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Biomedical subjects

J Varani

Publications and source records attributed to J Varani.

At least 217 records · Page 12Linked to original sources
PubMed1981

Responses of normal and malignant cells to collagen, collagen-derived peptides and the C5-related tumor cell chemotactic peptide.

Two variant subpopulations of murine fibrosarcoma cells that differ significantly in their malignant potential and normal mouse fibroblasts were compared with regard to ability to respond chemotactically to collagen, collagen-derived peptides and the C5-derived tumor cell chemotactic peptide. Two distinct patterns of responsiveness were observed. The normal fibroblasts and non-metastasizing fibrosarcoma cells responded to the collagen products but not the C5 peptide. The metastasizing fibrosarcoma cells responded to the C5 peptide but not to the collagen products. These findings emphasize the similarities between the normal fibroblasts and the non-metastasizing fibrosarcoma cells.

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PubMed1981

Chemotactic factor-induced adherence of tumor cells.

Two peptides which have previously been shown to induce chemotactic motility in a number of tumor cells were tested for their ability to alter the adhesiveness of Walker Carcinosarcoma cells (A chemotactically-responsive rat tumor) and normal rat fibroblasts (which have previously been shown to be chemotactically nonresponsive). Adherence of the tumor cells to nylon fibers was increased in a dose-dependent manner by the two active peptides. Adherence of the fibroblasts was not increased. Nonchemotactic peptide analogues of the two active peptides did not alter the adherence of either cell type. The increased adhesiveness to foreign surfaces may contribute to the chemotactic response.

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PubMed1981

Substrate hydrolysis by immune complex-activated neutrophils: effect of physical presentation of complexes and protease inhibitors.

The ability of rat leukocytes to hydrolyze a radiolabeled, surface-bound protein substrate in a solid phase assay was determined, and various factors that influence the process were measured. Unstimulated leukocytes hydrolyzed very little substrate. When the cell suspension was mixed with zymosan particles or incubated with preformed immune complexes, the amount of substrate hydrolysis increased dramatically. Not surprisingly, immune complexes at equivalence proved to be the most effective in eliciting the response. Immune complexes attached to the surface along with the protein substrate were able to effectively induce hydrolysis, though they were not as effective as immune complexes in suspension. Three protease inhibitors, alpha 1-antitrypsin, alpha 2-macroglobulin, and soybean trypsin inhibitor, which were able to neutralize nearly all of the protease activity in rat neutrophil lysates, were tested for their ability to inhibit immune complex-induced protein hydrolysis. It was found that when the inhibitors were surface bound along with the substrate protein, they were effective in preventing the neutrophils from hydrolyzing the protein. However, when the same inhibitors were present in the fluid phase, they were much less effective. The relative ineffectiveness of fluid phase protease inhibitors to block the protease activity of contact-activated leukocytes may explain how immune complex injury can take place in the presence of high concentrations of serum inhibitors.

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PubMed1981

Characteristics of the chemotactic factor-mediated cell swelling response of tumor cells.

The interaction between Walker carcinosarcoma cells, maintained in ascites form in noninbred Sprague-Dawley rats and in cell culture, and appropriate factors induced directed migration (chemotaxis) of these cells as measured in the Boyden chamber assay. The response of the tumor cells to these factors was very similar to that of leukocytes to their chemotactic factors. In addition to inducing chemotactic responses, the interaction between Walker carcinosarcoma cells and appropriate chemotactic factors also led to a swelling of the cells, which could be measured with the use of Coulter Channelyzer C-1000. Associated with the cell-swelling response was a temporary drop in the cell count of a suspension of cells as measured with the use of a Coulter counter, model ZBI. These responses were also similar to what occurs when leukocytes interact with their chemotactic factors. When the suspension of tumor cells was pretreated with 2-deoxyglucose, the responses measured with the Coulter counters were almost completely abrogated. In contrast to this, treatment of the cells with various chemical agents, including cytochalasin B, colchicine, cycloheximide, chlorpromazine, and the Ca2+ ionophore A23187 failed to significantly reduce the cell-swelling response. Cytochalasin B slightly potentiated the response. These similarities to the responses of leukocytes suggested a common underlying mechanism.

