Biomedical subjects

L Ossowski

Publications and source records attributed to L Ossowski.

At least 37 records · Page 2Linked to original sources

PubMed1991

Estradiol modulation of plasminogen activator production in organ cultures of human breast carcinomas: correlation with clinical outcome of anti-estrogen therapy.

We have studied the estradiol sensitivity of primary human breast carcinomas in organ culture in a prospective pilot series of 109 tumors. The effect on plasminogen activator (PA) production was used as the end-point of estrogen action. We found that: (i) All tumors secreted detectable levels of urokinase-type PA (uPA); the level of basal uPA production was markedly heterogeneous but showed a weak association with the level of estrogen receptor positivity (p = 0.049). (ii) Only 23.5% of the tumors secreted tissue-type PA (tPA) in addition to uPA; a higher proportion of these tumors had histological characteristics indicative of good prognosis (18% vs. 3% of tumors secreting only uPA). (iii) Estradiol modulated uPA production and this effect was receptor-mediated. (iv) Responsiveness to estradiol was limited to a subset (25 of 60 or 41.7%) of estrogen and progesterone-receptor-positive tumors. (v) Of 20 evaluable patients with lymph-node and receptor-positive breast cancer who received adjuvant anti-estrogen therapy, 11 were identified as estradiol-sensitive by the in vitro PA assay; of these, 10 had no evidence of disease after a median follow-up period of 3+ years. In contrast, of 9 patients with tumors identified as estradiol-insensitive, 4 developed metastases within 3+ years of follow-up. (vi) Consistent with the previously reported inhibitory effect of corticosteroids on uPA production in organ cultures of human tumors, the basal culture level of uPA produced by tumors from patients receiving corticosteroids at the time of surgery was significantly lower than the level of uPA in the remaining tumors (p = 0.029). Also, tumors from patients receiving thyroid hormone, known to stimulate uPA in vitro, showed a slight trend toward increased production of uPA. These results show that hormone effects on tumor PA production are qualitatively similar in organ culture and in the host. This and the emerging individual correlation between sensitivity to estradiol in vitro, as determined by PA, and the clinical effectiveness of anti-estrogen therapy, underscore the potential usefulness of the organ culture approach.

Breast Neoplasms↗

PubMed1991

Inhibition of urokinase-type plasminogen activator by antibodies: the effect on dissemination of a human tumor in the nude mouse.

Nude mice given inoculations s.c. of a human squamous carcinoma--HEp3 (1.5 x 10(6) cells/mouse)--developed invasive tumors that produced high levels of urokinase-type plasminogen activator (uPA) and metastasized predictably to the lungs and lymph nodes of the host. To investigate the role of uPA in invasion and metastasis, mice given inoculations of tumor cells were treated daily with s.c. injections of specific, anti-human uPA antibodies (rabbit polyclonal, 150 inhibitory units; mouse monoclonal, 3000 inhibitory units/mouse/day). Control mice received either saline or preimmune rabbit immunoglobulins. A total of approximately 50 mice was studied. The tumors were surgically excised 10 to 17 days postinoculation when weighing 1 to 2 g. Antibody administration was discontinued after tumor excision. Two strategies were used: (a) following the removal of tumors the mice were maintained and observed until respiratory distress, indicative of lung metastasis, was evident; or (b) their lungs were examined for evidence of metastasis on the day of tumor removal. While histological sections of s.c. tumors excised from control mice indicated extensive local invasion, evidence of invasion was absent in most tumors excised from mice in which tumor uPA was inhibited by the antibody (P less than 0.025). The inhibition of local invasion did not, however, lead to a reduced incidence of distant metastasis. Since we found that the presence of HEp3 tumors in mice elicits a pronounced granulocytosis, we propose that this response may facilitate the spread of tumor cells by a mechanism independent of endogenous tumor proteases.

Animals↗

PubMed1991

In vivo paracrine interaction between urokinase and its receptor: effect on tumor cell invasion.

