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Biomedical subjects

M R Freeman

Publications and source records attributed to M R Freeman.

At least 73 records · Page 4Linked to original sources
PubMed1994

Culture of a prostatic cell line in basement membrane gels results in an enhancement of malignant properties and constitutive alterations in gene expression.

Interaction of a transformed rat prostate epithelial cell (NbMC-2) with basement membrane gels (Matrigel) has been evaluated using a long-term matrix culture system. NbMC-2 cells, and single-cell clonal derivatives, formed spheroidal multicellular structures (aggregates) on Matrigel surfaces and were weakly invasive or noninvasive during a 1 week period. During subsequent 2-4 week periods, invasive cells originating from the aggregates and exhibiting a fusiform morphology became evident and increased in number in the matrix cultures. This biphasic pattern of behavior did not occur on laminin, type I or type IV collagen, or fibronectin substrates, but it did occur on Matrigel in serum-free medium. Characterization of sublines enriched in fusiform cells indicated that they maintained their distinct morphology with continuous culture. Further, they exhibited significantly greater invasive potential, saturation density, and random motility (chemokinesis) than the parent cell line. Steady-state levels of fibronectin mRNA were highly elevated in the fusiform variants, demonstrating a constitutive alteration in patterns of gene expression coinciding with the altered morphology. These results indicate that clonal NbMC-2 cells differentiate at a reproducible frequency into a more aggressive cell type in response to culture in the basement membrane-like matrix. The altered phenotypic properties appear to be stable since they can be inherited by daughter cells and because they are evident in the absence of matrix. These observations suggest a cell-specific mechanism for promotion of malignant growth by matrix-mediated induction of novel cell properties.

Animals↗
PubMed1994

Phenotypic and cytogenetic characterization of human bladder urothelia expanded in vitro.

A simple method for the harvest of bladder cell types from surgical specimens was used to generate strains of normal human urothelial cells that could be reproducibly cultivated, passaged and extensively expanded in serum-free medium. Immunostaining of the bladder epithelial cells with broadly reacting anti-cytokeratin antibodies and with an anti-cytokeratin antibody specific to cytokeratin 7, a transitional cell marker, indicated that they expressed a stable epithelial phenotype with serial passage. Low levels of immunostaining for E-cadherin and low levels of E-cadherin messenger ribonucleic acid, as determined by Northern blot analysis, and strongly positive immunostaining with an anti-vimentin antibody indicated collectively that the uroepithelial cells express a nonbarrier-forming phenotype under these culture conditions. However, when the urothelial cells were implanted subcutaneously into athymic mice on biodegradable synthetic polymers, they formed multilayered structures, suggesting that they retain the capability to differentiate in a living host. The urothelial cells proliferated in an epidermal growth factor independent manner and expressed high levels of transforming growth factor-alpha and amphiregulin messanger ribonucleic acids, suggesting the possibility of autocrine regulation of growth by epidermal growth factor-like factors. Cytogenetic analysis indicated that urothelial cells cultured for 6 passages possessed a normal chromosomal complement. These results demonstrate that primary cultures of autologous human bladder epithelial cells can be extensively expanded in vitro and, consequently, might be used in cell transplantation strategies for genitourinary reconstruction.

Amphiregulin↗
PubMed1994

Detection of human androgen receptor mRNA expression abnormalities by competitive PCR.

A competitive polymerase chain reaction (PCR) method for analysis of androgen receptor (AR) mRNA expression is described. The technique involves the use of an in vitro-transcribed RNA (cRNA) corresponding to a region of the AR mRNA transcript as a competitor in reverse transcription and PCR (RT-PCR) using total cellular RNA. The competitor RNA contains a site-directed mutation that produces a restriction fragment length polymorphism after RT-PCR and endonuclease digestion. We demonstrate that incorporation of the competitor RNA into RT-PCR reactions allows rapid semiquantitative determination of relative AR mRNA levels without the necessity of following PCR product formation kinetically; reaction products are assessed at the conclusion of the reaction sequence and without the use of radioactive probes or other specialized detection systems. We have used competitive PCR to demonstrate low levels of AR mRNA in an androgen-unresponsive human prostate cell line (PC3). In addition, we have also used this method to confirm that genital fibroblasts obtained from a subject with penoscrotal hypospadias (a non-intersex masculinization defect) that exhibit low levels of high-affinity androgen binding also exhibit abnormally low AR mRNA levels. These last results suggest that some non-intersex malformations of the urogenital tract are associated with abnormalities in the expression of the androgen receptor.

