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New perspectives on role of tumor microenvironment in progression of cutaneous squamous cell carcinoma

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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.

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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Authors and Affiliations

  1. The Department of Dermatology, University of Turku and Turku University Hospital, P.O.B 52, FI-20521, Turku, Finland

    Liisa Nissinen, Mehdi Farshchian, Pilvi Riihilä & Veli-Matti Kähäri

  2. MediCity Research Laboratory University of Turku, Turku, Finland

    Liisa Nissinen, Mehdi Farshchian, Pilvi Riihilä & Veli-Matti Kähäri

Authors
  1. Liisa Nissinen
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  2. Mehdi Farshchian
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  3. Pilvi Riihilä
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  4. Veli-Matti Kähäri
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Correspondence to Veli-Matti Kähäri.

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The authors declare that they have no conflict of interest.

Additional information

The original work of the authors was supported by the Finnish Cancer Research Foundation, Sigrid Jusélius Foundation, and Turku University Hospital VTR grant (project 13336) and by the Turku University Foundation.

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Nissinen, L., Farshchian, M., Riihilä, P. et al. New perspectives on role of tumor microenvironment in progression of cutaneous squamous cell carcinoma. Cell Tissue Res 365, 691–702 (2016). https://doi.org/10.1007/s00441-016-2457-z

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  • DOI: https://doi.org/10.1007/s00441-016-2457-z

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