Nissinen Liisa, Farshchian Mehdi, Riihilä Pilvi, Kähäri Veli-Matti
The Department of Dermatology, University of Turku and Turku University Hospital, P.O.B 52, FI-20521, Turku, Finland.
MediCity Research Laboratory University of Turku, Turku, Finland.
Cell Tissue Res. 2016 Sep;365(3):691-702. doi: 10.1007/s00441-016-2457-z. Epub 2016 Jul 14.
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.
表皮角质形成细胞来源的皮肤鳞状细胞癌（cSCC）是最常见的转移性皮肤癌，其发病率在全球范围内呈上升趋势。太阳紫外线辐射是cSCC的一个重要危险因素，会导致表皮角质形成细胞和真皮细胞发生基因和表观遗传变化。皮肤cSCC中的肿瘤细胞通常存在多个驱动基因突变，但暴露于阳光下的正常皮肤中的表皮角质形成细胞也含有这些相同基因的突变。因此，癌前病变微环境的改变显然是其进展为侵袭性和转移性cSCC所必需的。例如，基底膜和真皮细胞外基质组成的改变是cSCC进展的早期事件。微生物结构的存在和炎症细胞的流入促进蛋白酶的分泌，进而调节生长因子、细胞因子和趋化因子的可用性，从而影响cSCC的生长和侵袭。这些观察结果共同强调了肿瘤微环境在cSCC进展中的作用，并将其确定为cSCC和其他恶性肿瘤的一个新的治疗靶点。
皮肤鳞状细胞癌（cSCC）进展中的肿瘤-基质相互作用。表皮层通过组织良好的基底膜（BM）与真皮层分隔开。紫外线辐射、其他环境损伤和衰老作用于表皮角质形成细胞和真皮成纤维细胞，导致这些细胞发生基因和表观遗传变化。此外，暴露于阳光下的正常皮肤中的表皮角质形成细胞在cSCC驱动基因中存在多个突变。在向癌前光化性角化病（AK）转变过程中，角质形成细胞的分化受到干扰，导致具有增生细胞的肿瘤上皮形成。在AK中，肿瘤细胞以及活化的基质成纤维细胞和巨噬细胞诱导蛋白酶如基质金属蛋白酶（MMP）的表达，真皮BM中胶原蛋白XV和XVIII丢失。此外，炎症细胞在增生上皮部位积聚。在cSCC进展的后期，炎症细胞数量增加，肿瘤细胞诱导补体成分和抑制剂的表达（CFI补体因子I、CFH补体因子H、FHL-1因子H样蛋白1）。除MMPs外，活化的成纤维细胞还产生生长因子，并促进肿瘤细胞的炎症、生长和侵袭。