Base Sequence↗
PubMed1994

Measurement of left ventricular function during arm ergometry using the VEST nuclear probe.

A chest-mounted left ventricular (LV) nuclear probe (VEST) for use during arm and leg ergometry is presented, with a discussion of the validity and reproducibility of LV function measures at rest and exercise. During both arm and leg ergometry in trained subjects, transient changes in LV function/volumes were observed. LV ejection fraction and relative end-systolic and end-diastolic volumes were 25 to 30% less with the arms versus the legs, agreeing with data from other studies using conventional techniques. At peak exercise with both limbs, LV ejection fraction and relative LV end-systolic volume increased, followed by immediate postexercise normalization. The effect was greatest with the arms and reflects the effect of high intramuscular and arterial pressures generated during arm cranking, leading to increased LV afterloading. The VEST permits rapid and noninvasive assessment of LV function during arm exercise, avoiding the limitations of other techniques.

Blood Pressure↗
PubMed1994

Myocardial alterations during hemodialysis: insights from new noninvasive technology.

Eighteen patients with chronic renal failure had their cardiac status monitored during hemodialysis (HD). Ten studies were carried out using an ambulatory nuclear vest to assess ejection fraction (EF), heart rate (HR), relative end-systolic (ESV) and end-diastolic (EDV) volumes every 60 s. A total of 36 episodes of EF falls occurred in 9 patients, all asymptomatic. These EF falls were associated with a rise in ESV, while HR, BP, and EDV remained unchanged. The EF falls correlated best with the volume of ultrafiltrate removed. Ten patients had on-line ST-segment monitoring with sestamibi injection either at the time of ST depression (STD) or at the end of dialysis, if no STD occurred, in order to detect the presence of transient ischemia. Seven of ten patients had perfusion defects after dialysis, with STD occurring in 3 of 10 patients. Predialysis imaging was available in only 8 of 10 patients, and 6 of these patients had perfusion defects. Changes in perfusion defects were not significantly different in the 3 patients with STD compared with those without STD. EF falls and perfusion defects are common in HD patients even in the absence of known coronary artery disease; however, ST segment monitoring is not a sensitive tool for its detection. These changes in function and perfusion may represent myocardial ischemia and contribute to the high incidence of cardiovascular morbidity and mortality in this patient population.

Electrocardiography↗
PubMed1994

Abnormalities of cardiac sympathetic function in pacing-induced heart failure as assessed by [123I]metaiodobenzylguanidine scintigraphy.

BACKGROUND: Increased activity of the sympathetic nervous system contributes significantly to the pathophysiology of heart failure. However, cardiac efferent sympathetic function has not been well characterized in this disorder. In this study, we evaluated cardiac sympathetic innervation using [123I]metaiodobenzylguanidine (MIBG) and compared this with left ventricular (LV) tissue norepinephrine concentration and myocardial perfusion, assessed by 201Tl, in a canine model of heart failure. METHODS AND RESULTS: Planar and tomographic cardiac imaging was performed for MIBG and 201Tl in 23 dogs: 8 normal dogs (group 1) and 15 dogs with heart failure induced by right ventricular pacing at 250 beats per minute either continuously for 3 weeks (group 2) or intermittently for 7 weeks (group 3). Plasma and LV tissue norepinephrine concentrations were also measured. Scintigraphic studies in group 2 demonstrated reduced cardiac MIBG activity at heart failure (0.17 +/- 0.04 versus 0.29 +/- 0.05 counts per megabecquerel per pixel at baseline, mean +/- SD; P = .0001), whereas thallium activity was unchanged from baseline. This reduction in cardiac MIBG activity with heart failure was associated with increased intraimage variability in the distribution of MIBG activity (21 +/- 8% versus 13 +/- 7% at baseline, mean +/- SD; P = .0001). The MIBG heart-to-lung ratio was calculated for all groups to control for the inhibitory effect that plasma norepinephrine has on the neuronal uptake of MIBG. There was a positive correlation between LV tissue norepinephrine and the MIBG heart-to-lung ratio (r = .67; P < .001; n = 22), for which the group 2 heart failure animals had the lowest values. No relation existed between plasma norepinephrine concentration and the MIBG heart-to-lung ratio. In addition, regional LV tissue norepinephrine concentration and MIBG activity were both lowest at the apex in normal (group 1) and heart failure (group 2) dogs. The MIBG heart-to-lung ratio also correlated inversely with cardiac filling pressure (r = -.59; P < .05) and heart rate (r = -.65; P < .01) and positively with cardiac output (r = .53; P < .05). CONCLUSIONS: Heart failure is associated with severe cardiac adrenergic dysfunction manifested by reduced MIBG activity and increased heterogeneity in the LV distribution of MIBG. Furthermore, MIBG scintigraphy is a simple noninvasive method for assessing global and regional LV tissue norepinephrine levels.

