PubMed Health⌕ Search

Biomedical subjects

M Koutsilieris

Publications and source records attributed to M Koutsilieris.

At least 19 recordsLinked to original sources
PubMed2005

Bone microenvironment-related growth factors, zoledronic acid and dexamethasone differentially modulate PTHrP expression in PC-3 prostate cancer cells.

Bone metastasis microenvironment-related growth factors such as insulin-like growth factor 1 (IGF-1), transforming growth factor beta 1 (TGF-beta1), basic fibroblast growth factor (bFGF) and interleukin 6 (IL-6) show survival factor activity, thereby inhibiting chemotherapy-induced apoptosis of PC-3 prostate cancer cells in vitro. Recently, zoledronic acid has been shown to induce apoptosis in PC-3 prostate cancer cells while overexpression of parathyroid hormone-related protein (PTHrP) inhibits serum deprivation-induced apoptosis in PC-3 cells. Consequently, we have investigated whether IGF-1, TGF-beta1, bFGF, IL-6, zoledronic acid and/or dexamethasone affect the expression of the PTHrP and type I PTH/PTHrP receptor (PTH.1R) in PC-3 prostate cancer cells using relative quantitative PCR and real-time PCR (expression at mRNA level) and immunocytochemical and immunofluorescence analysis (expression at protein level). Our data show that IGF-1, TGF-beta1, bFGF and IL-6 increase PTHrP mRNA expression and its perinuclear localization, while zoledronic acid (50 muM, 100 muM for 24 h and 48 h) and dexamethasone suppress PTHrP expression in PC-3 cells. We did not detect any appreciable change of the PTH.1R expression due to IGF-1, TGF- beta1, bFGF, IL-6, zoledronic acid or dexamethasone in PC-3 cells. Therefore, it is conceivable that bone metastasis microenvironment-related survival factor/anti-apoptotic activity and zoledronic acid anticancer action/pro-apoptotic activity on PC-3 cells is mediated, at least in part, by differential modulation of PTHrP expression.

Bone and Bones↗
PubMed2005

Prostate cancer cell survival pathways activated by bone metastasis microenvironment.

The development of resistance to anti-cancer therapies in bones is a major hurdle preventing long-lasting clinical responses to anti-cancer therapies in hormone refractory prostate cancer. Herein, we present the major signal transduction pathways, which are activated in prostate cancer cells residing at bone metastasis microenvironment. These intracellular signal transduction pathways can inhibit anti-cancer therapy-induced apoptosis of metastatic prostate cancer cells, thereby optimizing their survival, locally. Employment of this knowledge in a clinical setting provides the conceptual framework for the development of bone-targeted therapies for advanced prostate cancer. Indeed, bone metastasis microenvironment-targeted therapies illustrate a novel paradigm in cancer treatment: anti-tumor treatment strategies may not only aim at directly inducing cancer cell apoptosis, but can also target the tumor metastasis microenvironment, and neutralize the protection it confers on metastatic cancer cells.

Androgen Antagonists↗
PubMed2003

Endocrine/paracrine/autocrine survival factor activity of bone microenvironment participates in the development of androgen ablation and chemotherapy refractoriness of prostate cancer metastasis in skeleton.

Bone is the most frequent site of metastases of prostate cancer and is almost always the first and frequently the only site of metastases where disease will progress to stage D3. In addition, the number of skeletal metastatic foci is the most powerful independent prognostic factor of limited response to hormone ablation therapy and poor survival of patients with advanced prostate cancer. Furthermore, disease progression frequently occurs in the osteoblastic metastases, even though androgen ablation therapy still provides adequate and sustained control of disease at the primary site. Notably, the management of metastatic disease onto bones has traditionally relied on therapeutic modalities, which almost exclusively aim at directly inducing cancer cell death. However, accumulating pieces of evidence, from both the clinical and the basic research front, point to major limitations of this conventional approach. The in vivo response of malignant cells to anticancer therapies is directly influenced by the local microenvironment in which they metastasize. In particular, organ sites frequently involved in metastatic diseases, such as the bones, appear to confer to metastatic cells protection from anticancer drug-induced apoptosis. This protection is mediated by soluble growth factors and cytokines released by the normal cellular constituents of the host tissue microenvironment. The characterization of bone microenvironment-related survival factors has led to the development of a novel hormone manipulation which can re-introduce clinical responses in patients with stage D3 prostate cancer.

