Pancreatic trypsinogen I expression during cell growth and differentiation of two human colon carcinoma cells

Bernard-Perrone, Francoise; Carrère, Jacqueline; Renaud, Wanda; Moriscot, Christine; Thoreux, Karine; Bernard, Patrice; Servin, Alain L.; Balas, D; Senegas-Balas, F.

doi:10.1152/ajpgi.1998.274.6.g1077

Cited by 11 publications

(13 citation statements)

References 42 publications

(56 reference statements)

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“…In this context, it is worth pointing out that several lines of evidence indicate the importance of locally secreted trypsin at the vicinity of colon tumours: (1) trypsin was shown to be expressed by the large intestine . Normal epithelial cells surrounding colon tumour cells are a likely source of active trypsin; (2) human colon cancer cells themselves were shown to express trypsin and trypsinogen (Bernard-Perrone et al, 1998;Miyata et al, 1999); (3) recent studies on gastric cancer indicate that blood vessels surrounding tumours express trypsin, whereas other blood vessels do not . Trypsin is also present in serum at nanomolar concentrations and could diffuse from blood to tumour cells.…”

Section: Discussionmentioning

confidence: 99%

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Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

et al. 2001

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SummaryThe protease-activated receptor-2 (PAR-2) is a G protein-coupled receptor that is cleaved and activated by trypsin. We investigated the expression of PAR-2 and the role of trypsin in cell proliferation in human colon cancer cell lines. A total of 10 cell lines were tested for expression of PAR-2 mRNA by Northern blot and RT-PCR. PAR-2 protein was detected by immunofluorescence. Trypsin and the peptide agonist SLIGKV (AP2) were tested for their ability to induce calcium mobilization and to promote cell proliferation on serum-deprived cells. PAR-2 mRNA was detected by Northern blot analysis in 6 out of 10 cell lines Cl.19A, SW480,. Other cell lines expressed low levels of transcripts, which were detected only by RT-PCR. Further results were obtained with HT-29 cells: (1) PAR-2 protein is expressed at the cell surface; (2) an increase in intracellular calcium concentration was observed upon trypsin (1-100 nM) or AP2 (10-100 µM) challenges; (3) cells grown in serum-deprived media supplemented with trypsin (0.1-1 nM) or AP2 (1-300 µM) exhibited important mitogenic responses (3-fold increase of cell number). Proliferative effects of trypsin or AP2 were also observed in other cell lines expressing PAR-2. These data show that subnanomolar concentrations of trypsin, acting at PAR-2, promoted the proliferation of human colon cancer cells. The results of this study indicate that trypsin could be considered as a growth factor and unravel a new mechanism whereby serine proteases control colon tumours.

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Section: Discussionmentioning

confidence: 99%

“…Extra-pancreatic production of trypsin was shown in ovarian (Hirahara et al, 1995), lung (Kawano et al, 1997), gastric and colonic tumours (Bernard-Perrone et al, 1998;Miyata et al, 1999); 2. The trypsinogen gene is significantly expressed in vascular endothelial cells around gastric tumours ; 3.…”

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Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

et al. 2001

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“…Therefore, EP localization on the luminal surface of the duodenal villi may contribute to enterocyte growth by generating active trypsin on the cell surface. Recently, it was reported that trypsinogen is expressed by various human epithelial cells (18) and is also secreted by human tumor cells including gastric (13) and colon cancer cells (2). Trypsinogen production was associated with metastatic phenotypes of these human cancer cells (13,25).…”

Section: Discussionmentioning

confidence: 99%

Expression of enteropeptidase in differentiated enterocytes, goblet cells, and the tumor cells in human duodenum

Imamura¹,

Kitamoto²

2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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Enteropeptidase (EP) is a serine proteinase and activates trypsinogen to trypsin, thus playing an important role in food digestion. Nevertheless, the localization of EP is still controversial, likely due to a lack of studies using specific antibodies against EP. The aim of this study was to define cellular localization of EP in human duodenum and expression in tumor cells at the duodenal region. Immunohistochemical staining for resected tissues was performed with two antibodies against recombinant EP light and heavy chains, respectively. In situ hybridization was done with two RNA probes that include either the light or the heavy chain sequences of proEP, respectively. The two antibodies reacted with enterocytes, accentuated on the brush border, and goblet cells, with increasing intensity from the bottom of crypts to the top of villi. Paneth cells, neuroendocrine cells, Brunner's glands, lymphocytes, smooth muscle, or connective tissue did not react with the antibodies. The two RNA probes detected EP mRNA expression only in enterocytes and goblet cells. EP is produced in enterocytes and goblet cells, and the localization on the brush border of the cells is reasonable for the physiological activation of digestive enzymes. Interestingly, the antibodies reacted with tumor cells in duodenal polyps and adenocarcinoma at the duodenum but not in Brunner's gland adenoma. EP seems to be a marker of differentiated enterocytes and goblet cells, which suggests the existence of a common progenitor of these cells. Furthermore, EP may be a useful marker of tumor cells originating from these cells.