Numerous studies have linked the production of increased levels of urokinase type plasminogen activator (uPA) with the malignant phenotype. It has also been shown that a specific cell surface receptor can bind uPA through a domain distinct and distant from the proteolytic domain. In an in vivo model of invasion, consisting of experimentally modified chorioallantoic membrane (CAM) of a chick embryo, only cells that concurrently expressed both uPA and a receptor for uPA, and in which the receptor was saturated with uPA, were efficient in invasion. To test whether uPA produced by one cell can, in a paracrine fashion, affect the invasive capacity of a receptor-expressing cell, we transfected LB6 mouse cells with human uPA (LB6[uPA]), or human uPA-receptor cDNA (LB6[uPAR]). LB6(uPA) cells released into the medium 1-2 Ploug units of human uPA per 10(6) cells in 24 h. The LB6(uPAR) cells expressed on their surface approximately 12,000 high affinity (Kd 1.7 x 10(-10) M uPA binding sites per cell. Unlabeled LB6(uPA) and 125-IUdR-labeled LB6(uPAR) cells were coinoculated onto experimentally wounded and resealed CAMs and their invasion was compared to that of homologous mixtures of labeled and unlabeled LB6(uPAR) or LB6(uPA) cells. Concurrent presence of both cell types in the CAMs resulted in a 1.8-fold increase of invasion of the uPA-receptor expressing cells. A four-fold stimulation of invasion was observed when cells were cocultured in vitro, prior to in vivo inoculation. Enhancement of invasion was prevented in both sets of experiments by treatment with specific antihuman uPA antibodies, indicating that uPA was the main mediator of the invasion-enhancing, paracrine effect on the receptor-expressing cells.

Animals↗

PubMed1990

Preservation of steroid hormone receptors in organ cultures of human breast carcinomas.

In a study of human breast carcinomas in short-term organ culture, in which plasminogen activator modulation by estrogen was used as a test of estrogen sensitivity (R. Mira-y-Lopez and L. Ossowski, Cancer Res., 47: 3558-3564, 1987), we found that the number of estrogen and progesterone receptor-positive cancers showing estrogen sensitivity was less than anticipated from reported rates of antiestrogen-induced clinical remission. Since in these experiments the estrogen receptor (ER) content of the tumor cultures was only inferred from determinations carried out before culture, we postulated that the apparent estrogen insensitivity of some tumors resulted from poor ER preservation. We have now measured ER levels directly in cultured tissue and found that (a) ER levels in slices of human breast cancers decreased 78% (median) after 1-4 days; 4 of 16 (25%) ER-positive breast cancers had no detectable estradiol binding activity after culture; (b) the drop in ER level was a result of net receptor loss rather than inactivation of binding activity; (c) loss of cell viability could be definitively ruled out as a cause of decreased receptor level; (d) cortisol receptor levels in human breast cancers and ER levels in other hormone-responsive cancers also decreased in culture, and to a similar extent. Higher ER levels (sometimes equal to preculture levels) were preserved by culture at subphysiological temperature or in slices of controlled thickness, not exceeding 0.6 mm. These findings should be considered when organ culture is used to predict tumor hormone responsiveness.

Biomarkers, Tumor↗

PubMed1988

Plasminogen activator dependent pathways in the dissemination of human tumor cells in the chick embryo.

We have previously shown that inhibition of uPA activity of a human tumor-HEp3-results in a drastic reduction of its metastasis in the chick embryo. Using 125IUdR-labeled tumor cells, we have now studied the role of uPA in individual steps of tumor metastasis. We found that, 48 hr after inoculation of tumor cells on the CAM, the organs of the embryos, inoculated with cells in which uPA was inhibited, contained 4-fold less cells than the controls. Neither the initial advance of the tumor mass into the CAM nor the process of extravasation was affected by the inhibition of tumor uPA. However, the infiltration of the CAM mesenchyme by individual tumor cells was blocked when tumor uPA activity or production was inhibited. In addition, indirect evidence implicated uPA as an essential factor in the tumor cell intravasation.

Allantois↗

PubMed1988

In vivo invasion of modified chorioallantoic membrane by tumor cells: the role of cell surface-bound urokinase.

The ability of the chick embryo chorioallantoic membrane (CAM) to withstand invasion by tumor cells can be intentionally compromised by altering its morphological integrity. Using a newly developed quantitative assay of invasion we showed that intact CAMs were completely resistant to invasion by tumor cells, wounded CAMs did not pose a barrier to penetration, and CAMs that were wounded and then allowed to reseal displayed partial susceptibility to invasion. The invasion of resealed CAMs required catalytically active plasminogen activator (PA) of the urokinase type (uPA); the invasive efficiency of tumor cells was reduced by 75% when tumor uPA activity or tumor uPA production was inhibited. The invasive ability of human tumor cells, which have surface uPA receptors but which do not produce the enzyme, could be augmented by saturating their receptors with exogenous uPA. The mere stimulation of either uPA or tissue plasminogen activator production, in absence of binding to cell receptors, did not result in an enhancement of invasiveness. These findings suggest that the increased invasive potential of tumor cells is correlated with cell surface-associated proteolytic activity stemming from the interaction between uPA and its surface receptor.