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PubMed1981

Localization of intravenously injected tumor cells in the rat mesentery after intraperitoneal administration of chemotactic stimuli.

The formation of metastases can be induced at sites injected with chemotactic factors in animals with circulating, chemotactically responsive tumor cells. This study was done to examine the possibilities that this phenomenon is due to enhanced tumor localization or stimulation of tumor growth. Walker carcinosarcoma cells labelled with 125I-iododeoxyuridine were injected into the tail veins of rats subsequently given intraperitoneal injections of chemotactic factor. 24 h later there was a 2.7- to 3.5-fold increase in the number of labelled cells in the mesenteries of animals given chemotactic factors compared to controls (p less than 0.001). The distribution of cells in other viscera was not affected by the injection. No effects were observed on the kinetics of tumor growth in vitro when cultures were supplemented with these chemotactic factors or with peritoneal lavage fluids from animals previously given intraperitoneal injections of chemotactic factor. Thus, in this model, the formation of metastases can be related to the arrest of circulating tumor cells in response to local chemotactic stimuli but the promotion of tumor growth has not been demonstrated.

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PubMed1981

The chemotactic response of tumor cells. A model for cancer metastasis.

Injection of a C5-derived chemotactic factor for tumor cells into the peritoneal cavities of Sprague-Dawley rats induced diffuse mesenteric metastasis following the intravenous injection of Walker carcinosarcoma cells. Intraperitoneal injections of culture medium, histamine, or of trypsin-treated albumin resulted in many fewer metastases. Intraperitoneal injections of the chemotactic factor, unlike histamine, did not alter mesenteric vasopermeability as measured by the exudation of Evans blue into the mesentery. In vitro, tumor cells responded to the chemotactic factor by demonstrating directed migration in the Boyden chamber, by volume changes, measurable in the Coulter counter, and by demonstrating an increased adherence to nylon fibers. These phenomena are similar to the behavior of neutrophils in the presence of their chemotactic factors. All the responses in vitro were markedly depressed by the addition of 2-deoxyglucose, while the cell swelling response was slightly enhanced by cytochalasin B (again similar to the responses of leukocytes). The data suggest that movement of tumor cells from the circulation may be under chemotactic influence in the manner similar to the responsiveness of neutrophils to leukotactic stimuli in vivo.

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PubMed1981

Comparison of the chemotactic responsiveness of two fibrosarcoma subpopulations of differing malignancy.

There are several points of similarity between the processes of cancer metastasis and inflammation. In both, cells circulate in the vasculature, arrest, and cross vessel walls, thereby entering the extravascular tissues. In vitro, leukocytes and some, but not all, tumor cells exhibit chemotaxis. Since the chemotactic response of leukocytes effect their transvascular migration, we propose that chemotactic responsiveness contributes to the ability of circulating tumor cells to localize in extravascular tissues. This study was done to seek a relationship between chemotactic responsiveness of tumor cells and their behavior in vivo. Two subpopulations of cells were isolated from a methylcholanthrene-induced fibrosarcoma. The two cell lines were compared with regard to their biologic behavior in vivo and their chemotactic responsiveness in vitro. In vivo one subpopulation was highly malignant. An injection of 2.0 x 10(5) cells into the footpad of syngeneic mice led to the development of primary tumors in 87% of the animals and lung metastases in 61% of the animals with primary tumors. This line demonstrated chemotaxis to a factor that behaved similarly in gel filtration and showed immunologic reactivity similar to that of a previously described tumor cell chemotactic factor derived from the fifth component of complement. In contrast, an injection of the same number of cells from the second subpopulation of fibrosarcoma cells led to the development of primary tumors in only 12% of syngeneic mice, and lung metastases did not occur. Neither this subpopulation nor normal embryonic fibroblasts demonstrated chemotactic responsiveness. We postulate that the ability of tumor cells to respond to specific chemotactic stimuli may be one of the many unique properties which distinguish malignant from benign tumor cells. This is the first report documenting the chemotactic responsiveness of non-ascites tumors and fibrosarcomas.

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PubMed1980

Size increase induced in Walker ascites cells by chemotactic factors.

