Collagens XV and XVIII show different expression and localisation in cutaneous squamous cell carcinoma: type XV appears in tumor stroma, while XVIII becomes upregulated in tumor cells and lost from microvessels

Abstract

As the second most common skin malignancy, cutaneous squamous cell carcinoma (cSCC) is an increasing health concern, while its pathogenesis at molecular level remains largely unknown. We studied the expression and localisation of two homologous basement membrane (BM) collagens, types XV and XVIII, at different stages of cSCC. These collagens are involved in angiogenesis and tumorigenesis, but their role in cancer development is incompletely understood. Quantitative RT-PCR analysis revealed upregulation of collagen XVIII, but not collagen XV, in primary cSCC cells in comparison with normal human epidermal keratinocytes. In addition, the Ha-ras-transformed invasive cell line II-4 expressed high levels of collagen XVIII mRNA, indicating upregulation in the course of malignant transformation. Immunohistochemical analyses of a large human tissue microarray material showed that collagen XVIII is expressed by tumor cells from grade 1 onwards, while keratinocytes in normal skin and in premalignant lesions showed negative staining for it. Collagen XV appeared instead as deposits in the tumor stroma. Our findings in human cSCCs and in mouse cSCCs from the DMBA-TPA skin carcinogenesis model showed that collagen XVIII, but not collagen XV or the BM markers collagen IV or laminin, was selectively reduced in the tumor vasculature, and this decrease associated significantly with cancer progression. Our results demonstrate that collagens XV and XVIII are expressed in different sites of cSCC and may contribute in a distinct manner to processes related to cSCC tumorigenesis, identifying these collagens as potential biomarkers in the disease.

p53-Regulated Long Noncoding RNA PRECSIT Promotes Progression of Cutaneous Squamous Cell Carcinoma via STAT3 Signaling

“…In this respect, it is important to note, that the structure of basement membrane is altered in AK and cSCCIS, indicating that alterations in the microenvironment of the premalignant and noninvasive lesions is important in their progression to invasive cSCC. 76 In conclusion, the authors have identified a lncRNA, PRECSIT, that is specifically expressed by cSCC cells in culture and in vivo, and show that it is regulated by p53 ( Figure 5). The levels of activated transcription factor STAT3 are up-regulated by PRECSIT, and this in turn upregulates the expression of several invasion-associated MMPs, that is, MMP-1 and MMP-13, which cleave fibrillar collagens, and MMP-3 and MMP-10, which can cleave a multitude of other extracellular matrix and basement membrane components, including type IV collagen, fibronectin, and laminin, and can activate latent MMP-1 and MMP-13.…”

Long non-coding RNA PICSAR decreases adhesion and promotes migration of squamous carcinoma cells by downregulating α2β1 and α5β1 integrin expression

“…Progression of cSCCs is characterized by an alteration of basement membrane structure at an early stage, and by an eventual loss of basement membrane at invasive stage ( Karppinen et al, 2016 ). There is also evidence that the cellular expression of lncRNAs is dependent on the composition and structure of the extracellular matrix ( Zhuang et al, 2013 ; Li et al, 2017 ), indicating that the lncRNA expression varies depending on the activation of different adhesion receptors.…”

Expression of claudin‐11 by tumor cells in cutaneous squamous cell carcinoma is dependent on the activity of p38δ

“…There is increasing evidence that the role of tumor microenvironment presents a significant role in initiation and progression of cSCC. The composition of epidermal basement membrane and dermal extracellular matrix, influx of inflammatory cells and presence of microbial structures have been revealed to affect cSCC progression …”