Animals↗

PubMed1987

Hormonal modulation of plasminogen activator: an approach to prediction of human breast tumor responsiveness.

We have determined that the primary reason for the frequently encountered poor survival of human scirrhous breast carcinomas in short-term (4 days) organ culture is mechanical injury to the tumor tissue during explant preparation. It was possible to minimize this injury by preparing 0.5-mm-thick slices using very sharp blades. This resulted in much improved preservation of tissue structure and function, as assessed by histology, DNA content, and enzyme synthesis and secretion. With the exception of insulin, which was always present in the culture medium, exogenous hormones, including estrogen, or serum did not further improve explant preservation. In rodent mammary tumors, growth in vivo and production of the serine protease plasminogen activator (PA) in organ culture are coordinately regulated by hormones, suggesting that PA may be a valuable indicator of tumor hormone responsiveness. We have now tested the effect of estrogen and other hormones on PA secretion in organ cultures of primary human breast carcinomas. We found that: modulation of PA by 17-beta-estradiol (10-8) M) occurred only in carcinomas which were positive for both estrogen and progesterone receptors; of 21 such tumors, 11 (52%) were responsive. Plasminogen activator was not modulated by estradiol in any of the 22 tumors which were negative for one or both receptors; hydrocortisone (10(-7) M) effectively inhibited, and 3,5,3'-L-triiodothyronine (10(-8) M) and adenylate cyclase activators effectively stimulated PA in most breast tumors, regardless of their estrogen and progesterone receptor status. Prolactin (5 micrograms/ml) had no effect when tested alone; urokinase-type PA was found to be the principal PA produced by human breast tumors. Changes in its rate of synthesis and secretion and not in the content of PA inhibitors appeared to be the prevailing mechanism of enzyme regulation by hormones. In summary, short-term organ culture coupled with the use of PA as an index of response appears to be a promising approach to the study of hormone sensitivity of primary human breast carcinomas.

Adenylyl Cyclases↗

PubMed1987

Growth of a human carcinoma (HEp3) in nude mice: rapid and efficient metastasis.

Our aim was to identify conditions which would permit the development of spontaneous metastasis of a human tumor in nude mice in a rapid and predictable manner and to explore ways to quantitate metastasis. Using a human squamous carcinoma--HEp3--we determined that invasiveness and metastasis were influenced by the host. HEp3 cells grew very rapidly and without a significant lag period in Balb/c and NIH(S)-II nude mice kept in aseptic conditions; a much longer lag period was observed in NIH-Swiss mice kept in conventional conditions. The HEp3 tumor displayed a highly invasive behavior in N-NIH(S)-II mice, in which it invaded the body wall, gaining access to the peritoneal cavity. Microinvasion was noted in all strains of mice inoculated with HEp3 cells. To prolong survival of the mice until metastases became evident, primary tumors were excised when they weighed 1-2 gm. N-NIH(S)-II and Balb/c nude mice, maintained in germ-free conditions, were most receptive to the development of metastases-lung metastases developed in 80% of these mice. Over 60% of all metastases were present within 4 weeks following the removal of the primary. Only 26% of tumor bearing NIH-Swiss developed lung metastases. Lung metastases were observed in some mice in the absence of local microinvasion, local tumor recurrence, and regardless of the presence of lymph node involvement. They were also noted in mice from which primary tumors were not excised. We compared three methods of lung metastasis detection: histology, detection of tumor cells in the cultures of lung minces, and the measurement of the levels of human urokinase-type plasminogen activator directly in the lysates of lungs. The detection of tumor cells in cultures of lung minces appeared to be the most sensitive of these methods and the determination of enzyme in lung lysates seemed to hold most promise for a quantitative approach. These data indicate that, the type of tumor, as well as the genetic background and the maintenance conditions of the host, have to be carefully selected to ensure the successful outcome of the particular tumor-host interaction being studied. Adherence to these guidelines allowed us, in the case of the HEp3 tumor, to develop a rapid, predictable, and efficient model in which to study factors affecting metastasis of this human tumor.