Upon interaction with the tumor cell chemotactic factor derived from zymosan-activated serum or with the synthetic chemotactic factor, formylmethionyl-leucyl-phenylalanine (f-met-leu-phe), the number of Walker 256 carcinosarcoma cells in suspension dropped as measured by a Coulter Counter. The drop in the number of cells counted by the Coulter Counter was accompanied by and possibly attributed to a swelling in the mean cell volume of approx. 20%. These effects were blocked by the addition of 2-deoxy-d-glucose, along with the chemotactic factors, to the tumor cells. The doses of the chemotactic factors which induced these responses paralleled closely the doses which have been shown to induce a chemotactic response as measured in the Boyden Chamber assay. These findings indicate that non-leukocytic cells, like leukocytes, are capable of other responses in addition to chemotactic migration in the Boyden chamber assay upon interaction with appropriate chemotactic factors.

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PubMed1980

Effect of Corynebacterium granulosum immunopotentiation on the pathogenesis of herpes simplex virus type 2 in BALB/c mice.

Treatment of 4- to 6-week-old, 18- to 22-g male BALB/c mice with 0.6 mg of Corynebacterium granulosum resulted in a significant decrease in mortality due to challenge with herpes simplex virus type 2 (HSV-2). Optimal protection occurred when C. granulosum was injected 1 week before HSV-2 infection. C. granulosum-induced resistance to HSV-2 lasted up to 4.5 weeks. Studies involving immune spleen cell transfer and treatment with antilymphocyte serum demonstrated the importance of cell-mediated immunity in HSV-2 infection. However, C. granulosum protection was not transferable with spleen cells from C. granulosum-treated animals nor was C. granulosum treatment capable of completely overcoming the increased mortality which resulted from antilymphocyte serum treatment of HSV-2 infected mice. Under our experimental conditions, silica did not affect the mortality in BALB/c mice due to HSV-2 but significantly reduced the protective effects induced by C. granulosum. Attempts to transfer protection of HSV-2 challenge in suckling mice by using either glass-adherent or mixed peritoneal cells from either HSV-2-immunized or C. granulosum-treated animals were unsuccessful.

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PubMed1980

Adhesive characteristics of tumor cell variants of high and low tumorigenic potential.

A variant subpopulation of C57BL/6 mouse fibrosarcoma cells that had very low tumorigenic potential was isolated from a highly tumorigenic parent fibrosarcoma cell culture. The adhesive characteristics of parent cells and variant cells were compared. The low-tumorigenic variant cells were released from the surfaces of plastic dishes, from protein-coated dishes, or from monolayers of fibroblasts or endothelial cells by protease treatment much more readily than were the parent cells. There was no difference between the variant cells and the parent cells in EDTA sensitivity or sensitivity to mechanical agitation under the conditions used. Also, no difference existed between the variant cells and the parent cells in rates of attachment to the surfaces of plastic dishes or to monolayers of endothelial cells. The variant cells were characterized by high levels of chymotrypsin-like esterase activity (two to three times increased over parent cell levels), but there was only a slight difference between the variant cells and the parent cells in caseinolytic or fibrinolytic activity.

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PubMed1980

Partial characterization of a bone-derived chemotactic factor for tumor cells.

Medium that has been bathing organ cultures of resorbing bone contains a factor that is chemotactic for cultured Walker carcinosarcoma cells, as assayed by the Boyden chamber technique. There is a positive correlation between the chemotactic activity released by the resorbing bones and the extent of resorption as measured by release of previously incorporated 45Ca from the bones. Generation of the chemotactic factor occurs independent of the humoral mediator of bone resorption. The tumor cell chemotactic factor has a steep dose-response curve, with a fall from maximal to minimal activity extending over a four-fold dilution. The chemotactic activity is stable to heating and has an estimated molecular weight of 6000 daltons, as determined by gel filtration chromatography and retention of activity following dialysis. The chemotactic activity has been distinguished from the tumor cell chemotactic factor derived from the fifth component of complement because the former is not inactivated by antiserum to C5 and because it is chemotactic for EL-4 lymphoma cells, whereas the latter is not chemotactically active for these cells.

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PubMed1980

In vitro and in vivo adherence of tumor cell variants correlated with tumor formation.