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“…Extra-pancreatic production of trypsin was shown in ovarian (5), lung (6), gastric (7), and colonic tumors (8) and also in colon cancer cell lines (9,10). In addition, overexpression of exogenous trypsinogen cDNA in human gastric cancer cells increases their tumorigenicity in nude mice (7).…”

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Protease-activated Receptor 2 in Colon Cancer

Darmoul

Gratio

Devaud

et al. 2004

Journal of Biological Chemistry

189

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Several lines of evidence suggest that tumor-derived trypsin contributes to the growth and invasion of cancer cells. We have recently shown that trypsin is a potent growth factor for colon cancer cells through activation of the G protein-coupled receptor protease-activated receptor 2 (PAR2). Here, we analyzed the signaling pathways downstream of PAR2 activation that lead to colon cancer cell proliferation in HT-29 cells. Our data are consistent with the following cascade of events upon activation of PAR2 by the serine protease trypsin or the specific PAR2-activating peptide (AP2): (i) a matrix metalloproteinasedependent release of transforming growth factor (TGF)-␣, as demonstrated with TGF-␣-blocking antibodies and measurement of TGF-␣ in culture medium; (ii) TGF-␣-mediated activation of epidermal growth factor receptor (EGF-R) and subsequent EGF-R phosphorylation; and (iii) activation of ERK1/2 and subsequent cell proliferation. The links between these events are demonstrated by the fact that stimulation of cell proliferation and ERK1/2 upon activation of PAR2 is reversed by the metalloproteinase inhibitor batimastat, TGF-␣-neutralizing antibodies, EGF-R ligand binding domain-blocking antibodies, and the EGF-R tyrosine kinase inhibitors AG1478 and PD168393. Therefore, transactivation of EGF-R appears to be a major mechanism whereby activation of PAR2 results in colon cancer cell growth. By using the Src tyrosine kinase inhibitor PP2, we further showed that Src plays a permissive role for PAR2-mediated ERK1/2 activation and cell proliferation, probably acting downstream of the EGF-R. These data explain how trypsin exerts robust trophic action on colon cancer cells and underline the critical role of EGF-R transactivation.Proteases have been increasingly recognized as important factors in pathophysiology of tumor diseases. Besides their contribution to cancer progression by the degradation of extracellular matrix proteins, there is now substantial evidence that certain proteases serve as signal molecules controlling cell functions through specific membrane receptors, the proteaseactivated receptors. PARs 1 are seven transmembrane-spanning domain G protein-coupled receptors comprising four receptors named PAR1, PAR2, PAR3, and PAR4 (1, 2). Thrombin is the physiological activator of PAR1, PAR3, and PAR4, whereas PAR2 is activated by multiple trypsin-like enzymes including trypsin and mast cell tryptase but not thrombin. The mechanism of activation of PARs was initially established for PAR1 (3) and seems to be a paradigm for the other PARs (1, 2, 4). They are irreversibly activated by a proteolytic mechanism in which the protease binds to and cleaves the amino-terminal exodomain of the receptor. This cleavage generates a new amino-terminal sequence that binds intramolecularly to the core receptor and serves as a tethered ligand. Synthetic activating peptides that mimic the tethered ligand domains of PAR1, PAR2, and PAR4 have been developed. The activation of PARs by these synthetic peptides APs is independent of rec...

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Pancreatic trypsinogen I expression during cell growth and differentiation of two human colon carcinoma cells

Cited by 11 publications

References 42 publications

Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

Initiation of human colon cancer cell proliferation by trypsin acting at protease-activated receptor-2

Expression of enteropeptidase in differentiated enterocytes, goblet cells, and the tumor cells in human duodenum

Protease-activated Receptor 2 in Colon Cancer

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