Animals↗

PubMed1986

Human neutrophil plasminogen activator is localized in specific granules and is translocated to the cell surface by exocytosis.

The subcellular localization of plasminogen activator (PA) in human neutrophils was studied. The cells were disrupted by nitrogen cavitation and fractionated on Percoll density gradients into three major components containing the plasma membranes, the specific granules, and the azurophilic granules. The biochemical markers we used to identify these organelles were alkaline phosphatase, vitamin B12-binding protein, and beta-glucuronidase, respectively. Using the radioactive fibrin plate method, PA activity and plasminogen-independent fibrinolytic activity were measured. In resting neutrophils, PA was associated mainly with the membranes of the specific granules. In five individual experiments the activity of this fraction varied from 79 to 100% of the total; the remaining activity was found to be associated with the plasma membrane, and no activity was present in the azurophilic granules. In neutrophils that were activated by exposure to PMA (20 ng/ml for 15 min at 37 degrees C), the total recoverable PA activity remained unchanged; however, the main peak of activity (85% of total) shifted from the specific granules to the plasma membranes. The magnitude of the reduction of the enzyme in the specific granules paralleled that of vitamin B12-binding protein. PMA-activated, intact neutrophils had approximately 12-fold more surface-bound PA activity than resting cells. Recovery of PA activity from neutrophils was critically dependent on pretreatment of the intact cells with DFP before cavitation; 100-fold more PA activity was detected in DFP-pretreated cells. At the same time, this pretreatment reduced the plasminogen-independent fibrinolytic activity by approximately sevenfold. We determined that PA present in the neutrophils is of the urokinase (UK) type and that the enzyme is produced and stored as a pro-UK, a form insensitive to DFP inhibition. The reduction in the level of proteases (measured as fibrinolytic activity) and the resistance of pro-UK to DFP are most likely the two major reasons for the greatly improved recovery of PA from the DFP-pretreated cells. These findings show that in resting neutrophils PA is stored in the specific granules, and that during activation, it translocates to the outer surface of the plasma membranes, thus equipping the cell with an ecto-proteolytic potential.

Cell Membrane↗

PubMed1986

Identification of a pituitary factor responsible for enhancement of plasminogen activator activity in breast tumor cells.

Sheep pituitary glands contain a protein that stimulates plasminogen activator (PA) activity 3- to 20-fold in serum-free cultures of T47D, MTW9/PL, and SC115 breast tumor cells. This protein was found to be similar to basic fibroblast growth factor (bFGF) in size, cationic nature, and affinity for heparin. Purified human placental bFGF, a homologue of human and bovine pituitary bFGF, was effective in stimulating mammary tumor cell PA at a concentration of 1 ng/ml. Antibodies to placental bFGF blocked the PA stimulatory activity of sheep pituitary extracts. Because of these properties, the active protein in sheep pituitary glands was identified as bFGF. This represents another function of bFGF, indicating that its spectrum of target cells is wider than previously thought. Because of previously established correlations between PA production in vitro and tumor growth in vivo, we suggest that bFGF may contribute to the growth of breast carcinomas in vivo. Other types of carcinomas may also be affected by bFGF.

Animals↗

PubMed1986

Efficient synthesis of human type alpha transforming growth factor: its physical and biological characterization.

Human transforming growth factor type alpha (TGF-alpha) was synthesized by a stepwise solid-phase method with an overall yield of 26%. Synthetic TGF-alpha, consisting of 50 amino acid residues deduced from a cDNA precursor sequence, was purified in a single HPLC step. The homogeneity and primary structure were confirmed by several criteria including Edman degradation and mass spectrometry. Synthetic TGF-alpha was as active as murine epidermal growth factor in binding to the epidermal growth factor receptor and in stimulation of anchorage-dependent and of anchorage-independent growth of normal indicator cells in culture. Synthetic TGF-alpha stimulated plasminogen activator production in A 431 and HeLa cells; the stimulation was similar to that induced by epidermal growth factor. Furthermore, synthetic human TGF-alpha showed similar immunoreactivity when compared with rat TGF-alpha. Thus, the 50-amino acid TGF-alpha is likely to be the bioactive principle produced and secreted by tumor cell lines.

