Abstract
From the conditioned medium of the human colon carcinoma cells, HT-29 5M21 (CM-5M21), expressing a spontaneous invasive phenotype, tumor-associated trypsin inhibitor (TATI) was identified and characterized by proteomics, cDNA microarray approaches and functional analyses. Both CM-5M21 and recombinant TATI, but not the K18Y-TATI mutant at the protease inhibitor site, trigger collagen type I invasion by several human adenoma and carcinoma cells of the colon and breast, through phosphoinositide-3-kinase, protein kinase C and Rho-GTPases/Rho kinase-dependent pathways. Conversely, the proinvasive action of TATI in parental HT29 cells was alleviated by the TATI antibody PSKAN2 and the K18Y-TATI mutant. Stable expression of K18Y-TATI in HT-29 5M21 cells downregulated tumor growth, angiogenesis and the expression of several metastasis-related genes, including CSPG4 (13.8-fold), BMP-7 (9.7-fold), the BMP antagonist CHORDIN (5.2-fold), IGFBP-2 and IGF2 (9.6- and 4.6-fold). Accordingly, ectopic expression of KY-TATI inhibited the development of lung metastases from HT-29 5M21 tumor xenografts in immunodeficient mice. These findings identify TATI as an autocrine transforming factor potentially involved in early and late events of colon cancer progression, including local invasion of the primary tumor and its metastatic spread. Targeting TATI, its molecular partners and effectors may bring novel therapeutic applications for high-grade human solid tumors in the digestive and urogenital systems.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
Accessions
GenBank/EMBL/DDBJ
References
Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T et al. (2004). Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350: 2343–2351.
Antila R, Jalkanen J, Heikinheimo O . (2006). Comparison of secondary and primary ovarian malignancies reveals differences in their pre- and perioperative characteristics. Gynecol Oncol 101: 97–101.
Bajou K, Noel A, Gerard RD, Masson V, Brunner N, Holst-Hansen C et al. (1998). Absence of plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 4: 923–928.
Bartelt DC, Shapanka R, Greene LJ . (1977). The primary structure of the human pancreatic secretory trypsin inhibitor. Amino acid sequence of the reduced S-aminoethylated protein. Arch Biochem Biophys 179: 189–199.
Balasubramani M, Day BW, Schoen RE, Getzenberg RH . (2006). Altered expression and localization of creatine kinase B, heterogeneous nuclear ribonucleoprotein F, and high mobility group box 1 protein in the nuclear matrix associated with colon cancer. Cancer Res 66: 763–769.
Ben-Baruch A . (2006). The multifaceted roles of chemokines in malignancy. Cancer Metastasis Rev 25: 357–371.
Burger JA, Kipps TJ . (2006). CXCR4: a key regulator in the crosstalk between tumor cells and their microenvironment. Blood 107: 1761–1767.
Chirco R, Liu XW, Jung KK, Kim HR . (2006). Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev 25: 99–113.
Delacour D, Gouyer V, Zanetta JP, Drobecq H, Leteurtre E, Grard G et al. (2005). Galectin-4 and sulfatides in apical membrane trafficking in enterocyte-like cells. J Cell Biol 169: 491–501.
Dunlap SM, Celestino J, Wang H, Jiang R, Holland EC, Fuller GN et al. (2007). Insulin-like growth factor binding protein 2 promotes glioma development and progression. Proc Natl Acad Sci USA 104: 11736–11741.
Dwyer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM et al. (2007). Monocyte chemotactic protein-1 secreted by primary breast tumors stimulates migration of mesenchymal stem cells. Clin Cancer Res 13: 5020–5027.
Empereur S, Djelloul S, Di Gioia Y, Bruyneel E, Mareel M, Van Hengel J et al. (1997). Progression of familial adenomatous polyposis (FAP) colonic cells after transfer of the src or polyoma middle T oncogenes: cooperation between src and HGF/Met in invasion. Br J Cancer 75: 241–250.
