Abstract
We have previously described InvEE transgenic mice in which non-dividing, differentiating epidermal cells express oncogenically activated MAPK kinase 1 (MEK1). Skin wounding triggers tumour formation in InvEE mice via a mechanism that involves epidermal release of IL-1α and attraction of a pro-tumorigenic inflammatory infiltrate. To look for potential effects on the underlying connective tissue, we screened InvEE and wild-type epidermis for differential expression of cytokines and immune modulators. We identified a single protein, CD26 (dipeptidyl peptidase-4). CD26 serum levels were not increased in InvEE mice. In contrast, CD26 was upregulated in keratinocytes expressing mutant MEK1 and in the epithelial compartment of InvEE tumours, where it accumulated at cell–cell borders. CD26 expression was increased in dermal fibroblasts following skin wounding but was downregulated in tumour stroma. CD26 activity was stimulated by calcium-induced intercellular adhesion in keratinocytes, suggesting that the upregulation of CD26 in InvEE epidermis is due to expansion of the differentiated cell layers. IL-1α treatment of dermal fibroblasts stimulated CD26 activity, and therefore epidermal IL-1α release may contribute to the upregulation of CD26 expression in wounded dermis. Pharmacological blockade of CD26, via Sitagliptin, reduced growth of InvEE tumours, while combined inhibition of IL-1α and CD26 delayed tumour onset and reduced tumour incidence. Our results demonstrate that inappropriate activation of MEK1 in the epidermis leads to changes in dermal fibroblasts that, like the skin inflammatory infiltrate, contribute to tumour formation.
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 Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Aertgeerts K, Ye S, Shi L, Prasad SG, Witmer D, Chi E et al. (2004). N-linked glycosylation of dipeptidyl peptidase IV (CD26): effects on enzyme activity, homodimer formation, and adenosine deaminase binding. Protein Sci 13: 145–154.
Ansorge S, Bank U, Heimburg A, Helmuth M, Koch G, Tadje J et al. (2009). Recent insights into the role of dipeptidyl aminopeptidase IV (DPIV) and aminopeptidase N (APN) families in immune functions. Clin Chem Lab Med 47: 253–261.
Arwert EN, Lal R, Quist S, Rosewell I, van Rooijen N, Watt FM . (2010). Tumor formation initiated by nondividing epidermal cells via an inflammatory infiltrate. Proc Natl Acad Sci USA 107: 19903–19908.
Cordero OJ, Salgado FJ, Nogueira M . (2009). On the origin of serum CD26 and its altered concentration in cancer patients. Cancer Immunol Immunother 58: 1723–1747.
Deacon CF . (2007). Dipeptidyl peptidase 4 inhibition with sitagliptin: a new therapy for type 2 diabetes. Expert Opin Investig Drugs 16: 533–545.
Egeblad M, Nakasone ES, Werb Z . (2010). Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18: 884–901.
Fan H, Meng W, Kilian C, Grams S, Reutter W . (1997). Domain-specific N-glycosylation of the membrane glycoprotein dipeptidylpeptidase IV (CD26) influences its subcellular trafficking, biological stability, enzyme activity and protein folding. Eur J Biochem 246: 243–251.
Hobbs RM, Silva-Vargas V, Groves R, Watt FM . (2004). Expression of activated MEK1 in differentiating epidermal cells is sufficient to generate hyperproliferative and inflammatory skin lesions. J Invest Dermatol 123: 503–515.
Iwata S, Morimoto C . (1999). CD26/dipeptidyl peptidase IV in context. The different roles of a multifunctional ectoenzyme in malignant transformation. J Exp Med 190: 301–306.
Jackson EK, Mi Z . (2008). Sitagliptin augments sympathetic enhancement of the renovascular effects of angiotensin II in genetic hypertension. Hypertension 51: 1637–1642.
Janes SM, Watt FM . (2006). New roles for integrins in squamous-cell carcinoma. Nat Rev Cancer 6: 175–183.
Jensen KB, Driskell RR, Watt FM . (2010). Assaying proliferation and differentiation capacity of stem cells using disaggregated adult mouse epidermis. Nat Protoc 5: 898–911.
Karlsson L, Bondjers C, Betsholtz C . (1999). Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle. Development 126: 2611–2621.
Kim D, Wang L, Beconi M, Eiermann GJ, Fisher MH, He H et al. (2005). (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin -7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 48: 141–151.