Androgen Antagonists↗
PubMed2001

A combination therapy of dexamethasone and somatostatin analog reintroduces objective clinical responses to LHRH analog in androgen ablation-refractory prostate cancer patients.

We evaluated whether the combination of triptorelin, a LHRH analog (LHRH-A), with dexamethasone and lanreotide, a somatostatin analog, can produce objective clinical responses in metastatic androgen ablation-refractory prostate cancer (stage D3) patients who have relapsed, after combined androgen blockade (LHRH-A plus antiandrogen) and antiandrogen withdrawal. Eleven stage D3 patients with diffuse bony metastases, who had progressed despite initial responses (lasting <12 months) to combined androgen blockade therapy and subsequently failed antiandrogen withdrawal, received oral dexamethasone (4 mg daily for the first month, tapered down to 2 mg after the first month and 1 mg after the second month, and continued on 1 mg thereafter) and lanreotide (30 mg im every 14 d) in combination with triptorelin (3.75 mg im every 28 d). Serum prostate-specific antigen, alkaline phosphatase, performance status, and bone pain were assessed monthly during therapy. Fasting blood glucose was measured biweekly, and serum IGF-I, T, and dehydroepiandrosterone sulfate levels were assessed at baseline, at response to the combination therapy, and at relapse from it. Ten of 11 stage D3 patients [90.9% of patients; 95% confidence interval (CI), 58.7-99.8%] had durable objective clinical responses (including > or = 50% prostate-specific antigen decline in 8 patients, 72.7%; 95% CI, 39-94%). All patients reported significant and durable improvement of bone pain (for a median duration of 13 months; 95% CI, 12-14 months; range, 6-22 months) and performance status (median duration, 19 months; 95% CI, 13-25 months; range, 7-22 months) without major treatment-related side effects. The median progression-free survival was 7 months (95% CI, 4-10 months; range, 3-17 months), and the median overall survival was 18 months (95% CI, 16-20 months; range, 7-22 months). Five of six total deaths occurred secondary to disease progression. We observed a statistically significant (P = 0.018) reduction in serum IGF-I levels at response to the combination therapy (60% reduction of baseline IGF-I levels). Dehydroepiandrosterone sulfate levels, although already significantly suppressed at baseline, had an additional significant reduction (P < 0.02) at response to therapy. T levels remained suppressed within castration levels (<3 nmol/liter, at baseline and throughout therapy, including relapse). The combination therapy of LHRH-A with dexamethasone plus somatostatin analog produces objective clinical responses and symptomatic improvement in androgen ablation (LHRH-A) refractory prostate cancer patients.

Aged↗
PubMed2001

Molecular biology and cellular physiology of refractoriness to androgen ablation therapy in advanced prostate cancer.

We review the extensive body of data on the molecular aetiology of hormone refractory disease in metastatic prostate cancer patients. Particular emphasis is placed on the crucial role of the bone micro-environment, especially the intercellular interactions of metastatic prostate cancer cells and osteoblasts in promoting the establishment of hormone refractory disease. Resistance of tumour cells to anticancer therapies is generally viewed as a phenomenon almost exclusively determined by chromosomal defects and/or gene mutations. However, it is now well-documented that the local milieu of the bone metastases can also protect tumour cells from anticancer therapy- induced apoptosis, either independently or synergistically with resistance-related genetic alterations. A key determinant of this protection is the urokinase/plasmin cascade which modulates the local concentration of survival factors, such as insulin-like growth factor (IGF-1). The molecular pathways whereby this major growth and survival factor for prostate cancer cells exerts its anti-apoptotic effect on prostate cancer cells are discussed.

