Cancer Epidemiology Biomarkers & Prevention Vol. 15, 1425-1426, August 2006
© 2006 American Association for Cancer Research
An Interlocker Concept of Carcinogenesis
Lee W. Wattenberg
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
Requests for reprints: Lee W. Wattenberg, Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN 55455. Phone: 612-626-9113; Fax: 612-626-9198. E-mail: watte002{at}umn.edu
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Abstract
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A critical feature in the sequence of events occurring during carcinogenesis is the development of irreversibility. The term "Interlocker" is used here to denote a mechanism by which irreversibility is brought about. The presentation focuses on conceptualizations of such processes. Two will be described below. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1425–6)
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Introduction
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The first concept is built around the occurrence of several common features found in cancers of solid organs. These include a loss of control of cell proliferation, disorganization, and infiltration. The concept is that the Interlocker is like a collar, which binds together these common features irreversibly into a whole entity. It becomes fully active at the transition of precancer to cancer. The concept is simple and leads to important consequences. The first of these is that it presents a target for chemoprevention of cancer and the second is that a knowledge of the composition of such a collar potentially could lead to strategies for its disruption and cancer therapy during its early phase.
The concept is highly attractive but information about the nature of the collar is deficient. One possibility is that the Interlocker involves aberrant glycoproteins. Supporting this conjecture are two lines of investigation. One is the finding of aberrant glycoproteins during carcinogenesis. These glycoproteins contain structural changes in their side chains, in particular increased ß1-6 branching asparagine-linked oligosaccharides. The changes are found in cancers of a number of organs, including breast, large bowel, lung, esophagus, and melanoma (1-9). A second line of investigation has been into the increased expression of N-acetylglucosaminyltransferase V, which is also found in cancers of a number of these organs as well as others (10-14). The association of glycoprotein defects with cancer is impressive as documented in the publications cited. Assuming that this represents a significant component of the Interlocker, the point of which the aberrations result in loss of reversibility would require elucidation.
The second concept of an Interlocker is quite different. Central to this concept is the understanding that a critical feature of cancer is disorganization. An important manifestation of this disorganization is loss of cell/cell adhesions. A striking finding in this regard is the loss of E-cadherin cell/cell adhesions. A considerable amount of information exists pertaining to this adhesion protein. Its loss is related to carcinogenesis in several tissues, including lung, breast, liver, colon, esophagus, stomach, pancreas, head and neck, and skin (15-22). In addition to binding cells together, E-cadherin is closely allied with catenins, actin filaments, and intracellular signaling pathways (17-19, 23, 24). Thus, E-cadherin loss or dysfunction as an Interlocker not only could result in impaired cell/cell contact but also be accompanied by differing degrees of malignant manifestations depending on the nature of alterations in the closely related signaling factors.
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Summary
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This article puts forth the conceptualization that irreversibility in carcinogenesis can be the result of an Interlocker. Two examples are discussed, one termed as a collar, binds together features of carcinogenesis so as to form an irreversible entity. The second is the loss or dysfunction of cell/cell adhesions with evidence that this can be due to E-cadherin. The existence of an Interlocker would be important for several reasons. For cancer prevention, it could provide a target for intervention and one existing until a late point in the progression of precancer to cancer. For a collar type of Interlocker, an agent that would break the collar could convert the lesion from being irreversible to being reversible, at least early in cancer. Finally, the conceptualization of the existence of Interlockers itself is of value in providing new areas of research and new ways of evaluating data.
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Footnotes
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 4/21/06;
accepted 6/ 1/06.
