRNA species of 1.6 kb accounted for 57% to 76% of the total coding capacity for PSA in different tissue specimens, but a variant mRNA species of 1.9 kb was also abundant. Most of the BPH samples contained marked amounts of an aberrant 0.9 kb mRNA, and long PSA mRNAs of 6.1 kb, 4.5 kb and 3.1 kb were found in elevated amounts in some of the CA samples. The amount of PSA mRNAs that would produce aberrant PSA proteins if translated into protein varied from 18% to 38% in these tissue samples. The major mRNA species originating from hGK-1 was of 1.6 kb, but other less abundant mRNA species could also be observed. The amount of PSA and hGK-1 mRNAs was determined from slot blots hybridized with specific oligonucleotide probes. No significant differences could be found in the PSA gene expression between BPH and CA samples. The total amount of the PSA mRNAs in all the different BPH specimens was fairly similar, but there was a 3-fold difference between the highest and lowest PSA mRNA levels in the CA samples. The hGK-1 mRNA levels in the BPH specimens studied demonstrated greater variance than the PSA mRNA levels in the same samples. The correlation between PSA gene and hGK-1 expression in the BPH samples was good, suggesting that there are similarities in the regulation of these genes. However, the lack of correlation between the amounts of PSA and hGK-1 mRNAs in the CA samples except in sample C1 indicates that there are also differences in the gene regulation. The observed 3.7- to 6.5-fold excess of PSA mRNAs as compared with the amount of hGK-1 mRNAs present in the same tissue specimen also indicated differences in the cis- or trans-acting regulatory elements of these genes.

Antigens, Neoplasm↗
PubMed1991

Molecular analysis of MHC-class-I alterations in human tumor cell lines.

Molecular characterization of HLA-class-I expression was investigated in human tumor cell lines at the protein and mRNA levels using locus-specific monoclonal antibodies (MAbs) and probes. Some cell lines exhibited a differential expression of HLA-A and HLA-B products and also showed differences in the inducibility of HLA-class-I genes by gamma-IFN. Thus, gamma-IFN stimulation induced predominantly HLA-B mRNA in the HeP-2 cell line, which showed imbalances in basal levels of HLA-A and HLA-B expression. This unequal inducibility of HLA genes may imply that locus-specific regulatory mechanisms are involved in the expression of individual HLA products. The specific mechanism controlling the differential expression of HLA subsets appears to be independent of c-myc activity. Northern blot analysis found no relationship between c-myc mRNA levels and specific mRNA for HLA-A and HLA-B antigens.

Antibodies, Monoclonal↗
PubMed1991

Human small-cell lung-cancer cells are cytokine-resistant but NK/LAK-sensitive.

We have studied the effects of 8 cytokines and their combinations on the in vitro growth of 10 human small-cell cancer lines (SCLC). Interferon-alpha and gamma (IFN-alpha and gamma) caused significant but slight growth inhibition over a 7-day incubation period. However, none of the other 6 cytokines, tumor necrosis factor (TNF), lymphotoxin (LT), interleukin-1 beta (IL-1 beta) interleukin-2 (IL-2), transforming growth factor-beta 1 (TGF-beta 1), or granulocyte colony-stimulating factor (G-CSF), modified SCLC cell proliferation. In contrast, all 10 lines were sensitive to lysis by natural killer (NK) and lymphokine-activated killer (LAK) cells. Sensitivity to LAK cells could be increased by pretreatment of SCLC cells with IFN-gamma. As resistance to the cytostatic/cytotoxic activity of some cytokines has been associated with autocrine production of cytokines, we screened the SCLC lines for cytokine mRNAs. Within the limits of detection of the assay we found no expression of TNF, TGF-beta 1, IL-1 beta or IL-6 mRNA in the 10 SCLC lines.

Blotting, Northern↗
PubMed1991

Nucleolar protein B23 translocation after deferoxamine treatment in a human leukemia cell line.