Fountoulakis M, Juranville JF, Roder D, Evers S, Berndt P, Langen H . (1998). Reference map of the low molecular mass proteins of Haemophilus influenzae. Electrophoresis 19: 1819–1827.
Gouyer V, Conti M, Devos P, Zerimech F, Copin MC, Creme E et al. (2005). Tissue inhibitor of metalloproteinase 1 is an independent predictor of prognosis in patients with nonsmall cell lung carcinoma who undergo resection with curative intent. Cancer 103: 1676–1684.
Grijelmo C, Rodrigue C, Svrcek M, Bruyneel E, Hendrix A, de Wever O et al. (2007). Proinvasive activity of BMP-7 through SMAD4/src-independent and ERK/Rac/JNK-dependent signaling pathways in colon cancer cells. Cell Signal 19: 1722–1732.
Harbeck M, Schmitt M, Paepke S, Allgayer H, Kates RE . (2007). Tumor-associated proteolytic factors uPA and PAI-1: critical appraisal of their clinical relevance in breast cancer and their integration into decision-support algorithms. Crit Rev Clin Lab Sci 44: 179–201.
Hu K, Xiong J, Ji K, Sun H, Wang J, Liu H . (2007). Recombined CC chemokine ligand 2 into B16 cells induces production of Th2-dominanted cytokines and inhibits melanoma metastasis. Immunol Lett 113: 19–28.
Huhtala ML, Pesonen K, Kalkkinen N, Stenman UH . (1982). Purification and characterization of a tumor-associated trypsin inhibitor from the urine of a patient with ovarian cancer. J Biol Chem 257: 13713–13716.
Janicke F, Prechtl A, Thomssen C, Harbeck N, Meisner C, Untch M et al. (2001). Randomized adjuvant chemotherapy trial in high-risk, lymph-node negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1. J Natl Cancer Inst 93: 913–920.
Kazal LA, Spicer DS, Brahinsky RA . (1948). Isolation of a cristalline trypsin inhibitor-anticoagulant protein from pancreas. J Am Chem Soc 70: 3034–3040.
Kebache S, Ash J, Annis MG, Hagan J, Huber M, Hassard J et al. (2007). Grb10 and active Raf-1 kinase promote Bad-dependent cell survival. J Biol Chem 282: 21873–21883.
Kikuchi N, Nagata K, Shin M, Mitsushima K, Teraoka H, Yoshida N . (1989). Site-directed mutagenesis of human pancreatic secretory trypsin inhibitor. J Biochem (Tokyo) 106: 1059–1063.
Klezovitch O, Chevillet J, Mirosevich J, Roberts RL, Matusik RJ, Vasioukhin V . (2006). Hepsin promotes prostate cancer progression and metastasis. Cancer cell 6: 185–195.
Kotelevets L, Noë V, Bruyneel E, Myssiakine E, Chastre E, Mareel M et al. (1998). Inhibition by platelet-activating factor of Src- and hepatocyte growth factor-dependent invasiveness of intestinal and kidney epithelial cells. Phosphatidylinositol 3′-kinase is a critical mediator of tumor invasion. J Biol Chem 273: 14138–14145.
Kosinski C, Li VSW, Chan ASY, Zhang J, Ho C, Yin Tsui W et al. (2007). Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci USA 104: 15418–15423.
Le Floch N, Rivat C, De Wever O, Bruyneel E, Mareel M, Dale T et al. (2005). The proinvasive activity of Wnt-2 is mediated through a noncanonical Wnt pathway coupled to GSK-3beta and c-Jun/AP-1 signaling. FASEB J 19: 144–146.
Lee YC, Pan HW, Penq SY, Lai PL, Kuo WS, Ou YH et al. (2007). Overexpression of tumour-associated trypsin inhibitor (TATI) enhances tumour growth and is associated with portal vein invasion, early recurrence and a stage-independent prognostic factor of hepatocellular carcinoma. Eur J Cancer 43: 736–744.
