Involvement of a cathepsin B-like cysteine proteinase in platelet aggregation induced by tumor cells and their shed membrane vesicles

Cavanaugh, Philip G.; Sloane, Bonnie F.; Bajkowski, Andrew S.; Gasic, Gabriel J.; Gasic, Tatiana B.; Honn, Kenneth V.

doi:10.1007/bf00121192

Cited by 39 publications

(28 citation statements)

References 23 publications

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“…Cathepsin B is localised primarily in the lysosomal fraction of normal tissues in a 30-35 kDa precursor form, although activity has also been measured in the plasma membrane fraction of some tumour cells in a 20-kDa mature form (Pietras & Roberts, 1981;Gavanaugh et al, 1983;Koppel et al, 1984;Sloane et al, 1986;Rozhin et al, 1987;Erdel et al, 1990;Weiss et al, 1990). Release of cathepsin B from tumour cells into the plasma membrane and extracellular matrix may be due to a defect in intracellular processing.…”

Section: Discussionmentioning

confidence: 99%

Pancreatic trypsinogen and cathepsin B in human pancreatic carcinomas and associated metastatic lesions

Ohta

Terada²,

Nagakawa³

et al. 1994

Br J Cancer

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Summary Expression of pancreatic trypsinogen and cathepsin B in 23 surgically resected pancreatic ductal adenocarcinomas was evaluated immunohistochemically, using a monoclonal antibody against human pancreatic trypsinogen and a polyclonal antibody against human cathepsin B. Fifteen of 20 invasive tubular adenocarcinomas (75%) expressed pancreatic trypsinogen in a coarse granular pattern located in the supranuclear cytoplasm of the carcinoma cells. In addition, metastatic lesions, including those in peripancreatic lymph nodes and neural plexuses, expressed pancreatic trypsinogen. In contrast, three intraductal (noninvasive) papillary adenocarcinomas did not express pancreatic trypsinogen. Cathepsin B expression was recognised in 14 of 20 invasive tubular adenocarcinomas (70%) in a fine granular pattern located diffusely in the cytoplasm of the carcinoma cells, while none of the three intraductal papillary adenocarcinomas had detectable cathepsin B. These findings suggest that pancreatic invasive ductal adenocarcinomas express pancreatic trypsinogen and cathepsin B immunoreactive peptides, raising the possibility that pancreatic trypsinogen and cathepsin B may act independently of each other in the process of carcinoma invasion and metastasis, like other different classes of proteases involved in the proteolytic modification of the matrix barrier.Pancreatic trypsinogen is one of the proteolytic enzymes produced by pancreatic acinar cells. A recent study (Miszczuk-Jamska et al., 1991) has shown that a new human pancreatic adenocarcinoma cell line (CFPAC-1) and a previously established human pancreatic carcinoma cell line (CAPAN-1) produce human pancreatic trypsinogen. This enzyme is a target protease for pancreatic secretory trypsin inhibitor (PSTI). Tumour-associated trypsinogen is also known to be a serine protease produced by malignant tumour cells, and is believed to play an essential role in cancer invasion and metastasis by degrading trypsin-sensitive extracellular matrix components (Tryggvason et al., 1987;Koivunen et al., 1991a). Tumour-associated trypsinogen has been identified as a target protease for a tumour-associated trypsin inhibitor (TATI), also referred to as PSTI (Huhtala et al., 1982;Halila et al., 1988;Stenman et al., 1988). A recent study (Koivunen et al., 1989) has shown that tumourassociated trypsinogen and pancreatic trypsinogen are similar with respect to amino-terminal sequence, molecular weight and immunoreactivity, but that significant differences exist with respect to isoelectrophoretic mobility and stability. Therefore, it is possible that pancreatic trypsinogen may also take part in the protease cascade associated with tumour invasion and metastasis. It is currently not known whether the differences between tumour-associated trypsinogen and pancreatic trypsinogen are a result of tissue-specific trypsinogen modification or distinct genes.We have therefore evaluated the presence or absence of pancreatic trypsinogen immunohistochemically in 23 surgically resected pancreatic ductal adeno...

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Section: Discussionmentioning

confidence: 99%

Pancreatic trypsinogen and cathepsin B in human pancreatic carcinomas and associated metastatic lesions

Ohta

Terada²,

Nagakawa³

et al. 1994

Br J Cancer

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“…The cathepsin B activity in the L-1 fraction of the metastatic B16 melanomas does not appear to be due to a second population of lysosomes (primary or GERL) since plasma membrane fractions isolated from tumor cells of four species by five separate methods have now been shown to possess cathepsin B-like cysteine proteinase activities (12)(13)(14)(15)35 (14) attached a rat anaplastic sarcoma to Affi-Gel 731 beads, disrupted the cells by sonication, and assayed the cell membranes, which remained attached to the beads. Differential centrifugation at high speed (100,000 x g) was used to isolate membrane vesicles spontaneously shed into the culture medium by 15091A murine mammary adenocarcinoma cells (15).…”

Section: Discussionmentioning

confidence: 99%

“…Differential centrifugation at high speed (100,000 x g) was used to isolate membrane vesicles spontaneously shed into the culture medium by 15091A murine mammary adenocarcinoma cells (15). In the present study Percoll density gradient centrifugation was used to purify a plasma membrane fraction.…”

Section: Discussionmentioning

confidence: 99%

“…Koppel et al (14) have found that the spontaneous BDX rat anaplastic sarcoma (BSp 73) manifests membrane-associated cathepsin B activity. In our laboratory we had established that membrane vesicles spontaneously shed from murine tumor cells (15091A mammary adenocarcinoma) in culture possess cathepsin B activity (15). In the present study we performed a systematic analysis of lysosomal hydrolase activity in subcellular fractions of murine melanomas of various metastatic potentials.…”

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confidence: 94%

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Cathepsin B: association with plasma membrane in metastatic tumors.