Androgen Antagonists↗
PubMed2001

Increased insulin-like growth factor 1 activity can rescue KLE endometrial-like cells from apoptosis.

BACKGROUND: The peritoneal fluid (PF) of women with endometriosis contains protease(s) activity able to hydrolyze insulin-like growth factor-binding protein 3 (IGFBP-3), increasing the bioavailability of insulin-like growth factor-1 (IGF-1) locally. Therefore, we characterized the effects of IGF-1 on KLE endometrial-like cells in vitro. MATERIALS AND METHODS: The mitogenic effect of IGF-1 was assessed by the analysis of the DNA content and cell count. Apoptosis was triggered experimentally by the 48 hr exposure of KLE cells to 100 nM of adriamycin in the presence and absence of IGF-1 (50 ng/ml). Adriamycin apoptosis of KLE cells was determined by the number of dead KLE cells using trypan blue exclusion and by the DNA fragmentation on simple agarose gel and flow cytometry of propidium iodide and HOECHST 33342-stained KLE cells using an EPICS 753 pulse cytometer. RESULTS: IGF-1 stimulated the growth of KLE cells in a dose-dependent manner (optimal dose of 50 ng/ml) and protected KLE cells from adriamycin (100 nM)-induced apoptosis. CONCLUSIONS: These data suggest that IGF-1 is a survival factor for KLE cells. Conceivably, increased IGF-1 activity in the PF can optimize both the survival and ectopic growth of endometrial cells in the peritoneal cavity.

Apoptosis↗
PubMed2000

Three-dimensional type I collagen co-culture systems for the study of cell-cell interactions and treatment response in bone metastases.

The available monolayer culture systems for the study of bone metastases constitute a suboptimal simulation of the in vivo pathophysiology of bone metastases, and therefore, do not provide sufficient information to assess the morphologic evidence of bone reaction to cancer cells, the nature of cell-specific mediators of osteolysis and osteoplasia and the response to treatment. Therefore, we have developed a three-dimensional (3-D) type I collagen gel system that allows co-culture of human osteoblasts (MG-63) with cancer cells, such as MCF-7, MDA-MB-231 or ZR-75 breast cancer cells, PC-3 prostate cancer, KLE endometrial cancer cells and Calu-1 lung cancer cells. We used type I collagen purified from rat tail tendons and the 3-D system was prepared by mixing MG-63 cells with type I collagen in 24-well plates. The 3-D system was inoculated with cancer cells and processed with standard cell culture procedures. After 1 week of culture, the matrix gel was fixed with formalin and embedded in paraffin. Serial sections were stained with trichrome Masson stain and modified Masson-Goldner stain, as well as analyzed by in situ hybridization, immunohistochemistry and the TUNEL technique for semi-quantitative detection of apoptotic cell death, assessing the response to adriamycin therapy. The inoculation of PC-3 cells in this collagen matrix produced a blastic reaction, documented by an increased number of MG-63 cells and increased density of type I collagen. The human KLE cells and inoculation of cell-free media produced no reaction, while ZR-75, MCF-7 and Calu-1 cells produced local degradation of the collagen matrix. In situ hybridization revealed the expression of Insulin-like growth factor 1 (IGF-1) and urokinase-type plasminogen activator (uPA) mRNA, while immunohistochemistry detected differential expression of uPA and cathepsin D. Adriamycin induced apoptotic cell death in prostate cancer cells and estrogen receptor negative (ER-) MDA-MB-231 breast cancer cells, while adriamycin did not induce apoptosis but cytostasis in ER+ MCF-7 cells. The adriamycin-induced apoptosis was inhibited by co-culture with osteoblast-like cells (MG-63). We conclude that this 3-D culture system is a useful in vitro model allowing the analysis of local mediators of osteolytic and osteoblastic reactions to bone metastases and treatment response.

Journal Article↗
PubMed2000

Cancer and bone repair mechanism: clinical applications for hormone refractory prostate cancer.