Murine fibrosarcoma variants that differed greatly in tumorgenicity, in vivo growth rate, and rate of spontaneous metastasis formation were compared for their ability to induce tumors in the lungs of syngeneic mice after intravenous injection of a suspension of single cells. Significantly more tumors were observed in the lungs of mice that received 1 x 10(5) of the cells of high malignant potential than in the lungs of animals that received 1 x 10(5) cells of lower malignant potential (54 tumors per animal vs 3 tumors per animal). When the tumor cells were prelabeled in culture for 24 hours with 125I-IUDR prior to intravenous injection, it was found that both the "high" and "low malignant" cells rapidly accumulated in the lungs (55-59% of the radioactivity was found in the lung tissue by 5 minutes after injection). However, by 4 hours only 4% of the low malignant cells (as indicated by the amount of radioactivity present) were still in the lungs, while a significantly higher percentage (13%) of the high malignant cells were still present in the lungs. The difference between the high and low malignant cells with regard to ability to remain sequestered in the lungs of syngeneic mice and to subsequently form tumors in the lungs of these animals correlated with the ability of the cells to form stable attachments to monolayers of endothelial cells in culture. While both the high and low malignant cells attached at the same rate to monolayers of bovine endothelial cells, once the cells were attached, the low malignant cells were released by trypsin treatment more easily than the high malignant cells. These observations suggest that the difference in malignant potential between the variants may be due, at least in part, to differences in ability to form stable attachments.

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PubMed1979

Chemotactic responses of tumor cells to products of resorbing bone.

To explore possible mechanisms for the metastasis of malignant cells to bone, a model of tumor cell migration was developed, using Walker carcinosarcoma or malignant lymphoma cells. It was found that bone contains a factor that is strongly chemotactic for tumor cells. This factoor is released by a variety of agents that induce resorption of bone.

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PubMed1979

Chemotactic factor for tumor cells derived from the C5a fragment of complement component C5.

Previously, we have stablished that the fifth component of complement (C5) serves as an important source of mediators that have locomotory (chemotactic) activity for leukocytes and tumor cells. C5a, a fragment (Mr 11,200) derived from the NH2-terminal portion of the alpha chain of C5, is the major chemotactic peptide for leukocytes. The present studies demonstrate that cleavage of C5a with trypsin generates a derivative peptide that is chemotactic for tumor cells (Walker carcinosarcoma). This fragment has an estimated Mr of 6000 as assessed by gel filtration and does not require the COOH-terminal arginine of C5a, because equivalent amounts of chemotactic activity for tumor cells can be generated from des-Arg-C5a by digestion with trypsin. The C5a-derived chemotactic peptide for tumor cells demonstrates peak activity at approximately 1 pM. These studies emphasize the key role of the C5a region of the C5 molecule in the generation of peptides that affect locomotory responses of cells.

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PubMed1979

Cell-associated proteases affect tumour cell migration in vitro.

The in vitro migratory activity of mouse fibrosarcoma cells in medium containing either foetal calf serum or normal human serum was studied. These 2 sera were studied because foetal calf serum contains high levels of protease inhibitor activity while human serum contains much less. The cells migrated actively in medium with foetal calf serum but migration was greatly inhibited in human serum-containing medium. When protease inhibitors such as soybean trypsin inhibitor, lima bean trypsin inhibitor and bovine pancreas trypsin inhibitor were added to human serum-containing medium cell migration was supported almost as effectively as in medium with foetal calf serum. Addition of epsilon-amino-n-caproic acid to human serum or depletion of the plasminogen from human serum did not enable it to support enhanced migration. epsilon-amino-n-caproic acid actually inhibited migration. A variant cell population with elevated levels of caseinolytic activity and elevated levels of activity against the substrate n-acetyl-DL-phenylalanine-beta-naphthyl ester (a substrate specific for chymotrypsin-like enzymes) was isolated from the parent cells. When the variant cells were compared to the parent cells regarding migratory activity in foetal calf serum or human serum-containing medium, the variant cells showed much less activity. Only a few, widely scattered variant cells migrated in the human serum-containing medium. These data suggest that a cell-associated factor interferes with the migration of the cells in medium with human serum. This factor apparently is neutralized in medium sontaining human serum to which protease inhibitors with antitrypsin activity have been added.

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