3-Iodobenzylguanidine↗
PubMed1994

Increased G-suit coverage improves cardiac preloading conditions during positive pressure breathing.

A miniaturized nuclear probe (MNP) and multiple gated cardiac blood pool imaging (RCBI) were used to measure left ventricular function during positive pressure breathing (PPB) while wearing an extended-coverage (EC) vs. standard-coverage (SC) anti-G-suit. Seven subjects were exposed to 4.0 and 9.3 kPa PPB wearing each anti-G-suit during 3 min of PPB at ground level. Ejection fraction was unchanged using both techniques. The atrial component to diastolic filling was greater with the SC suit (p < 0.02). Using the MNP, end-diastolic and end-systolic volumes declined non-linearly over time at both PPB levels; these declines were greater with the SC G-suit (p < 0.001). Left ventricular preload declines during PPB. This is attenuated with increased G-suit coverage, confirming prior results using impedance cardiography. RCBI is less sensitive than MNP's for measuring non-steady-state cardiac physiology such as PPB.

Adult↗
PubMed1993

Implantation in vivo and retrieval of artificial structures consisting of rabbit and human urothelium and human bladder muscle.

The harvest of human bladder muscle and urothelial cells with subsequent growth may be useful for tissue replacement in genitourinary reconstruction. We previously reported the development of a system for the harvest, delivery and growth of rabbit urothelium in vivo using biodegradable polymers. We have now expanded and adapted this system for the harvest and in vivo implantation of human bladder urothelial and muscle cells. Synthetic polymer fibers of polyglycolic acid can serve as a scaffold and a delivery vehicle for the implantation of rabbit uroepithelial cells into athymic host animals. The polymers, which slowly degrade in vivo, allow the urothelial cells to survive at the implant site. We demonstrate that polyglycolic acid polymers support the proliferation of rabbit urothelial cells in situ and can serve as a maleable substrate for the creation of new urological structures that replace the degrading polymer fibers. We also show that human urothelial cells and bladder muscle cells, when implanted on polyglycolic acid fibers, from new urological structures in vivo composed of both cell types. The human cell-polymer xenografts can be recovered from host animals at extended times after implantation. These data suggest that feasibility of using polyglycolic acid polymers as substrates for the creation of human urothelial and muscle grafts for genitourinary reconstruction.

Animals↗
PubMed1993

Juvenile cystic kidneys (jck): a new mouse mutation which causes polycystic kidneys.

We have characterized a new recessive mutation in the mouse which predisposes to the development of polycystic kidney disease. This mutation, called juvenile cystic kidneys (jck), arose in a transgenic line of mice, but appears unrelated to the transgene since it segregates freely from it. While focal cysts are evident in affected animals as early as three days of life and the disease is progressive, the mice are fertile and generally survive to four or more months of age. Complementation analysis indicates that the jck mutation is not allelic with three other known recessive polycystic kidney mutations (cpk and two as yet unnamed mutations), and linkage studies demonstrate it is unlikely to be allelic with a fourth (pcy). The study of these five mutations and their interactions should prove useful for understanding the mechanisms required to maintain the normal integrity of renal tubules.

Alleles↗
PubMed1993

Coculture of mouse embryos with cells isolated from the human ovarian follicle, oviduct, and uterine endometrium.

OBJECTIVE: To examine the specificity of somatic cell support by comparing embryonic development during long-term in vitro coculture with feeder cells derived from the human ovarian follicle, oviduct, and endometrium. DESIGN: Comparative study of murine embryo development and degeneration during 6 days of in vitro coculture. RESULTS: All feeder-cell cultures were beneficial to embryonic development and viability. Few differences were observed between feeder cell types (epithelial or fibroblastic) or cell origin (ovarian follicle, oviductal, or endometrial). Embryos developed to the eight-cell stage in 24 hours whether in coculture (83.6% to 100%) or in media alone (85.2%); however, further development in media alone decreased compared with coculture (15.6% versus 63.4% to 87.7%, plating) and embryo degeneration increased (67.9% versus 5.5% to 19.4%) after 6 days. CONCLUSIONS: [1] Coculture of embryos with human reproductive tract cells is beneficial to embryonic development and viability. [2] Human somatic cell support of murine embryos during long-term in vitro coculture is not tissue specific nor dependent on cell type.