It is a long-standing clinical observation that the bone corresponds to the prevalent site for metastatic growth of prostate cancer. In addition, bone metastases of this malignancy produce a potent blastic reaction, in contrast to the overwhelming majority of other osteotropic neoplasms, whose metastases are generally associated with an osteolytic reaction. Osteoblastic metastases represent almost always the first and, frequently, the exclusive site of disease progression to hormone refractory stage, stage D3. Moreover, the number of skeletal metastatic foci is the most powerful independent prognostic factor associated with a limited response to hormone ablation therapy and poor survival of advanced prostate cancer. It is noteworthy that disease progression to hormone refractory stage occurs almost always in osteoblastic metastases. These clinical observations suggested that the osteoblastic reaction is possibly not an innocent bystander of the metastatic prostate tumour growth, simply suffering its consequences, but it may in fact facilitate the efforts of metastatic cells to expand their population. An extensive line of research in the pathophysiology of osteoblastic metastases has established that the local blastic reaction involves the uPA/plasmin/IGF/IGFBP-3/TGFbs bioregulation system which can stimulate both the growth of osteoblasts and prostate cancer cells. Furthermore, we were the first to characterize osteoblast-derived 'survival factors' able to rescue metastatic prostate cancer cells from chemotherapy-induced apoptosis. These data resulted in the development of a novel concept of an anti-survival factor therapy, namely an anti-IGF-1 therapy, which has provided encouraging preliminary data in a phase II clinical trial with terminally-ill hormone/chemotherapy-resistant prostate cancer patients.

Journal Article↗
PubMed1999

Novel concept of antisurvival factor (ASF) therapy produces an objective clinical response in four patients with hormone-refractory prostate cancer: case report.

BACKGROUND: Osteoblasts and osteoblast-derived survival growth factors, such as insulin-like growth factor I (IGF I), inhibit chemotherapy apoptosis of prostate cancer cells, thereby producing cytotoxic drug-resistant tumor growth, in vitro. METHODS: We tested a novel therapeutic approach, referred to as antisurvival factor (AFS) therapy, that aimed at reduction of osteoblast-derived IGFs, using dexamethasone (4 mg per os, qD) and growth hormone (GH)-dependent liver-derived IGFs, using a somatostatin-analog (lanreotide, 30 mg, intramuscularly (i.m.), q14D) in combination with triptorelin (3.75 mg, intramuscularly, q28D) to produce a clinical response in 4 patients with progressing hormone-refractory prostate cancer. RESULTS: The patients given ASF therapy exhibited an excellent improvement of clinical performance and a decline of prostate-specific antigen (PSA) within 2 months of ASF therapy. One of them experienced excellent clinical response (normalization of PSA), two experienced good clinical response (decline of PSA of more than 50%), and one experienced stabilization (decline of PSA of less than 50%). CONCLUSIONS: We conclude that this novel concept of combination therapy, using ASF with hormone ablation, is a promising salvage therapy that should be further assessed with a randomized clinical trial.

Aged↗
PubMed1999

Immunohistochemical localization of insulin-like growth factor-binding protein-3 in eutopic and ectopic endometrial tissues.

OBJECTIVE: To evaluate the expression of insulin-like growth factor-binding protein-3 (IGFBP-3) in the eutopic endometrium and in endometriotic lesions. DESIGN: Retrospective immunohistochemical study. PATIENT(S): Twenty-five normal women and 39 women with endometriosis. INTERVENTION(S): Endometrial and endometriotic tissue biopsies obtained at laparoscopy. MAIN OUTCOME MEASURE(S): Expression of IGFBP-3 assessed by immunohistochemistry. RESULT(S): In the endometrium, positive immunostaining of IGFBP-3 was observed both in the stroma and the epithelial glands. The intensity of staining in the glands during the secretory phase was significantly higher in women with endometriosis compared with controls (P = .018). An increased expression of IGFBP-3 over controls was found in stages I and II of the disease (P = .018), whereas in stages III and IV, the difference between controls and women with endometriosis was not significant (P = .300). In endometriotic tissues, a much-marked immunostaining of IGFBP-3 was noted in 90% of the glands and 67% of the stroma without apparent differences related to cycle phase. CONCLUSION(S): These data show intense staining of IGFBP-3 in endometriosis lesions and increased expression of the protein in the endometrium of patients with endometriosis compared to controls. This marked expression of IGFBP-3 could be related to its previous finding in the peritoneal fluid and to its potential involvement in the pathophysiology of endometriosis.

