Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.4 (trypsin)
 42,187 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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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PMID:Chemotactic factor for tumor cells derived from the C5a fragment of complement component C5. 28 38

Leukocytes contain within their lysosomal granules enzymatic activity that will generate from C5 chemotactic activity for leukocytes (neutrophils) and tumor (Walker carcinosarcoma) cells. Similar activity has been found in phagocytic supernatant fluids from neutrophils and in purified preparations of the leukocyte neutral proteases elastase and cathepsin G. White leukotactic activities can be generated from either the third (C3) or the fifth (C5) components of complement, only C5 serves as a source for generation of the chemotactic activity for tumor cells. As has been previously shown with trypsin, the C5-related chemotactic activities generated by leukocyte proteases are time-dependent: leukotactic activity appears early, then disappears, and is replaced by chemotactic activity for tumor cells. The generation of these chemotactic activities from C5 is blocked by prior treatment of leukocyte preparations with the neutral protease inhibitor Trasylol. The demonstration that enzyme activities from leukocytes have the ability to generate tumor cell chemotactic factors from C5 suggests a possible mechanism by which the development of metastatic lesions may be promoted at sites of tissue injury or inflammation.
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PMID:Digestion of the fifth component of complement by leukocyte enzymes. Sequential generation of chemotactic activities for leukocytes and for tumor cells. 56 81

We have examined the ability of 5 tumour cell types to attach to plastic flasks in medium containing either 10% foetal calf serum or 10% normal human serum and compared this ability with cell-associated caseinolytic activity. The cell types used included fibrosarcoma cells which were obtained from a methylcholanthrene-induced tumour in a C57 BL/6 mouse, the SV40-transformed 3T3 (BALB/c) cells, the Walker carcinosarcoma cells and 2 lines of HeLa cells. All 5 cell types attached to the flasks and spread out efficiently in medium containing 10% foetal calf serum. The walker carcinosarcoma cells and the 2 lines of HeLa cells also attached efficiently in medium containing 10% normal human serum and grew into monolayers in this medium. These 3 cell types had no detectable caseinolytic activity. The fibrosarcoma cells and the SV40-transformed 3T3 (BALB/c) cells did not attach in normal human serum-containing medium. These 2 cell types had readily detected caseinolytic activity. Normal human serum and foetal calf serum were compared for levels of protease-inhibitor activity. Human serum was found to have less activity than foetal calf serum against both trypsin and plasmin as well as the cell-associated caseinolytic activity. The low level of protease inhibitor activity in normal human serum may contribute to the inability of this serum to support the attachment of cells with detectable protease activity because the addition of protease inhibitors such as soybean trypsin inhibitor, lima bean trypsin inhibitor and bovine pancreas trypsin inhibitor to normal human serum dramatically enhanced cell attachment. In contrast to this, the addition of E-amino-n-caproic acid to normal human serum and the removal of plasminogen from normal human serum did not enhance its capacity to support cell attachment.
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PMID:Comparison of cell attachment and caseinolytic activities of five tumour cell types. 74 34

Demineralized extracts of bone matrix and conditioned media from cultured fetal rat calvaria have been reported to contain growth stimulatory activity for bone cells. To investigate the potential role of these local bone growth factors in the development of bone metastases, we chose the Walker 256 carcinosarcoma, a rat mammary tumor which causes osteolytic bone metastases and hypercalcemia. 45Ca-labeled, 19-day fetal Sprague-Dawley rat calvaria were cultured for 96 hours in BGJb medium. Walker cells from ascites tumors or cultures were grown in unconditioned media or in conditioned media harvested from the bone cultures, in the presence of 10% fetal calf serum. Media were changed every 2 days, cells were counted daily for 5 days, and 3H-thymidine uptake into acid insoluble residues was measured. The growth of tumor cells was 5-6-fold greater in conditioned media than in unconditioned media and the effect was dose dependent. Cells cultured in conditioned media demonstrated a approximately 3-fold enhancement of 3H-thymidine incorporation. Generation of growth stimulatory activity correlated with the extent of bone resorption, measured by release of 45Ca from the fetal parietal bones (r = 0.85; P less than 0.001). Conditioned media from bones cultured with 10(-7) M prostaglandin E2 (PGE2) contained greater amounts of growth stimulatory activity than untreated conditioned media, but PGE2 itself did not stimulate tumor cell growth. Addition of 3.5 mM PO4 to bone cultures blocked bone resorption and the generation of growth factors. Growth stimulatory activity was stable to heat (56 C for 30 minutes) and trypsin digestion, with an apparent molecular weight of less than 17,000 daltons by high-performance liquid chromatography. Conditioned medium also stimulated the growth of 13762 rat mammary adenocarcinoma cells, MB-MDA-231 human breast carcinoma cells, TE-85 osteosarcoma cells, a murine fibrosarcoma and rat embryonic fibroblasts, with the most potent effects noted for Walker tumor cells, the TE-85 osteosarcoma, and human breast carcinoma lines. These results suggest a mechanism by which bone resorption could promote the development of skeletal metastasis.
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PMID:Resorbing bone stimulates tumor cell growth. A role for the host microenvironment in bone metastasis. 345 36

Cells from the Walker 256 carcinosarcoma, a rat breast tumor with a propensity to metastasize to bone, were labeled with [131I]5-iodo-2'-deoxyuridine and then added to 96-hour organ cultures of fetal Sprague-Dawley rat calvaria that had been prelabeled with 45Ca and incubated with various stimulators or inhibitors of resorption. In conditioned media from resorbing bone cultures, the number of cells that attached to the bone surfaces correlated with the degree of bone resorption (r = 0.65; P less than .005). The attachment response was maximal after 180 minutes of cocultivation and was inhibited by preincubation of the tumor cells with 10(-5) M cytochalasin B. Cellular attachment appeared to be promoted by a trypsin-sensitive factor released into the organ culture medium from resorbing bones. Enhanced tumor cell attachment did not appear to be related to a change in the surface properties of the resorbing bone, since it was not observed when the conditioned media were replaced with fresh medium. Furthermore, tumor cells placed in conditioned medium demonstrated increased attachment to plastic surfaces and formed aggregates. While there was a direct correlation between the ability of conditioned medium to promote cellular adhesion and chemotactic migration (r = 0.85; P less than .05), the factors responsible for chemotaxis and adhesion could be separated by gel filtration. The release of such factors from resorbing bones may promote the formation of secondary bone tumors, since in this system attachment of unlabeled cells was followed by proliferation of tumor cells and evidence of bone invasion.
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PMID:Adhesion, chemotaxis, and aggregation of Walker carcinosarcoma cells in response to products of resorbing bone. 385 80

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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PMID:The chemotactic response of tumor cells. A model for cancer metastasis. 725 97