Localization of nucleolar protein B23 in HL-60 cells under the treatment by iron chelator deferoxamine (DSF) was studied using indirect immunofluorescence. Bright nucleolar fluorescence was observed in exponentially growing control cells. The addition of DSF in the culture system resulted in time- and dose-dependent induction of protein B23 translocation from nucleoli to nucleoplasm, inhibition of cell growth, DNA and RNA synthesis. The addition of FeCl3 at culture initiation completely reversed the effects of DSF. Furthermore, significant numbers of HL-60 cells could be rescued from the effects of DSF when iron was added back as late as 24 hr after exposure to DSF. Cells resumed their abilities to grow and to synthesize DNA and RNA upon the iron rescue. Protein B23, accordingly, relocated from nucleoplasm to nucleoli. These results indicate the importance of iron for proliferation of leukemic cells and localization of protein B23 in nucleoli. Preribosomal ribonucleoprotein particles (pre-rRNPs) were extracted from isolated nucleoli of HL-60 cells and fractionated on sucrose density gradients. Protein B23 was found to be co-localized with the pre-rRNPs as determined by ELISA assays. No such B23-associated pre-rRNPs or other pre-rRNP fractions were obtained from nucleoli of DSF-treated cells. These results suggest that one of the effects of the anti-proliferative action of DSF is the inhibition of rRNA synthesis in nucleoli. Due to the lack of new synthesis of rRNA in nucleoli, protein B23 loses its binding target and translocates into the nucleoplasm. B23 translocation, as observed by immunofluorescence, may be a simple and rapid method for assessing inhibition of cell growth in response to anti-proliferative drugs such as deferoxamine in cancer chemotherapy.

Antibodies, Monoclonal↗
PubMed1992

Transforming growth factor beta 1 (TGF-beta 1) inhibits growth of a human ovarian carcinoma cell line (OVCCR1) and is expressed in human ovarian tumors.

The effects of EGF and TGF-beta 1 on the proliferation of 2 ovarian carcinoma cell lines (IGROV1 and OVCCR1) were evaluated. The cell lines were adapted to grow in a restricted serum (0.5%) medium. EGF was required for proliferation of both ovarian cell lines. Low doses of TGF-beta 1 inhibited clonogenic capacity and attenuated the EGF-mediated stimulation of DNA synthesis in OVCCR1 cells. TGF-beta 1 inhibited OVCCR1 cell proliferation by blocking the cell cycle at the G1/S transition. TGF-beta 1 did not affect either clonal or monolayer growth of IGROV1 cells. Both cell lines express type-I and type-III TGF-beta receptors, suggesting that the unresponsiveness of IGROV1 cells to TGF-beta 1 occurs at a post-receptor level. TGF-beta 1 mRNA was detected in OVCCR1 cells and in 8 out of 11 of the ovarian tumor specimens examined.

Cell Division↗
PubMed1993

De novo expression of intercellular adhesion molecule 1 (ICAM-1, CD54) in pancreas cancer.

We examined the expression of intercellular--adhesion molecule-I (ICAM-I, CD54) in 6 surgically removed pancreatic tumors and 8 pancreatic tumor cell lines. Immunohistochemistry revealed a varying percentage of ICAM-I-positive pancreas tumor cells, while normal pancreatic tissue (except for slight reactivity of endothelial cells) was not stained. The presence of the ICAM-I molecule on the cell surface and the expression of ICAM-I mRNA were investigated for 8 different pancreatic tumor cell lines. Three of these (Capan-I, Capan-2, QGP-I) expressed ICAM-I constitutively. In 4 of the ICAM-I-negative pancreas cancer cell lines, it was possible to induce a remarkable expression of ICAM-I by incubating the cells in the presence of inflammatory cytokines, whereas one cell line, 818-4, remained ICAM-I-negative. The responsiveness to either IFN-gamma, TNF-alpha, or IL-I beta treatment was shown to vary from cell line to cell line, indicating complex mechanisms that regulate the expression of ICAM-I at both, the transcriptional and the post-transcriptional level. Interestingly, ICAM-I is shed by pancreatic tumor cells, since soluble sICAM-I was detected in the cell-culture supernatants. In comparison with normal sera, the mean level of sICAM-I in sera of patients with pancreas carcinoma is elevated 2-fold.

Antigens, CD↗
PubMed1993

Altered expression of basement-membrane components and collagenases in ascitic xenografts of OVCAR-3 ovarian cancer cells.

Ascitic ovarian cancer cells, which derive from solid tumors, complicate the treatment of ovarian cancer by spreading throughout the peritoneal cavity. Because basement-membrane components may influence tumor-cell proliferation and dissemination, the present studies examined the production of (a) basement-membrane attachment and migration factors (laminin, fibronectin and type IV collagen); (b) a laminin receptor, the 32/67-kDa laminin-binding protein, the presence of which correlates with malignancy; and (c) metalloproteinases (types I and IV collagenase and stromelysin), by ascitic and cultured OVCAR-3 cells and solid OVCAR-3 tumors. The cultured cells and solid tumors produced high levels of mRNA encoding attachment factors and metalloproteinases, and low levels of mRNA for the 32/67-kDa laminin receptor. In contrast, the ascitic ovarian cells had low or undetectable levels of mRNA encoding laminin, type IV collagen and metalloproteinases, but higher levels of transcripts for the laminin receptor. Our results suggest that the apparent inability of ascitic OVCAR-3 cells to attach to host-tissue surfaces may be a consequence, in part, of low levels of expression of laminin, type IV collagen and/or type IV collagenase.