Adult↗
PubMed1999

Repetitive and site-specific molecular staging of prostate cancer using nested reverse transcriptase polymerase chain reaction for prostate specific antigen and prostate specific membrane antigen.

We performed repetitive molecular staging using, nested rt-PCR for PSA and PSM at the peripheral blood (PB) and bone marrow (BM) of patients with prostate cancer (Pr.Ca) and benign prostate hyperplasia (BPH) after transrectal ultrasonography-guided biopsy (TRUS-B; 6-9 biopsies/patient), Pr.Ca patients after radical prostatectomy (RP), and Pr.Ca patients with diffuse bony metastases. All BPH patients (N = 20) tested negative at BM. Of the 2 who tested positive at PB 2 weeks after TRUS-B tested negative 8 weeks after TRUS-B. Of the 17 Pr.Ca, 7 (41.2%) tested positive at PB for PSA and PSM 2 weeks after TRUS-B while only 4 (23.5%) of them tested positive at repetitive analysis 8 weeks after TRUS-B. Two (11.8%) of the 17 Pr.Ca patients had positive analysis at BM for PSA and PSM 2 and 8 weeks after TRUS-B. Of 12 Pr.Ca patients with negative pre-operative molecular staging, 7 (58.3%) tested positive at PB for PSA and PSM 2 months post-RP but only 3 (25%) of them re-tested positive 12 months post-RP. Of these 12 Pr.Ca, 4 (33.3%) tested positive at BM for PSA and PSM 2 months post-RP while none re-tested positive 12 months post-RP. All Pr.Ca (N = 20) with diffuse bony lesions tested positive at BM. At PB, 6 of them (30%) tested negative for both PSA and PSM. Our data suggest that nested rt-PCR for PSA and PSM at PB is affected by TRUS-B and RP, while such analysis at BM concerted diffuse bony disease.

Adult↗
PubMed1999

Chemotherapy cytotoxicity of human MCF-7 and MDA-MB 231 breast cancer cells is altered by osteoblast-derived growth factors.

One-third of women with breast cancer will develop bone metastases and eventually die from disease progression at these sites. Therefore, we analyzed the ability of human MG-63 osteoblast-like cells (MG-63 cells), MG-63 conditioned media (MG-63 CM), insulin-like growth factor I (IGF-I), and transforming growth factor beta 1 (TGF-beta1) to alter the effects of adriamycin on cell cycle and apoptosis of estrogen receptor negative (ER-) MDA-MB-231 and positive (ER+) MCF-7 breast cancer cells, using cell count, trypan blue exclusion, flow cytometry, detection of DNA fragmentation by simple agarose gel, and the terminal deoxynucleotidyl transferase (TdT)-mediated nick end-labeling method for apoptosis (TUNEL assay). Adriamycin arrested MCF-7 and MDA-MB-231 cells at G2/M phase in the cell cycle and inhibited cell growth. In addition, adriamycin arrested the MCF-7 cells at G1/G0 phase and induced apoptosis of MDA-MB-231 cells. Exogenous IGF-I partially neutralized the adriamycin cytotoxicity/cytostasis of cancer cells. MG-63 CM and TGF-beta1 partially neutralized the adriamycin cytotoxicity of MDA-MB-231 cells but enhanced adriamycin blockade of MCF-7 cells at G1/G0 phase. MG-63 osteoblast-like cells inhibited growth of MCF-7 cells while promoting growth and rescued MDA-MB-231 cells from adriamycin apoptosis in a collagen co-culture system. These data suggest that osteoblast-derived growth factors can alter the chemotherapy response of breast cancer cells. Conceivably, host tissue (bone)-tumor cell interactions can modify the clinical response to chemotherapy in patients with advanced breast cancer.