Lesuffleur T, Violette S, Vasile-Pandrea I, Dussaulx E, Barbat A, Muleris M et al. (1998). Resistance to high concentrations of methotrexate and 5-fluorouracil of differentiated HT-29 colon-cancer cells is restricted to cells of enterocytic phenotype. Int J Cancer 76: 383–392.
Loberg RD, Ying C, Craig M, Day LL, Sargent E, Neeley C et al. (2007). Targeting CCL2 with systemic delivery of neutralizing antibodies induces prostate cancer tumor regression in vivo. Cancer Res 67: 9417–9942.
Louvet C, Coudray AM, Tournigand C, Prévost S, Raymond E, de Gramont A et al. (2000). Synergistic antitumoral activity of combined UFT, folinic acid and oxaliplatin against human colorectal tumor HT29 cell xenografts in athymic nude mice. Anticancer Drugs 11: 579–582.
Makagiansar IT, Williams S, Mustelin T, Stallcup WB . (2007). Differential phosphorylation of NG2 proteoglycan by ERK and PKCα helps balance cell proliferation and migration. J Cell Biol 178: 155–165.
McCarthy K, Maguire T, McGreal G, McDermott E, O'Higgins N, Duffy MJ . (1999). High levels of tissue inhibitor of metalloproteinase-1 predict poor outcome in patients with breast cancer. Int J Cancer 84: 44–48.
Monti P, Leone BE, Marchesi F, Balzano G, Zerbi A, Scaltrini F et al. (2003). The CC chemokine MCP-1/CCL2 in pancreatic cancer progression: regulation of expression and potential mechanisms of antimalignant activity. Cancer Res 63: 7451–7461.
Nguyen QD, De Wever O, Bruyneel E, Hendrix A, Xie WZ, Lombet A et al. (2005). Communtators of PAR-1 signaling in cancer cell invasion reveal an essential role of the Rho-Rho kinase axis and tumor microenvironment. Oncogene 24: 8240–8251.
Nyberg P, Ylipalosaari M, Sorsa T, Salo T . (2006). Trypsins and their role in carcinoma growth. Exp Cell Res 312: 1219–1228.
Ohmachi Y, Murata A, Matsuura N, Yasuda T, Yasuda T, Monden M et al. (1993). Specific expression of the pancreatic-secretory-trypsin-inhibitor (PSTI) gene in hepatocellular carcinoma. Int J Cancer 55: 728–734.
Paju A, Stenman UH . (2006). Biochemistry and clinical role of trypsinogens and pancreatic secretory trypsin inhibitor. Crit Rev Clin Lab Sci 43: 103–142.
Paju A, Vartiainen J, Haglund C, Itkonen O, von Boguslawski K, Leminen A et al. (2004). Expression of trypsinogen-1, trypsinogen-2, and tumor-associated trypsin inhibitor in ovarian cancer: prognostic study on tissue and serum. Clin Cancer Res 10: 4761–4768.
Paju A, Hotakainen K, Cao Y, Laurila T, Gadaleanu V, Hemminki A et al. (2007). Increased expression of tumor-associated trypsin inhibitor, TATI, in prostate cancer and in androgen-independent 22Rv1 cells. Eur Urol 52: 1670–1679.in press.
Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ et al. (2006). Epirubicin and cyclophosphamide, methotrexate and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med 355: 1851–1862.
Raftopoulou M, Hall A . (2004). Cell migration: Rho GTPases lead the way. Dev Biol 265: 23–32.
Stenman UH . (2002). Tumor-associated trypsin inhibitor. Clin Chem 48: 1206–1209.
Truant S, Bruyneel E, Gouyer V, De Wever O, Pruvot FR, Mareel M et al. (2003). Requirement of both mucins and proteoglycans in cell-cell dissociation and invasiveness of colon carcinoma HT-29 cells. Int J Cancer 104: 683–694.