Amino Acids↗

PubMed1985

Effect of dimethyl sulfoxide on human carcinoma cells, inhibition of plasminogen activator synthesis, change in cell morphology, and alteration of response to cholera toxin.

Human carcinoma HEp-3 lost its tumorigenic and metastatic potential upon prolonged culture in vitro. This change was accompanied by a reduced production of plasminogen activator (PA) of the urokinase type (uPA), which is secreted by HEp-3 cells, a change in response to effectors that modulate uPA production, and an alteration of cell morphology. Similar but more rapid changes occurred when malignant HEp-3 cells were exposed to dimethyl sulfoxide (DMSO). uPA activity in the culture medium dropped below 50% of the control level within 6 h after the addition of DMSO and became undetectable after 24 h of treatment. This drop in uPA activity was not caused by an increased production of PA inhibitors. The cell-associated uPA decreased to 25 to 30% of the control level within 6 h of DMSO treatment and remained at this level for at least 96 h; the reduced uPA production was partially accounted for by a rapid decrease in the functional and chemical concentration of uPA mRNA. In contrast, the concentrations of most of the abundant mRNA species did not appear to be significantly affected, and cell growth was only slightly inhibited in the presence of DMSO. Malignant HEp-3 cells treated with DMSO responded to cholera toxin with an enhanced production of uPA, and their morphology became indistinguishable from that of nonmalignant HEp-3 cells grown in vitro for prolonged periods of time. All of the above changes were fully and rapidly reversible. The inhibitory effect of DMSO on PA production appears to be specific for uPA of human cell lines.

Cell Line↗

PubMed1985

Coordinate inhibition of plasminogen activator and tumor growth by hydrocortisone in mouse mammary carcinoma.

A body of evidence has suggested that hormones which modulate plasminogen activator production by cultured tumor explants in vitro may have a qualitatively comparable effect on the growth of the same tumors in vivo. As a test of this correlation and to explore its potential for predicting the in vivo response of tumors to hormones, we have studied here the effect of hydrocortisone on the growth of primary and first generation transplants of mouse mammary tumor virus-determined mammary tumors in BALB/c X DBA/8 F1 (hereafter called CD8F1) mice; hydrocortisone had been found previously to inhibit plasminogen activator production by explants of these tumors. The results were: (a) hydrocortisone reversibly blocked the growth of palpable primary tumors; growth resumed at control rates following withdrawal of exogenous hormone; (b) hydrocortisone inhibited the growth of first-generation tumor transplants when administered either before or after the appearance of palpable tumors; (c) pretreatment with hydrocortisone both delayed the appearance of primary tumors and greatly reduced tumor incidence in susceptible mice; a substantial part of the decrease in tumor incidence was apparently irreversible; (d) hydrocortisone reduction of tumor growth was accompanied by inhibition of tumor plasminogen activator content, and these effects displayed a similar dose dependence (enzyme content of tumor lysates was measured by the 125I-fibrin plate assay); the enzyme present in control and hormone-treated tumors was predominantly of the urokinase type. These findings suggest that plasminogen activator production and mammary tumor growth in CD8F1 mice are coordinately regulated and thus encourage the view that plasminogen activator might be useful as an in vitro marker for predicting the in vivo response of tumors to hormones.

Animals↗

PubMed1983

Antibodies to plasminogen activator inhibit human tumor metastasis.

The human carcinoma HEp3 grows on the chorioallantoic membrane and metastasizes to the chicken embryo with kinetics that are quantitatively predictable. We have used this experimental system to test whether plasminogen activator produced by the tumor is required for metastasis. Rabbit antibodies were raised against human urinary urokinase; these cross-reacted with and blocked the catalytic activity of HEp3-PA but did not inhibit chicken PA. When administered intravenously to embryos that had received an inoculum of HEp3 cells, the anti-urokinase antibodies did not inhibit tumor growth at the site of primary inoculation on the chorioallantoic membrane, but they either prevented or strongly inhibited metastasis to the embryo lung. Antibody treatment delayed the onset of pulmonary metastasis, indicating that plasminogen activator is required during early stages of the process.

Animals↗

PubMed1983

Changes in malignant phenotype of a human carcinoma conditioned by growth environment.