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References
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- Dennis JW, Laferte S. Oncodevelopmental expression of—GlcNAc ß1-6Man
1-6Man ß1—branched asparagine-linked oligosaccharides in murine tissues and human breast carcinomas. Cancer Res 1989;49:945–50.[Abstract/Free Full Text] - Fernandes B, Sagman U, Auger M, et al. ß1-6 branched oligosaccharides as a marker of tumor progression in human breast and colon neoplasia. Cancer Res 1991;51:718–23.[Abstract/Free Full Text]
- Seelentag WK, Li WP, Schmitz SF, et al. Prognostic value of ß1,6-branched oligosaccharides in human colorectal carcinoma. Cancer Res 1998;58:5559–64.[Abstract/Free Full Text]
- Lu Y, Pelling JC, Chaney WG. Tumor cell surface ß1-6 branched oligosaccharides and lung metastasis. Clin Exp Metastasis 1994;12:47–54.[CrossRef][Medline]
- Dosaka-Akita H, Miyoshi E, Suzuki O, et al. Expression of N-acetylglucosaminyltransferase V is associated with prognosis and histology in non-small cell lung cancers. Clin Cancer Res 2004;10:1773–9.[Abstract/Free Full Text]
- Takano R, Nose M, Nishihira T, et al. Increase of ß1-6-branched oligosaccharides in human esophageal carcinomas invasive against surrounding tissue in vivo and in vitro. Am J Pathol 1990;137:1007–11.[Abstract]
- Ochwat D, Hoja-Lukowicz D, Litynska A. N-glycoproteins bearing ß1-6 branched oligosaccharides from the A375 human melanoma cell line analysed by tandem mass spectrometry. Melanoma Res 2004;14:479–85.[CrossRef][Medline]
- Kobata A, Amano J. Altered glycosylation of proteins produced by malignant cells, and application for the diagnosis and immunotherapy of tumours. Immunol Cell Biol 2005;83:429–39.[CrossRef][Medline]
- Dennis JW, Laferte S, Waghorne C, et al. ß1-6 branching of Asn-linked oligosaccharides is directly associated with metastasis. Science 1987;236:582–5.[Abstract/Free Full Text]
- Miyoshi E, Nishikawa A, Ihara Y, et al. N-acetylglucosaminyltransferase III and V messenger RNA levels in LEC rats during hepatocarcinogenesis. Cancer Res 1993;53:3899–902.[Abstract/Free Full Text]
- Yanagi M, Aoyagi Y, Suda T, et al. N-acetylglucosaminyltransferase V as a possible aid for the evaluation of tumor invasiveness in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2001;16:1282–9.[CrossRef][Medline]
- Takahashi T, Hagisawa S, Yoshikawa K, et al. Predictive value of N-acetylglucosaminyltransferase-V for superficial bladder cancer recurrence. J Urol 2006;175:90–3; discussion 3.[CrossRef][Medline]
- Granovsky M, Fata J, Pawling J, et al. Suppression of tumor growth and metastasis in Mgat5-deficient mice. Nat Med 2000;6:306–12.[CrossRef][Medline]
- Korczak B, Le T, Elowe S, et al. Minimal catalytic domain of N-acetylglucosaminyltransferase V. Glycobiology 2000;10:595–9.[Abstract/Free Full Text]
- Bremnes RM, Veve R, Hirsch FR, et al. The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis. Lung Cancer 2002;36:115–24.[CrossRef][Medline]
- Bremnes RM, Veve R, Gabrielson E, et al. High-throughput tissue microarray analysis used to evaluate biology and prognostic significance of the E-cadherin pathway in non-small-cell lung cancer. J Clin Oncol 2002;20:2417–28.[Abstract/Free Full Text]
- Kato Y, Hirano T, Yoshida K, et al. Frequent loss of E-cadherin and/or catenins in intrabronchial lesions during carcinogenesis of the bronchial epithelium. Lung Cancer 2005;48:323–30.[CrossRef][Medline]
- Cowin P, Rowlands TM, Hatsell SJ. Cadherins and catenins in breast cancer. Curr Opin Cell Biol 2005;17:499–508.[CrossRef][Medline]
- Pierceall WE, Woodard AS, Morrow JS, et al. Frequent alterations in E-cadherin and - and ß-catenin expression in human breast cancer cell lines. Oncogene 1995;11:1319–26.[Medline]
- Doki Y, Shiozaki H, Tahara H, et al. Correlation between E-cadherin expression and invasiveness in vitro in a human esophageal cancer cell line. Cancer Res 1993;53:3421–6.[Abstract/Free Full Text]
- Perl AK, Wilgenbus P, Dahl U, et al. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 1998;392:190–3.[CrossRef][Medline]
- Calvisi DF, Ladu S, Conner EA, et al. Disregulation of E-cadherin in transgenic mouse models of liver cancer. Lab Invest 2004;84:1137–47.
- Su LK, Vogelstein B, Kinzler KW. Association of the APC tumor suppressor protein with catenins. Science 1993;262:1734–7.[Abstract/Free Full Text]
- Wijnhoven BP, Dinjens WN, Pignatelli M. E-cadherin-catenin cell-cell adhesion complex and human cancer. Br J Surg 2000;87:992–1005.[CrossRef][Medline]
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Abstract
Introduction