Adult↗
PubMed1992

Formation of urothelial structures in vivo from dissociated cells attached to biodegradable polymer scaffolds in vitro.

The use of autologous urothelium would be advantageous for urothelial replacement in many genitourinary reconstructive procedures. Urothelial tissue grafts might be created using isolated populations of transitional epithelium or tissue in concert with an appropriate synthetic substrate. We describe the results of experiments designed to determine the feasibility of using biodegradable polymers as delivery vehicles for the creation of new urothelial structures in vivo from dissociated cells. Primary cultures enriched in uroepithelial cells were obtained from New Zealand white rabbits using a new technique of cell harvest. Cells were seeded onto nonwoven meshes of polyglycolic acid polymers in culture and, after 1 to 4 days in vitro, the cell-polymer scaffolds were implanted into the mesentery, omentum or retroperitoneum of athymic mice. Polymers implanted without cells served as controls. Animals were sacrificed at 5, 10, 20 and 30 days after implantation and 75 implants were examined histologically. Ten days after implantation isolated single cell layers were seen lining the polymer fibers. At 20 and 30 days polymer degradation was evident and urothelial cells lined the polymer in continuous layers of 1 to 3-cell thickness. Anticytokeratin western blots demonstrated the presence of a urothelium-associated cytokeratin in cell-polymer implants recovered after 30 days. These results demonstrate that urothelial cells can be successfully harvested, survive in culture and attach to artificial biodegradable polymers. The urothelial-polymer scaffolds can be implanted into host animals and the implanted cells can achieve spatial orientation as the polymer undergoes biodegradation. These findings suggest that it may be possible to use autologous urothelium, reconfigured on a synthetic substrate, in reconstructive procedures involving the ureter, bladder and urethra.

Animals↗
PubMed1992

Thrombolysis in unstable angina. Randomized double-blind trial of t-PA and placebo.

BACKGROUND: Because coronary thrombosis is important in the pathogenesis of unstable angina and correlates with in-hospital cardiac events, we hypothesized that thrombolytic therapy would decrease cardiac events. METHODS AND RESULTS: We randomized 70 patients with unstable angina to tissue-type plasminogen activator (t-PA) (0.49 MU/kg for 1 hour followed by 0.07 MU/kg per hour for 9 hours) or placebo. All patients received full doses of intravenous heparin for 96 hours and aspirin (325 mg beginning at 72 hours). The primary end points of the study were in-hospital death, myocardial infarction, and urgent revascularization. Three secondary end points were also evaluated. Myocardial perfusion was assessed with resting planar thallium scintigraphy 90 minutes after initiation of therapy. Silent ischemia was assessed with 48-hour Holter monitoring for ST shift beginning at time of initiation of drug therapy. Coronary angiography was performed at 18 +/- 6 hours and analyzed quantitatively to assess the stenosis responsible for unstable angina, the presence of intraluminal filling defects consistent with intracoronary thrombus, and stenosis morphology and severity. There was no difference in total in-hospital cardiac events between patients receiving t-PA (5% or 14%) and those receiving placebo (7% or 20%) (p = 0.83). Resting thallium defects were larger in the patients receiving t-PA than in those receiving placebo (130 +/- 118 versus 76 +/- 84 degrees, p less than 0.04), and this difference persisted when corrected for previous infarction. Although the numbers of patients with ST shift were similar, the duration of ST shift was significantly longer in the patients receiving t-PA than with placebo (20 +/- 46 versus 3 +/- 10 minutes, p less than 0.045). The frequency of intracoronary thrombi in patients with stenoses greater than 50% was significantly less in patients treated with t-PA (11 of 22, 52%) as compared with placebo (23 of 25, 92%) (p = 0.002), but there was no significant difference in minimal lesion cross-sectional area (0.49 +/- 0.42 versus 0.57 +/- 1.08 cm2, p = 0.75) or ulceration index (0.79 +/- 0.16 versus 0.77 +/- 0.15, p = 0.71) of the culprit artery. CONCLUSIONS: We conclude that a prolonged infusion of t-PA in unstable angina reduces intracoronary thrombi but does not significantly decrease in-hospital cardiac events. The sample size, however, does not provide sufficient power to rule out a treatment effect. Paradoxically, there appears to be an increase in ST shift and worsening of myocardial perfusion with t-PA compared with therapy with heparin alone.