The human epidermoid carcinoma HEp3 exhibits highly malignant growth in chicken embryos that disappears progressively in cell culture. When studied by clonal analysis, loss of tumorigenicity was apparent within 20 generations and essentially complete after 40 generations in culture; affected all clones; and occurred under conditions which excluded the selection of variants based on superior growth rate in culture. Once ostensibly lost, the malignant phenotype reappeared after prolonged exposure of nontumorigenic cells to in vivo conditions. This similarly affected all clones assayed over a wide range of inoculum sizes. There was no evidence that HEp3 populations were heterogeneous with respect to tumorigenicity, or that the results were due to preferential selection of genetically determined subpopulations. It is suggested that the malignant phenotype of HEp3 is expressed in response to conditions in the physiological environment.

Air↗

PubMed1983

Loss of tumorigenicity of Lewis lung carcinoma on the chorioallantoic membrane of the chick embryo.

The Lewis lung carcinoma is a transplantable metastatic tumor of the C57BL mouse strain. When cells derived from this tumor are inoculated onto the chorioallantoic membrane (CAM) of 9- to 11-day-old chick embryos, large tumors are produced. Although most of these tumors contain mouse cells, they can no longer be transplanted either in C57BL mice or on the CAM. Cloned cells obtained from Lewis lung carcinoma grown in vitro produce CAM tumors which are different from those produced by the parental cells in that the former retain some tumorigenic potential in mice. The phenotype associated with the cloned cell populations appears to be stable in vitro and in vivo. Phenotypes similar to those observed when both the parental and the clonal populations of Lewis lung carcinoma cells are grown on the CAM can be reproduced in culture conditions.

Allantois↗

PubMed1983

Modulation of plasminogen activator in rodent mammary tumors by hormones and other effectors.

The production of plasminogen activator (PA) and its regulation by hormones and other effectors were studied in organ cultures of primary rat and mouse mammary tumors. PA was quantitated using the radioiodinated fibrin plate method. The level of PA in tumor tissue was 10- to 100-fold higher than that in normal rat or mouse mammary glands; the rates of PA secretion were 10- to 1000-fold higher in the tumor cultures. PA production was stimulated by prolactin and pituitary extracts in N-nitrosomethylurea- and 7,12-dimethylbenz(a)anthracene-induced rat tumors but not in mammary tumor virus-induced mouse tumors; hydrocortisone inhibited PA production in all three tumor categories. Sex hormones and agents such as cholera toxin and retinoic acid effectively modulated enzyme production by some tumors. Three major points of interest emerge from our findings: (a) the pattern of tumor PA response to hormones differs qualitatively and quantitatively from that previously determined for the normal mammary; (b) the profile of responses of tumor PA and tumor growth to hormones shows numerous correlations suggesting that these two parameters may be coordinately regulated; (c) pituitary extracts contain an apparently novel factor that stimulates rat mammary tumor PA synthesis.

Animals↗

PubMed1982

A proenzyme form of human urokinase.

A culture of the human epidermoid carcinoma HEp 3 produces a plasminogen activator of Mr = 53,000 which we have purified to apparent homogeneity from serum-free conditioned medium by the combination of immunoaffinity chromatography and preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The highly purified protein has the following properties: 1) It is indistinguishable from urinary urokinase in electrophoretic mobility, in immunodiffusion, and in autoradiographically visualized tryptic peptide maps obtained from the 125I-labeled proteins. 2) The HEp 3 protein differs from urinary urokinase in the following respects: (a) although the apparent molecular weights of the two are identical (Mr = 53,000), the urinary enzyme consists of two polypeptide chains, whereas the HEp 3 protein is a single chain form. (b) Urinary urokinase can be labeled easily by incubation with radioactive diisopropylfluorophosphate but the HEp 3 protein cannot. (c) When assayed by the hydrolysis of a synthetic chromogenic peptide substrate, the HEp 3 enzyme has less than 1% of the catalytic activity of urinary urokinase. 3) On controlled exposure to plasmin, the HEp 3 protein is converted to an active enzyme that is identical with urinary urokinase in molecular weight, polypeptide chain composition, diisopropylfluorophosphate labeling, and specific catalytic activity. We conclude that the HEp 3 protein is a proenzyme that can be converted to active two-chain urokinase by plasmin, probably by a single proteolytic nick in the polypeptide chain.

Carcinoma, Squamous Cell↗