Antineoplastic Agents↗
PubMed1998

Expression of functional major histocompatibility complex class II molecules on HMC-1 human mast cells.

Mast cells hold a key position in the defensive mechanisms against exogenous intruders. In this study, we investigated whether human mast cells express functional major histocompatibility complex (MHC) class II molecules that can transduce endogenous signals and present staphylococcal enterotoxin A (SEA) to T cells. Similar to HMC-1 human mast cell line, umbilical cord blood-derived mast cells express HLA-DR, -DP and -DQ molecules on their surface. MHC class II molecules expressed on HMC-1 cells bind significantly the SEA (a natural MHC class II ligand), and their ligation with specific mAbs or with SEA, leads ultrastructural changes, suggesting their degranulation. Recognition of SEA-bound MHC class II molecules on HMC-1 mast cells by the T cell receptor of K25 cells, an SEA-specific murine T cell hybridoma, triggers significant IL-2 secretion by these T cell hybridomas. Hence, our data point out the expression of functional MHC class II molecules on human mast cells, reinforcing the implication of these cells in the defense mechanisms of acquired immunity.

Animals↗
PubMed1998

Osteoblast-derived survival factors protect PC-3 human prostate cancer cells from adriamycin apoptosis.

OBJECTIVES: Hormone-independent and cytotoxic drug-resistant tumor growth in osteoblastic metastases defines poor survival in patients with advanced prostate cancer. Therefore, we analyzed the ability of human osteoblast-like cells (MG-63 cells) and MG-63 conditioned media (MG-63 CM) to protect PC-3 human prostate cancer cells from adriamycin cytotoxicity in vitro. METHODS: Adriamycin cytotoxicity was assessed in MG-63 osteoblast-like and PC-3 prostate cancer monolayer and three-dimensional collagen coculture systems using the DNA content and trypan blue exclusion assays, analysis of indexes of cell cycle by flow cytometry, determination of DNA fragmentation on simple agarose gel and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, and immunocytochemistry. RESULTS: Adriamycin (100 nM) arrested both the PC-3 and MG-63 cells at the G2/M phase in the cell cycle but induced apoptosis only in PC-3 cells, as assessed by flow cytometry, trypan blue exclusion, and agarose gel. Optimal doses of MG-63 CM (50 microg/mL), insulin-like growth factor I (50 ng/mL), and transforming growth factor-beta-1 (25 ng/mL), as determined by DNA content assay, partially neutralized the adriamycin cytotoxicity of PC-3 cells detected by flow cytometry and trypan blue exclusion. In addition, MG-63 cells rescued PC-3 cells from adriamycin apoptosis in the three-dimensional type I collagen gel coculture system, as analyzed by TUNEL assay. CONCLUSIONS: These data suggest that osteoblast-like cells and osteoblast-derived growth factors can optimize survival of metastatic prostate cancer cells, thereby helping to develop cytotoxic drug-resistant growth in vitro.

Biological Factors↗
PubMed1997

Loss of heterozygosity and reduced expression of the CUTL1 gene in uterine leiomyomas.

Cytogenetic analyses has revealed deletions and/or rearrangments at several chromosomal positions in approximately half of uterine leiomyomas. The most frequent genetic alteration, deletion of 7q22, was found in approximately 35% of studied cases with cytogenetic abnormalities (128/366=35%). The same chromosomal band was also found to be deleted in a fraction of acute myeloid leukemias and myelodysplastic syndromes. The frequent deletion of 7q22 in some tumors suggest that a tumor suppressor gene may be located in this region. The human Cut-like homeobox gene, CUTL1, is one of the genes localized to 7q22 and it was shown previously to encode a transcriptional repressor that down-modulates the expression of c-Myc. Activation of the c-Myc oncogenic potential has been shown in many cancers to result from alterations in one or the other of its several mechanisms of regulation. These observations led us to hypothesize that CUTL1 could act as a tumor suppressor gene. In the present study, we have identified polymorphic markers within and directly adjacent to CUTL1 at 7q22 and demonstrated that these markers are present in a commonly deleted region in seven out of 50 uterine leiomyomas samples examined. Furthermore, Northern blot analysis revealed that CUTL1 mRNA levels were reduced in eight tumors out of 13. These results suggest that CUTL1 may act as a tumor suppressor gene whose inactivation could be of pathological importance in the etiology of uterine leiomyomas.