Aged↗
PubMed1992

Acute reduction of lipoprotein(a) by tissue-type plasminogen activator.

BACKGROUND: Lipoprotein(a) [Lp(a)] is a low density lipoprotein-like particle whose apolipoprotein B (apo B) moiety is disulfide-linked to apo(a), a plasminogen-like inhibitor of fibrinolysis in vitro. We hypothesized that plasma concentrations of Lp(a) are acutely affected by intravenous tissue-type plasminogen activator (t-PA). METHODS AND RESULTS: Patients with unstable angina were randomized to receive either intravenous t-PA (n = 15) or placebo (n = 11). Two-way ANOVA using repeated measures revealed a significant effect of t-PA on concentrations of Lp(a) (p = 0.026). There was a 48% fall in Lp(a) from baseline concentrations in the t-PA group at 12 hours (p = 0.031) but not at 72 hours. Lp(a) in the placebo group was unchanged. CONCLUSIONS: We conclude that t-PA produces a sharp and substantial but reversible reduction in plasma Lp(a). These data suggest that Lp(a) concentration is not as static in vivo as had been believed and might be acutely modifiable through some mechanism that induces its removal from the freely circulating state.

Angina, Unstable↗
PubMed1992

Reverse redistribution on exercise thallium scintigraphy: relationship to coronary patency and ventricular function after myocardial infarction.

OBJECTIVE: To define prevalence, pathophysiology and relation to thrombolytic therapy of reverse redistribution (appearance of a new, or worsening of an existing, scintigraphic defect on 4 h delayed images compared with the stress thallium image). DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Referral centre. PATIENTS: Sixty-three patients with acute myocardial infarction. INTERVENTIONS: Tomographic exercise thallium scintigraphy, radionuclide angiography, and quantitative coronary angiography. MAIN RESULTS: Tomographic exercise thallium scintigraphy performed at day 10 revealed fixed defects in 15 patients, reversible defects in 22 patients and reverse redistribution in 26 patients; no difference in treatment assignment (tissue plasminogen activator versus placebo) was found among the three groups. Left ventricular function was similar in patients with fixed or reversible defects and reverse redistribution; global ejection fraction was 48 +/- 14, 51 +/- 10 and 48 +/- 5%, respectively, and regional infarct ejection fraction was 36 +/- 15, 40 +/- 13 and 37 +/- 18%, respectively. However, nitroglycerin administration resulted in a significantly greater improvement in regional ejection fraction in reverse redistribution patients (5 +/- 4%) than that in patients with fixed defect (2 +/- 5%, P < 0.05) or reversible defects (3 +/- 5%, P < 0.05). The infarct-related artery had a greater cross-sectional area in reverse redistribution patients (1.5 +/- 1.42 mm2) compared with those with reversible defects (0.50 +/- 0.26 mm2, P < 0.05), but was similar to fixed defect patients (1.04 +/- 0.88). CONCLUSIONS: Reverse redistribution on tomographic thallium scintigraphy is a frequent phenomenon (occurring in 40% of patients following acute myocardial infarction) and is independent of thrombolytic therapy. Patients with reverse redistribution have a more widely patent infarct-related artery and similar ventricular function, but significantly greater functional improvement following nitroglycerin administration compared with those with reversible or fixed defects. These data suggest myocardial salvage within the infarct zone in some patients with reverse redistribution.

Animals↗
PubMed1992

Patients with symptomatic ischemia have larger thallium perfusion abnormalities and more adverse prognosis than patients with silent ischemia.