Animals↗
PubMed1994

Comparative analysis of mutations in the p53 and K-ras genes in pancreatic cancer.

Mutations in codon 12 of K-ras occur in a high proportion of pancreatic cancer cases. Although there is evidence that p53 mutations also occur in this tumor, few studies have been reported to date and no comparison has been made of K-ras and p53 mutations in the same tissues. Single-strand conformation polymorphism and sequencing of the PCR products were used to determine mutations in p53 gene; to detect mutations in K-ras genes, the artificial restriction fragment length polymorphism (RFLP) approach was used. Eight out of 30 tissues from primary pancreas cancer and 3 of 4 samples from metastases showed p53 mutations. Fifteen out of 17 pancreatic cancer cell lines had p53 mutations. In 2 cases, the same p53 mutation was identified in the original tumor and in a tumor-derived cell line. The majority of p53 mutations were present in exons 5-9 of the gene. Mutations at codon 12 of the K-ras gene were identified in 23/32 pancreas cancer tissues and in 14/17 cell lines. There was no relationship between the types of mutation observed in the 2 genes. In conclusion, mutations in K-ras and p53 genes are common in pancreatic cancer. p53 mutations may occur more frequently in metastatic lesions than in primary tumors, although further work is necessary to investigate this point.

Base Sequence↗
PubMed1994

Molecular analysis of the retinoblastoma gene in primary ovarian cancer cells.

Loss of heterozygosity (LOH) at the site of the retinoblastoma (RB1) gene, at 13q14, has been shown to occur in a high proportion of ovarian cancer patients. Based on this, RB1 gene inactivation was studied in primary tumor cells from 15 patients with ovarian cancer. Structural changes as well as expression of the RB1 gene were investigated. One patient had a nondisjunctional deletion at the RB1 locus, and the duplicated remaining allele carried a deletion of exon 21. In another patient, without detectable structural changes of the RB1 gene, no RB protein was detected. Allelic losses at the RB1 locus were observed in 8/13 informative cases (61%). Our results indicate that inactivation of the RB1 gene plays a role in tumor development in a minority of ovarian cancer patients. Another gene(s) on 13q also seem(s) to influence malignant transformation in patients with ovarian cancer.

Chromosomes, Human, Pair 13↗
PubMed1995

Expression of a B-cell marker, CD24, on nasopharyngeal carcinoma cells.

Random sequencing of clones from a lambda gt10 cDNA library, made from mRNA expressed in an Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) has revealed the gene transcript of human CD24. The CD24 antigen, a glycosylphosphatidylinositol-anchored cell surface molecule, has been identified as a B-cell marker that is lost during cell maturation. We show here that it is expressed on 3 NPC xenografts, previously defined as consisting of poorly differentiated epithelial cells, and on an NPC biopsy. In the case of the former, the level of expression of CD24 corresponds to the EBV load. A B-lymphoblastoid cell line carrying the same EBV genome as one of the tumours, C15, and an EBV-negative Burkitt's lymphoma cell line do not display the antigen, but epithelial-like cells of a laryngeal tumour cell line (Hep2) do express it. Our data suggest that CD24 may be a marker of cell differentiation not only for B cells but also for epithelial cells and may have an indirect association with EBV gene expression.

Animals↗
PubMed1995

An in vivo model to compare human leukocyte infiltration in carcinoma xenografts producing different chemokines.

In this study we tested whether the pattern of cytokines expressed by human carcinomas could account for a different in vivo recruitment of leukocyte subpopulations as a part of the anti-tumor immune response. Two carcinoma cell lines, SK-OV-3 ovary carcinoma and CALU-3 lung carcinoma, were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR), immunofluorescence and ELISA for the expression and in vitro production of cytokines with chemotactic, proinflammatory and growth-stimulating activity. Although both cell lines displayed a constitutive expression of granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage-CSF (GM-CSF), M-CSF, interleukin (IL-) 1 alpha and IL-8, only CALU-3 cell line expressed IL-10, RANTES (Regulated upon Activation, Normal T Expressed and Secreted) and monocyte-activating protein (MCP)-1. MCP-1 and IL-8 were detected by immunohistochemistry on sections from tumors xenografted in nude mice. To analyze whether the tumor-released cytokines modulate leukocytes in tumor infiltration, we studied the distribution of human peripheral blood leukocytes injected in the proximity of SK-OV-3 and of CALU-3 tumor xenografts. While SK-OV-3 was unable to recruit human leukocytes and appeared to be barely infiltrated by murine CD45+ cells, CALU-3 appeared to be rapidly and heavily infiltrated by human leukocytes which induced tumor necrosis within 18-24 hr.

Adenocarcinoma↗