Alternative Splicing↗
PubMed1997

Glucocorticoid receptor function possibly modulates cell-cell interactions in osteoblastic metastases on rat skeleton.

We analysed the glucocorticoid receptor (GR) function and its ability to modulate cell-cell interactions between the PA-III rat prostate cancer and UMR 106 osteoblast-like rat osteosarcoma cells as an in vitro model for studying GR function in PA-III cell-induced tumor and blastic reaction in rat bone. Intact GR was detected by ligand binding assays, DNA band-shift, and GR trans-activation analysis of PA-III and UMR 106 cells transiently transfected with the mouse mammary tumor virus thymidine kinase-chloramphenicol acetyltransferase reporter gene. Dexamethasone and transforming growth factor beta 1 (TGFbeta1) inhibited the growth of PA-III and UMR 106 cells. Dexamethasone's inhibition of PA-III and UMR 106 cells was reversed by anti-TGFbeta1 antibody and exogenous insulin-like growth factor I (IGF-I). Exogenous IGF-I, urokinase-type plasminogen activator (uPA), UMR 106 conditioned media (CM) and PA-III CM stimulated the proliferation of PA-III and UMR 106 cells. The mitogenic activity exerted by uPA and PA-III CM in UMR 106 cells was completely neutralized by anti-IGF-I specific antibody. In addition, dexamethasone up-regulated TGFbeta1 mRNA and down-regulated uPA mRNA expression in PA-III cells without affecting TGFbeta1 and uPA mRNA expression in UMR 106 cells. These data suggested that TGFbeta1, uPA, and IGF-I mediate at least in part cell-cell interactions and GR function in PA-III prostate cancer and UMR 106 osteosarcoma cells.

Animals↗
PubMed1996

Plasminogen activator inhibitor 1 messenger RNA expression and molecular evidence for del(7)(q22) in uterine leiomyomas.

We analyzed the expression of plasminogen activator inhibitor 1 (PAI-1) in 16 leiomyomas and adjacent myometrium of women who underwent a hysterectomy while in the proliferative (n = 8) and secretory phases (n = 8) of the menstrual cycle. We localized the PAI-1 and its mRNA expression in smooth muscle and vessel endothelial cells of uterine tissues using immunocytochemistry and in situ hybridization. The expression of PAI-1 mRNA was higher in 11 (68.75%) of 16 leiomyomas compared with the adjacent myometrium (leiomyoma/myometrium ratio, 1.4-3.0; mean, 2.045). The leiomyoma:myometrium ratio of PAI-1 mRNA expression did not change during the proliferative (Phase I) and secretory (Phase II) phases of the menstrual cycle. In the remaining five samples, the leiomyoma:myometrium ratio of PAI-1 mRNA expression was close to 1 (0.8-1.2; mean, 0.92). Because the locus of the PAI-1 gene is on chromosome 7q22, we screened for loss of heterozygosity (LOH) in these samples using the PAI-1 marker and D7S471, an anonymous marker 12 cM telomeric to PAI-1. Four of five samples with low leiomyoma:myometrium ratio had LOH for the PAI-1 and/or D7S471 markers. The fifth sample demonstrated a noninformative analysis for these markers but had LOH for the D7S515, D7S666, and D7S518 markers, all centromeric to PAI-1. Because del(7)(q22), associated with a relatively low PAI-1 mRNA expression, can deregulate matrix proteinases and growth factors' activity in leiomyomas, it is conceivable that del(7)(q22) results in heterogeneous leiomyoma biology.

Adult↗