OBJECTIVE: To evaluate the mechanism for silent ischemia and the effect on prognosis. DESIGN: To test the hypothesis that patients with silent (compared with symptomatic) ischemia have less severe ischemia and a more favorable prognosis, the authors prospectively evaluated 152 consecutive patients with a positive exercise electrocardiogram with exercise thallium scintigraphy and followed them for two years. SETTING: Tertiary care university-based hospital. RESULTS: Asymptomatic patients during the exercise test had a greater exercise duration (9.4 +/- 3.1 versus 6.3 +/- 2.5 mins, P < 0.01), maximal heart rate (155 +/- 20 versus 136 +/- 20 beats/min, P < 0.01), systolic blood pressure (184 +/- 21 versus 176 +/- 23 mmHg, P < 0.05) and double product than patients who were symptomatic with chest pain. Although there was no difference in the magnitude of ST depression, time to ST depression was greater in the asymptomatic (5.6 +/- 2.7 mins), compared with symptomatic (4.6 +/- 2.6 mins), group (P < 0.01). Thallium ischemic score was smaller during asymptomatic ischemia (2.1 +/- 2.7) compared with symptomatic ischemia (3.9 +/- 3.1, P < 0.01). These findings were also demonstrated in a subgroup of 107 patients with both a positive exercise electrocardiogram and positive thallium scan. The patients with asymptomatic ischemia had a two-year cardiac event rate of 5.1% compared with 13.8% in the symptomatic patients (P = 0.065). CONCLUSIONS: Patients with asymptomatic ischemia have less severe myocardial ischemia and a better prognosis than patients with symptomatic myocardial ischemia during exercise testing.

Angina Pectoris↗
PubMed1991

Detection of silent myocardial ischemia in diabetes mellitus.

The prevalence of silent myocardial ischemia and its relation to autonomic dysfunction and pain threshold was studied in 58 men with diabetes mellitus and without cardiac symptoms. All patients underwent 48-hour ambulatory electrocardiographic monitoring and exercise testing after assessment of their autonomic function and pain threshold. Silent myocardial ischemia, defined as greater than or equal to 1 mm of ST-segment depression on either exercise testing or ambulatory electrocardiographic monitoring, was corroborated by exercise-induced reversible defect(s) on tomographic thallium scintigraphy. Autonomic function was assessed by heart rate response to: (1) Valsalva maneuver, (2) deep breathing, and (3) upright posture, as well as by diastolic blood pressure response to sustained handgrip and systolic blood pressure response to upright posture. Autonomic dysfunction was defined as greater than or equal to 2 abnormal responses. Pain threshold measurements were performed using electrical cutaneous stimulation of both forearms. Of the 58 diabetic patients, 21 were found to have autonomic dysfunction (36%). Silent myocardial ischemia was detected in 10 patients (17%), and was significantly more frequent in patients with than without autonomic dysfunction (38 vs 5%, p = 0.003). There was no difference in the electrical pain threshold or tolerance in subjects with and without silent myocardial ischemia. It is concluded that silent myocardial ischemia in asymptomatic diabetic men occurs frequently and in association with autonomic dysfunction, suggesting that diabetic neuropathy may be implicated in the mechanism of silent myocardial ischemia.

Adult↗
PubMed1991

Extracellular matrix and androgen receptor expression associated with spontaneous transformation of rat prostate fibroblasts.

Spontaneous transformation in continuous culture of the androgen-sensitive rat prostate fibroblast cell line, NbF-1, resulted in an aggressively tumorigenic nonmetastatic phenotype that coincided with few gross chromosome abnormalities. This study identified transformation-associated alterations in extracellular matrix and androgen receptor expression in the NbF-1 cell line. Substantial levels of procollagens I, III, and IV and fibronectin mRNAs were detected in nontumorigenic NbF-1 cells. Laminin B1 and B2 mRNAs were also detectable, but at lower levels. Expression of all six extracellular matrix mRNAs was nonuniformly lower in tumorigenic NbF-1 cells. This decrease in expression was greatest for alpha 2 procollagen IV mRNA, which was reduced 17-fold. Proteoglycans and glycosaminoglycans synthesized by the NbF-1 cultures were also characterized. The NbF-1 cell line expressed chondroitin sulfate proteoglycans predominantly, and expression was reduced 5- to 10-fold in tumorigenic cultures. In contrast to the extensive alterations in the extracellular matrix, measurement of high-affinity androgen binding and androgen receptor mRNA levels showed substantial expression of androgen receptors in both NbF-1 cultures. Cultures of early and late passage NbF-1 cells demonstrated a mitogenic response to dihydrotestosterone. These data indicate (a) that alterations in expression of extracellular matrix components may represent early markers for tumorigenic transformation in prostatic mesenchymal cells and (b) that these changes can occur without disrupting androgen receptor expression and androgen sensitivity.

Animals↗