New perspectives on role of tumor microenvironment in progression of cutaneous squamous cell carcinoma
Abstract
Epidermal keratinocyte-derived cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer, and its incidence is increasing worldwide. Solar UV radiation is an important risk factor for cSCC and leads to genetic and epigenetic changes both in epidermal keratinocytes and dermal cells. Tumor cells in cutaneous cSCCs typically harbor several driver gene mutations, but epidermal keratinocytes in sun-exposed normal skin also contain mutations in these same genes. Therefore, alterations in the microenvironment of premalignant lesions are evidently required for their progression to invasive and metastatic cSCC. For example, alterations in the composition of basement membrane and dermal extracellular matrix are early events in cSCC progression. The presence of microbial structures and the influx of inflammatory cells promote the secretion of proteases, which in turn regulate the availability of growth factors, cytokines, and chemokines and thus influence the growth and invasion of cSCC. Together, these observations emphasize the role of the tumor microenvironment in the progression of cSCC and identify it as a novel therapeutic target in cSCC and other malignant tumors. Graphical abstract Tumor-stroma interactions in the progression of cutaneous squamous cell carcinoma (cSCC). Epidermal layer is separated by a well-organized basement membrane (BM) from the dermal layer. UV radiation, other environmental insults, and aging target both epidermal keratinocytes and dermal fibroblasts and lead to genetic and epigenetic changes in these cells. In addition, epidermal keratinocytes in normal sun-exposed skin harbor several mutations in the cSCC driver genes. During transition to premalignant actinic keratosis (AK), the differentiation of keratinocytes is disturbed resulting in a neoplastic epithelium with hyperplastic cells. Expression of proteinases, such as matrix metalloproteinases (MMP) by neoplastic cells and activated stromal fibroblasts and macrophages is induced in AK, and collagen XV and XVIII are lost from the dermal BM. Furthermore, inflammatory cells accumulate at the site of the hyperplastic epithelium. During a later stage of cSCC progression, the number of inflammatory cells increases, and the expression of complement components and inhibitors by tumor cells is induced (CFI complement factor I, CFH complement factor H, FHL-1 Factor H-like protein 1). In addition to MMPs, activated fibroblasts also produce growth factors and promote inflammation, growth, and invasion of tumor cells.
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Overexposure to sunlight is directly connected with the onset of skin cancers such as basal cell carcinoma (BSC), squamous cell carcinoma (SCC), and malignant melanoma (MM).
“Overexposure to sunlight is directly connected the with onset of skin cancers such as basal cell carcinoma (BSC) [165], squamous cell carcinoma (SCC) [166,167], and malignant melanoma (MM) [168,169].”
From Focus on UV-Induced DNA Damage and Repair—Disease Relevance and Protective Strategies (2020) · cites this paper as [166]
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Additional file 2 of Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing
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Additional file 1 of Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing
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Heiskanen, L., Nissinen, L. M., Siljamäki, E., Rappu, P., Suwal, U., Pellinen, T. S., Knuutila, J. S., Huvila, J. K., Heino, J., Kähäri, V., et al. (2026) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2026.10.019
Self-citation
- Authors
- Nissinen, L., Farshchian, M., Riihilä, P., & Kähäri, V.-M.
- Affiliations
- University of Turku (FI)
- Corresponding author
- Kähäri, Veli-Matti
- Venue
- Cell and Tissue Research
- Published
- 2016-07-14
- Volume
- 365
- Issue
- 3
- Pages
- 691-702
- ISSN
- 0302-766X (ISSN-L)
- 1432-0878
- OpenAlex
- W2469171914
- Cited by
- 80
- References
- 99
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 9 · 2023: 5 · 2022: 11 · 2021: 11 · 2020: 6 · 2019: 12 · 2018: 8 · 2017: 6 · 2016: 1
- FWCI
- 1.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cell and Tissue Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Nonmelanoma Skin Cancer Studies
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Health Sciences › Medicine › Dermatology › Cancer and Skin Lesions
- Keywords
- cutaneous squamous cell carcinoma, tumor microenvironment, tumor progression, actinic keratosis, ultraviolet radiation, keratinocytes, basement membrane, dermal extracellular matrix, matrix metalloproteinases, proteolytic enzymes, dermal fibroblasts, macrophages, inflammation, complement system, FHL1, collagen XV, collagen XVIII, precancerous lesions
- MeSH terms
- Carcinoma, Squamous Cell, Humans, Models, Biological, Skin Neoplasms, Disease Progression, Matrix Metalloproteinases, Tumor Microenvironment
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