University of Oulu

Martínez-Nieto, G. A., Teppo, H.-R., Petrelius, N., Izzi, V., Devarajan, R., Petäistö, T., Liu, H., Kim, K. S., Karppinen, S.-M., Ruotsalainen, H., Koivunen, J., Mäki, J. M., Walker, G. C., Pihlajaniemi, T., Gullberg, D., & Heljasvaara, R. (2022). Upregulated integrin α11 in the stroma of cutaneous squamous cell carcinoma promotes skin carcinogenesis. Frontiers in Oncology, 12, 981009.

Upregulated integrin α11 in the stroma of cutaneous squamous cell carcinoma promotes skin carcinogenesis

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Author: Martínez-Nieto, Guillermo A.1; Teppo, Hanna-Riikka2,3,4; Petrelius, Noora1;
Organizations: 1ECM-Hypoxia Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
2Cancer Research and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
3Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
4Department of Pathology, Oulu University Hospital, Oulu, Finland
5Research Unit of Biomedicine, University of Oulu, Oulu, Finland
6Finnish Cancer Institute, Helsinki, Finland
7Matrix Biology Group, Department of Biomedicine, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway
8Department of Chemistry, University of Toronto, Toronto, ON, Canada
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 12.9 MB)
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Language: English
Published: Frontiers Media, 2022
Publish Date: 2023-02-06


Integrin α11β1 is a collagen-binding integrin that is needed to induce and maintain the myofibroblast phenotype in fibrotic tissues and during wound healing. The expression of the α11 is upregulated in cancer-associated fibroblasts (CAFs) in various human neoplasms. We investigated α11 expression in human cutaneous squamous cell carcinoma (cSCC) and in benign and premalignant human skin lesions and monitored its effects on cSCC development by subjecting α11-knockout (Itga11−/−) mice to the DMBA/TPA skin carcinogenesis protocol. α11-deficient mice showed significantly decreased tumor cell proliferation, leading to delayed tumor development and reduced tumor burden. Integrin α11 expression was significantly upregulated in the desmoplastic tumor stroma of human and mouse cSCCs, and the highest α11 expression was detected in high-grade tumors. Our results point to a reduced ability of α11-deficient stromal cells to differentiate into matrix-producing and tumor-promoting CAFs and suggest that this is one causative mechanism underlying the observed decreased tumor growth. An unexpected finding in our study was that, despite reduced CAF activation, the α11-deficient skin tumors were characterized by the presence of thick and regularly aligned collagen bundles. This finding was attributed to a higher expression of TGFβ1 and collagen crosslinking lysyl oxidases in the Itga11−/− tumor stroma. In summary, our data suggest that α11β1 operates in a complex interactive tumor environment to regulate ECM synthesis and collagen organization and thus foster cSCC growth. Further studies with advanced experimental models are still needed to define the exact roles and molecular mechanisms of stromal α11β1 in skin tumorigenesis.

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Series: Frontiers in oncology
ISSN: 2234-943X
ISSN-E: 2234-943X
ISSN-L: 2234-943X
Volume: 12
Article number: 981009
DOI: 10.3389/fonc.2022.981009
Type of Publication: A1 Journal article – refereed
Field of Science: 3122 Cancers
Funding: The research leading to these results has received funding from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007-2013/under REA grant agreement no. 316610 (for GM-N and HL) and from the Academy of Finland (grants 308867 and 284065 for TPi), the Cancer Foundation Finland (grants 190147 and 170138 for TPi), the Sigrid Jusélius Foundation (TPi and RH), the Jane and Aatos Erkko Foundation (TPi), the Norwegian Centre of Excellence grant from the Research Council of Norway (ID 223250) (DG), the Western Norway Regional Health Authority (ID 911899) (DG), the National Science and Engineering Research Council of Canada (GW), the Finnish Medical Society Duodecim (H-RT and NP), the Finnish Medical Foundation (H-RT and NP), and the Kerttu Saalasti Foundation (TPe).
EU Grant Number: (316610) CAFFEIN - Cancer Associated Fibroblasts (CAF) Function in Tumor Expansion and Invasion
Academy of Finland Grant Number: 308867
Detailed Information: 308867 (Academy of Finland Funding decision)
Copyright information: © 2022 Martínez-Nieto, Teppo, Petrelius, Izzi, Devarajan, Petäistö, Liu, Kim, Karppinen, Ruotsalainen, Koivunen, Mäki, Walker, Pihlajaniemi, Gullberg and Heljasvaara. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.