Association of trypsin expression with tumour progression and matrilysin expression in human colorectal cancer

Yamamoto, Hiroyuki; Iku, Shouhei; Adachi, Yasushi; Imsumran, Arisa; Taniguchi, Hiroaki; Nosho, Katsuhiko; Min, Yongfen; Horiuchi, Shina; Yoshida, Mio; Itoh, Fumio; Imai, Kohzoh

doi:10.1002/path.1277

Cited by 123 publications

(100 citation statements)

References 35 publications

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“…These proteins comprise proliferating cell nuclear antigen, 39,40 CEA, 41 NF-kappa B, 42 matrilysin 43 and trypsin. 44 The expression level of these proteins in the invasive front was shown to predict the malignant potential of CRC. Therefore, the area-specific multiple sampling method employed for the construction of TMAs in the present study seemed particularly applicable for analyzing the clinical and histopathological significance of molecules associated with cancer invasion and metastasis.…”

Section: Comparison Of Incidence and Prognostic Implication Of Ln-5c2mentioning

confidence: 99%

Prognostic implication of laminin-5 gamma 2 chain expression in the invasive front of colorectal cancers, disclosed by area-specific four-point tissue microarrays

Shinto

Tsuda

Ueno

et al. 2005

Laboratory Investigation

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The laminin-5 gamma 2 chain (LN-5c2) is known to be a marker of invasion in several cancer types. Our purpose was to examine the prognostic significance of LN-5c2 expression in different areas of individual colorectal cancers (CRCs) by using tissue microarrays (TMAs), and to clarify the optimal areas for prognostic assessment. Using formalin-fixed paraffin-embedded tissue blocks of pT3 primary CRCs resected from 120 patients, we constructed TMA blocks of tissue core specimens taken from the submucosal invasive front, subserosal invasive front, central area, and rolled edge of each tumor. Using these four-point TMA sets, cytoplasmic LN-5c2 expression was immunohistochemically surveyed, and the area-specific prognostic significance of LN-5c2 expression was evaluated. The data revealed that 35, 30, 15 and 10% of the 120 CRCs showed highgrade LN-5c2 expression in the submucosal invasive front, subserosal invasive front, central area and rolled edge, respectively. Disease-specific survival curves for the groups with high-and low-grade LN-5c2 in the submucosal invasive front and subserosal invasive front were different significantly or of marginal difference (respective 5-year survival rates: 54 and 78% for submucosal invasive front (P ¼ 0.030) and 58 and 75% for subserosal invasive front (P ¼ 0.055)). Multivariate analysis revealed that the grades of LN-5c2 expression in submucosal invasive front (hazard ratio ¼ 2.0, P ¼ 0.047) and subserosal invasive front (hazard ratio ¼ 2.9, P ¼ 0.0033) were independent prognostic factors. In contrast, the grades of LN-5c2 expression in the central area and rolled edge did not have a significant impact on patient prognosis. Analysis using area-specific fourpoint TMAs clearly demonstrated that LN-5c2 expression in the invasive front largely influences the degree of clinical aggressiveness of CRC and its tendency to metastasize.

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Section: Comparison Of Incidence and Prognostic Implication Of Ln-5c2mentioning

confidence: 99%

Prognostic implication of laminin-5 gamma 2 chain expression in the invasive front of colorectal cancers, disclosed by area-specific four-point tissue microarrays

Shinto

Tsuda

Ueno

et al. 2005

Laboratory Investigation

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“…Elevated levels of trypsin, the main endogenous PAR2 activator, have been found in a variety of tumors including colorectal carcinomas (8,9,51). Trypsin can also originate from vessels in the vicinity of the tumors (52) or could diffuse from blood to tumor cells.…”

Section: Par2 Transactivates Egf-r In Colon Cancermentioning

confidence: 99%

Protease-activated Receptor 2 in Colon Cancer

Darmoul

Gratio

Devaud

et al. 2004

Journal of Biological Chemistry

187

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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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“…It is a candidate tumour marker since its expression is restricted to epithelial cells. Finally, matrix metalloproteinase 7 (MMP7)/matrilysin is an interesting candidate biomarker since it is expressed in the invasive front of the primary tumour and MMP7 expression is correlated with capacity to form metastases in CRC transfer experiments (Adachi et al, 2001;Yamamoto et al, 2003).…”

mentioning

confidence: 99%

Biomarker selection for detection of occult tumour cells in lymph nodes of colorectal cancer patients using real-time quantitative RT–PCR

et al. 2006

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Accurate identification of lymph node involvement is critical for successful treatment of patients with colorectal carcinoma (CRC). Real-time quantitative RT -PCR with a specific probe and RNA copy standard for biomarker mRNA has proven very powerful for detection of disseminated tumour cells. Which properties of biomarker mRNAs are important for identification of disseminated CRC cells? Seven biomarker candidates, CEA, CEACAM1-S/L, CEACAM6, CEACAM7-1/2, MUC2, MMP7 and CK20, were compared in a test-set of lymph nodes from 51 CRC patients (Dukes' A -D) and 10 controls. Normal colon epithelial cells, primary tumours, and different immune cells were also analysed. The biomarkers were ranked according to: (1) detection of haematoxylin/eosin positive nodes, (2) detection of Dukes' A and B patients, who developed metastases during a 54 months follow-up period and (3) identification of patients with Dukes' C and D tumours using the highest value of control nodes as cutoff. The following properties appear to be of importance; (a) no expression in immune cells, (b) relatively high and constant expression in tumour tissue irrespective of Dukes' stage and (c) no or weak downregulation in tumours compared to normal tissue. CEA fulfilled these criteria best, followed by CK20 and MUC2.

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Association of trypsin expression with tumour progression and matrilysin expression in human colorectal cancer

Cited by 123 publications

References 35 publications

Prognostic implication of laminin-5 gamma 2 chain expression in the invasive front of colorectal cancers, disclosed by area-specific four-point tissue microarrays

Prognostic implication of laminin-5 gamma 2 chain expression in the invasive front of colorectal cancers, disclosed by area-specific four-point tissue microarrays

Protease-activated Receptor 2 in Colon Cancer

Biomarker selection for detection of occult tumour cells in lymph nodes of colorectal cancer patients using real-time quantitative RT–PCR

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