Kohl A, Volk HD, Buntrock P, Kohl G, Diamantstein T, von Baehr R . (1991). The role of dipeptidylpeptidase IV positive T cells in wound healing and angiogenesis. Agents Actions 32: 125–127.
Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO et al. (2010). Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science 330: 827–830.
Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ . (2010). Metformin associated with lower cancer mortality in type 2 diabetes (ZODIAC-16). Diabet Care 33: 322–326.
Lindsay JR, Duffy NA, McKillop AM, Ardill J, O'Harte FP, Flatt PR et al. (2005). Inhibition of dipeptidyl peptidase IV activity by oral metformin in Type 2 diabetes. Diabet Med 22: 654–657.
Maley F, Trimble RB, Tarentino AL, Plummer Jr TH . (1989). Characterization of glycoproteins and their associated oligosaccharides through the use of endoglycosidases. Anal Biochem 180: 195–204.
Nemoto E, Sugawara S, Takada H, Shoji S, Horiuch H . (1999). Increase of CD26/dipeptidyl peptidase IV expression on human gingival fibroblasts upon stimulation with cytokines and bacterial components. Infect Immun 67: 6225–6233.
Novelli M, Savoia P, Fierro MT, Verrone A, Quaglino P, Bernengo MG . (1996). Keratinocytes express dipeptidyl-peptidase IV (CD26) in benign and malignant skin diseases. Br J Dermatol 134: 1052–1056.
Ohnuma K, Dang NH, Morimoto C . (2008). Revisiting an old acquaintance: CD26 and its molecular mechanisms in T cell function. Trends Immunol 29: 295–301.
Owens DM, Watt FM . (2003). Contribution of stem cells and differentiated cells to epidermal tumours. Nat Rev Cancer 3: 444–451.
Pereira DA, Gomes L, El-Cheikh MC, Borojevic R . (2003). Dipeptidyl peptidase IV (CD26) activity in the hematopoietic system: differences between the membrane-anchored and the released enzyme activity. Braz J Med Biol Res 36: 567–578.
Reinhold D, Vetter RW, Mnich K, Buhling F, Lendeckel U, Born I et al. (1998). Dipeptidyl peptidase IV (DP IV, CD26) is involved in regulation of DNA synthesis in human keratinocytes. FEBS Lett 428: 100–104.
Romero MR, Carroll JM, Watt FM . (1999). Analysis of cultured keratinocytes from a transgenic mouse model of psoriasis: effects of suprabasal integrin expression on keratinocyte adhesion, proliferation and terminal differentiation. Exp Dermatol 8: 53–67.
Ta NN, Li Y, Schuyler CA, Lopes-Virella MF, Huang Y . (2010). DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes. Atherosclerosis 213: 429–435.
Takasawa W, Ohnuma K, Hatano R, Endo Y, Dang NH, Morimoto C . (2010). Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines. Biochem Biophys Res Commun 401: 7–12.
Vivier I, Marguet D, Naquet P, Bonicel J, Black D, Li CX et al. (1991). Evidence that thymocyte-activating molecule is mouse CD26 (dipeptidyl peptidase IV). J Immunol 147: 447–454.
Watt FM . (1984). Selective migration of terminally differentiating cells from the basal layer of cultured human epidermis. J Cell Biol 98: 16–21.
Willheim M, Ebner C, Baier K, Kern W, Schrattbauer K, Thien R et al. (1997). Cell surface characterization of T lymphocytes and allergen-specific T cell clones: correlation of CD26 expression with T(H1) subsets. J Allergy Clin Immunol 100: 348–355.
Acknowledgements
We are grateful to Donna Michelle Smith for performing SG chromatography. We acknowledge support from Cancer Research UK, the Dutch Cancer Society (to RM), the Wellcome Trust, the MRC, the European Union, Hutchison Whampoa and Cambridge University.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Arwert, E., Mentink, R., Driskell, R. et al. Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation. Oncogene 31, 992–1000 (2012). https://doi.org/10.1038/onc.2011.298
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2011.298
Keywords
This article is cited by
-
Epidermal β-catenin activation remodels the dermis via paracrine signalling to distinct fibroblast lineages
Nature Communications (2016)
-
The Androgen Receptor Antagonizes Wnt/β-Catenin Signaling in Epidermal Stem Cells
Journal of Investigative Dermatology (2015)
-
Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy
Nature Immunology (2015)
-
Suppression of lung metastases by the CD26/DPP4 inhibitor Vildagliptin in mice
Clinical & Experimental Metastasis (2015)