Previous immunolabeling studies have indicated that increased expression of the matrix metalloproteinase-2 (MMP-2) zymogen is associated with an increased Gleason score for human prostate cancer. In the accompanying paper, we have found by immunoblotting and ELISA that the MMP-2 enzyme (termed MMP-2a) is expressed in prostate cancer and that increased expression is associated with progression. Monoclonal antibodies specific for MMP-2a were used to investigate the expression of MMP-2a in human prostate tissue sections of benign and malignant cancers. Immunohistochemistry indicated that MMP-2a expression was undetectable in fetal (n = 4), benign (n = 11), and low Gleason score 4 (n = 8) tissue. MMP-2a was faintly expressed (+) in cancer assigned Gleason scores 5 (n = 20) and 6 (n = 13). In comparison, MMP-2a was expressed at an intermediate level (++) in tissues of Gleason score 7 (n = 24), and at a intense level ( to +) in tissues of score 8 (n = 48), 9 (n = 9) and 10 (n = 35) and in lymph node metastases (n = 10). These observations were confirmed by quantitative Computer Assisted Imaging Analysis. In general, MMP-2a was primarily expressed by the glandular epithelial cells, and in high Gleason score 10 specimens (n = 25/35) there was clear evidence of MMP-2a localization at the cell surface. These data suggest that increased MMP-2a expression may be associated with malignant progression and metastases.

Enzyme Activation↗

PubMed1996

Evidence for increased activated metalloproteinase 2 (MMP-2a) expression associated with human prostate cancer progression.

Immunolabeling studies have previously indicated that increased expression of the 72-kDa matrix metalloproteinase 2 (MMP-2) is associated with human prostate cancer progression. It is not known if the enzymatically active MMP-2 is expressed in prostate cancer and if increased expression is associated with progression. Monoclonal antibodies specific for the activated MMP-2 molecule (MMP-2a, 66 kDa) were used (along with previously developed MMP-2 antibodies) to investigate the expression of MMP-2a and MMP-2 in human prostate tissue extracts. SDS-PAGE, Western blots, and zymography indicated that MMP-2a expression was undetectable in normal prostate (n = 6), benign prostatic hyperplasia (n = 9), and in prostate cancer of low Gleason score (GS) 4 (n = 11). MMP-2a was expressed in prostate cancer of increased GS (n = 37) and in lymph node metastases (n = 7). Quantitative ELISAs of human prostate cancer tissue extracts revealed that the levels of MMP-2 and MMP-2a per microgram of protein increased in prostate cancer tissues of increased GS (n = 48). MMP-2a levels were also high in prostatic lymph node metastases, but MMP-2 was not expressed or was barely detectable in these tissues. The molar ratios of MMP-2a to MMP-2 increased from 0 to 6.23 in tissues of GS 4 to 10, respectively. We conclude that significant increases in MMP-2a are associated with the malignant progression of prostate cancer and with tumor cell metastases to lymph nodes.

Blotting, Western↗

PubMed1995

IL-10 blocks collagen IV invasion by "invasion stimulating factor" activated PC-3 ML cells: upregulation of TIMP-1 expression.

We have previously shown that a 78-kDa "invasion stimulating factor" (ISF) triggers collagenase IV (MMP-2) secretion and the invasive behavior of metastatic PC-3 ML subclones in modified Boyden chamber assays [Stearns, M. E.; Stearns, M. Autocrine factors, type IV collagenase secretion and prostatic cancer cell invasion. Cancer Metastasis Rev. 12:39-52; 1993. Wang, M.; Stearns, M.; Stearns, M. E. Identification of the receptor for a novel M(r) 78,000 "invasion stimulating factor" from metastatic human prostatic PC-3 ML clones. Cancer Res. 54:2492-2495; 1994.]. Recently, we have shown that interleukin 10 (IL-10) preferentially stimulates tissue inhibitor of metalloproteinase-1 (TIMP-1) production in these cells [Wang, M.; Stearns, M. E. Characterization of a novel TIMP-1 enhancer element. J. Biol. Chem., submitted.]. In this paper, we report that IL-10 (20-40 ng) can inhibit the invasion stimulatory effects of ISF (30-60 ng) on PC-3 ML cells. "Checkerboard analysis" with modified Boyden chambers (precoated with 10 and 100 micrograms collagen IV) shows that IL-10 inhibits the stimulatory effects of ISF on both cell motility and chemoinvasion processes. In support of these data, exogenously supplied TIMP-1 (10 micrograms/ml) and collagenase antibodies (1:200 dilution) both completely blocked invasion. Quantitative ELISAs comparing the molar ratios of TIMP-1:MMP-2 and TIMP-2:MMP-2 further demonstrate that IL-10 (10-40 ng) preferentially activates TIMP-1 secretion to increase the molar ratio of TIMP-1:MMP-2 in the presence of increasing amounts of ISF (0-60 ng). IL-10 did not elevate TIMP-2 secretion or influence the molar ratio of TIMP-2:MMP-2.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Cytokine (IL-10, IL-6) induction of tissue inhibitor of metalloproteinase 1 in primary human prostate tumor cell lines.