Sloane¹,

Rozhin²,

Johnson³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

199

102

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The subcellular localization of cathepsin B activity (EC 3.4.22.1) in three murine melanomas of increasing metastatic potential (Cloudman < B16-F1 < B16 amelanotic) was determined. Cathepsin B activity was localized in the heavy mitochondrial fraction of normal murine liver but in the light mitochondrial fraction of the metastatic melanomas; the localization of three other lysosomal hydrolases did not shift.Further purification of the light mitochondrial fraction into L-1 (density = 1.045 g/ml) and L-2 (density = 1.07 g/ml) fractions was achieved on a 30% iso-osmotic Percoll gradient. The L-1 fraction of liver and melanomas contained Na',K+-ATPase activity; the L-2 fraction of liver contained four lysosomal hydrolase (cathepsins B and H, N-acetyl-p-glucosaminidase, and j3-glucuronidase) and glucose-6-phosphatase activities. Ultrastructural examination revealed that the L-1 fraction consisted of membrane vesicles and the L-2 fraction of secondary lysosomes. In the B16 melanomas cathepsin B and N-acetyl-,B-glucosaminidase activities were found in both L-1 and L-2 fractions. Specific activities of the two enzymes in the plasma membrane (L-1) fractions increased in correspondence with metastatic potential. Cathepsin H and 8-glucuronidase activities were not localized in the plasma membrane fractions of the B16 melanomas. Localization of hydrolytic enzymes in the plasma membrane ofmetastatic tumor cells could result in focal dissolution of the extraceliular matrix and thereby invasion and metastasis. (4)(5)(6).Although cathepsin B is a lysosomal cysteine proteinase (7), cathepsin B activity (mainly latent) has been measured in the media of tumor cells and explants in culture (5, 8) and in ascites fluid of women with ovarian carcinoma (9). Macrophages release mature lysosomal enzymes in response to stimuli (10); other cell types seem to release only a small proportion of their lysosomal enzymes (latent and mature), perhaps due to a defect in intracellular processing (11). The presence of tumor cathepsin B extracellularly might indicate that tumor cells are defective in the intracellular processing of this enzyme, resulting in its delivery to plasma membrane rather than to the lysosome. The fact that the cathepsin B released from breast carcinoma explants and present in ascites fluid is latent and has a higher molecular weight (8, 9) lends support to this hypothesis. Cathepsin B activity has been found in a plasma membrane fraction of squamous carcinoma cells from human ectocervix but not of nonneoplastic cervical cells (12). Bohmer et al. (13) reported acid cysteine proteinase activity in plasma membrane fractions of bovine lymphosarcoma cells and normal lymphoid cells; the acid cysteine proteinase was not identified. Koppel et al. (14) have found that the spontaneous BDX rat anaplastic sarcoma (BSp 73) manifests membrane-associated cathepsin B activity. In our laboratory we had established that membrane vesicles spontaneously shed from murine tumor cells (15091A mammary adenocarcinoma) in culture possess cat...

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“…However, activity (primarily latent) similar to that of cathepsin B, i.e., a cathepsin B-like cysteine proteinase (CB), has been measured in the media of tumor cells and explants in culture [37,38], in the ascites fluid of women with ovarian carcinomas [39] and in the me dia of mammary gland explants [40]. In ad dition, several laboratories including our own have reported that in animal and hu man tumor cells cathepsin B activity is found in association with the plasma mem brane [18, [41][42][43][44][45]. Recently the major ex creted protein (MEP) from transformed mouse fibroblasts has been identified to be a high Mr inactive (acid activatable) precursor of cathepsin L [46][47][48][49][50], Lysosomal enzymes are processed and transported to the lysosomes via receptordependent pathways such as the mannose-6-phosphate pathway [51], This intracellular sorting has been extensively studied in fibro blasts for certain lysosomal enzymes not in cluding cathepsins B and L. Defects in these transport systems have been identified in fibroblasts from patients with lysosomal storage diseases [52] and in some murine tumor cell lines [53,54], In both cases the defect results in increased secretion of lyso somal enzymes.…”

Section: Lysosomal Cysteine Proteinasesmentioning

confidence: 99%

Plasma Membrane-Associated Cysteine Proteinases in Human and Animal Tumors

Sloane¹,

Rozhin

Hatfield

et al. 1987

Pathobiology

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The ability of tumor cells to invade into and through normal tissue during the metastatic cascade has been attributed to tumor-associated degradative enzymes including proteinases of the metallo, serine and cysteine classes. Work from several laboratories has established that the cysteine proteinases cathepsins L and B are released from tumor cells, primarily as latent precursor forms. In addition, a cathepsin B-like cysteine proteinase has been shown to be associated with the plasma membrane fraction of several animal and human tumors. This form of the enzyme retains activity under physiologic (or pathologic) conditions including at neutral pH and in the presence of low Mr inhibitors. Since we have established that cathepsin B can degrade the basement membrane attachment glycoprotein laminin, we speculate that plasma membrane-associated cathepsin B may participate in focal dissolution of the basement membrane during tumor cell extravasation.

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Involvement of a cathepsin B-like cysteine proteinase in platelet aggregation induced by tumor cells and their shed membrane vesicles

Cited by 39 publications

References 23 publications

Pancreatic trypsinogen and cathepsin B in human pancreatic carcinomas and associated metastatic lesions

Pancreatic trypsinogen and cathepsin B in human pancreatic carcinomas and associated metastatic lesions

Cathepsin B: association with plasma membrane in metastatic tumors.

Plasma Membrane-Associated Cysteine Proteinases in Human and Animal Tumors

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