Turpeinen U, Koivunen E, Stenman UH . (1988). Reaction of a tumour-associated trypsin inhibitor with serine proteinases associated with coagulation and tumor invasion. Biochem J 254: 911–914.
Van der Zee M, Stockhammer O, Von Levetzow C, Nunes da Fonseca R, Roth S . (2006). Sog/Chordin is required for ventral-to-dorsal Dpp/BMP transport and head formation in a short germ insect. Proc Natl Acad Sci USA 103: 16307–16312.
Xuan JA, Schneider D, Toy P, Lin R, Newton A, Zhu Y et al. (2006). Antibodies neutralizing hepsin protease activity do not impact cell growth but inhibit invasion of prostate and ovarian tumor cells in culture. Cancer Res 66: 3611–3619.
Yan R, Zu X, Ma J, Liu Z, Adeyanju M, Cao D . (2007). Aldo-keto reductase family 1 B10 gene silencing results in growth inhibition of colorectal cancer cells: implication for cancer intervention. Int J Cancer 121: 2301–2306.
Yang J, price MA, Neudauer CL, Wilson C, Ferrone S, Xia H et al. (2004). Melanoma chondroitin sulfate proteoglycan enhances FAK and ERK activation by distinct mechanisms. J Cell Biol 165: 881–891.
Yasuda T, Ogawa M, Murata A, Ohmachi Y, Yasuda T, Mori T et al. (1993). Identification of the IL-6-responsive element in an acute-phase-responsive human pancreatic secretory trypsin inhibitor-encoding gene. Gene 131: 275–280.
Yasuda T, Yasuda T, Ohmachi Y, Katsuki M, Yokoyama M, Murata A et al. (1998). Identification of novel pancreas-specific regulatory sequences in the promoter region of human pancreatic secretory trypsin inhibitor gene. J Biol Chem 273: 34413–34421.
Acknowledgements
In the memory of Hélène Fontayne-Devaud (TR INSERM) who passed away on 15 April 2007. We thank Dominique Demeyer, Marie-José Dejonghe and Georges Grard for technical assistance, Sabine Quief and Céline Villenet for performing microarrays (Genomic Platform), Marie-Hélène Gevaert and Rosemary Siminsky (Department of Histology, Faculty of Medicine, University of Lille II) and the technicians of the Laboratory of Immunohistochemistry (Center of Biology-Pathology, CHRU-Lille). This work was supported by Cancéropôle Nord-Ouest, La Ligue Contre le Cancer, La Région Nord-Pas de Calais, INSERM and ARC No. 3765.
Author information
Authors and Affiliations
Corresponding author
Additional information
Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
Supplementary information
Rights and permissions
About this article
Cite this article
Gouyer, V., Fontaine, D., Dumont, P. et al. Autocrine induction of invasion and metastasis by tumor-associated trypsin inhibitor in human colon cancer cells. Oncogene 27, 4024–4033 (2008). https://doi.org/10.1038/onc.2008.42
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2008.42
Keywords
This article is cited by
-
Raised SPINK1 levels play a role in angiogenesis and the transendothelial migration of ALL cells
Scientific Reports (2022)
-
Serine protease inhibitor Kazal type 1 (SPINK1) promotes proliferation, migration, invasion and radiation resistance in rectal cancer patients receiving concurrent chemoradiotherapy: a potential target for precision medicine
Human Cell (2022)
-
Targeting SPINK1 in the damaged tumour microenvironment alleviates therapeutic resistance
Nature Communications (2018)
-
SPINK1 promotes colorectal cancer progression by downregulating Metallothioneins expression
Oncogenesis (2015)
-
Serine Protease Inhibitor Kazal Type 1 (SPINK1) Promotes Proliferation of Colorectal Cancer Through the Epidermal Growth Factor as a Prognostic Marker
Pathology & Oncology Research (2015)