Northern blots and scintillation counting showed that tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA was expressed by low passage, primary epithelial cultures (n = 5) of low-grade human prostatic carcinoma. TIMP-1 mRNA levels were normally low in the primary cell lines, but were inducible by interleukin (IL) 10 and 6. Dose and time-course studies indicated that IL-10 was the most potent stimulator of TIMP-1 expression. Cycloheximide blocked the effects of IL-10 in a reversible manner. In situ hybridization assays with TIMP-1 oligonucleotide antisense probes confirmed the northern blot results and indicated that IL-10 preferentially stimulated TIMP-1 mRNA synthesis. We suggest that IL-10, and to a lesser extent IL-6, may normally influence TIMP-1 expression by human prostatic epithelial cells.

Blotting, Northern↗

PubMed1994

Identification of the receptor for a novel M(r) 78,000 "invasion stimulating factor" from metastatic human prostatic PC-3 ML clones.

A M(r) 78,000 protein (reduced), termed invasion stimulating factor (ISF), was purified from the conditioned medium of a bone metastasizing human prostatic PC-3 ML clone (M. E. Stearns and M. Stearns. Cancer Metastasis Rev., 12: 39-52, 1993). Scatchard analysis and affinity cross-linking studies revealed that the producer PC-3 ML cells expressed a receptor binding site (M(r) approximately 115,000). We found a Kd approximately 425 pM and about 22,000 sites/cell. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiograms confirmed that the PC-3 ML cells expressed the receptor, whereas the ISF non-producing, noninvasive PC-3 clones (i.e., 3-4 x N.I. PC-3 cells) failed to express the ISF receptor. We conclude that a unique ISF autocrine loop characterizes the bone metastatic PC-3 ML cells.

Bone Neoplasms↗

PubMed1993

Autocrine factors, type IV collagenase secretion and prostatic cancer cell invasion.

Motility factors play a major role in tumor cell invasion and metastases. The biochemical properties of various motility factors; the receptor mediated mechanism of action; the role of microtubules; the potential influence of oncogenes; and the influence of motility factors on type IV collagenase secretion and invasion are discussed. We report on expression of a 70 kDa motility factor, termed invasion stimulating factor (ISF), in human prostatic PC-3 sublines. Boyden chamber chemotactic assays and measurements of type IV collagenase synthesis and secretion suggest that an ISF-receptor dependent mechanism influences tumor cell invasion and protease secretion. Taken together, the evidence that autocrine motility factors play an essential role in tumor cell invasion and metastases is compelling.

Animals↗

PubMed1989

Corpus callosotomy for refractory seizures in a patient with cortical heterotopia: case report.

Heterotopia of the cerebral cortex, a disorder of neuronal migration, may be associated with medically intractable seizures. We report on a patient with bihemispheric cortical heterotopia who had medically intractable atonic seizures that were successfully treated by corpus callosotomy. The clinical and radiographic aspects of cortical heterotopia and the surgical management of seizures associated with heterotopia are discussed.

Adult↗

PubMed1989

Reversal of desferrioxamine induced auditory neurotoxicity during treatment with Ca-DTPA.

Auditory neurotoxicity occurred in 13 (26%) of 50 evaluable patients receiving long term desferrioxamine chelation. In five of these patients, all of whom were receiving high doses of desferrioxamine, the toxicity caused deafness. These five patients were treated with subcutaneous calcium diethylene triamine pentacetic acid (Ca-DTPA) with zinc supplements instead of desferrioxamine, and their hearing improved during periods of seven to 19 months. Their serum ion concentrations remained unchanged. We suggest that all patients receiving long term desferrioxamine should have audiometric assessments at 6-12 monthly intervals. Ca-DTPA with oral zinc supplements should be considered as alternative to desferrioxamine as an iron chelating treatment in patients with auditory neurotoxicity.

Adolescent↗

PubMed1983

The relationship of adenoid weight to tonsillar weight.

Nearly 70 per cent of contemporary ENT consultants perform adenoidectomy as a routine when removing the tonsils. It has been stated in the literature that adenoid and tonsillar hypertrophy tend to co-exist and so a study was set up to investigate this hypothesis, with the possibility that it may be of diagnostic importance. A series of 45 children admitted for the operations of tonsillectomy and adenoidectomy was investigated. No correlation was found between adenoid weight and tonsil weight. In view of this, it was concluded that tonsil and adenoid hypertrophy do not necessarily co-exist and that tonsil size cannot be used to predict adenoid size.

Adenoidectomy↗

PubMed1983

Effect of experimental hypothyroidism on hearing in adult guinea pigs.

A group of guinea pigs was rendered hypothyroid using propylthiouracil solution in their drinking water. The animals were hypothyroid for at least 120 days. During this time no change was noted in their hearing thresholds for high-frequency clicks. The audiometric evaluation was performed using brainstem evoked response audiometry.

Animals↗

PubMed1983

Some factors affecting nerve regeneration in relation to radiotherapy.

The effect of delay and irradiation, both separately and combined, on regeneration of rat sciatic nerve was evaluated in adult Wistar rats. Those animals which had received irradiation at some stage fared significantly worse than those which had immediate division and reanastomosis of the sciatic nerve without irradiation. The possible relevance of these findings to nerve regeneration in patients treated by surgery and radiotherapy for parotid cancer is discussed.

Action Potentials↗

PubMed1980

Immune reactivity in patients with colorectal cancer: assessment of biologic risk by immunoparameters.

Explore the source record for details and available documents.

Carcinoembryonic Antigen↗