Molecular Profiling of Keratinocyte Skin Tumors Links Staphylococcus aureus Overabundance and Increased Human β-Defensin-2 Expression to Growth Promotion of Squamous Cell Carcinoma

Abstract

The skin microbiota plays a prominent role in health and disease; however, its contribution to skin tumorigenesis is not well understood. We comparatively assessed the microbial community compositions from excision specimens of the main human non-melanoma skin cancers, actinic keratosis (AK), squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). Keratinocyte skin tumors are characterized by significantly different microbial community compositions, wherein AK and SCC are more similar to each other than to BCC. Notably, in SCC, which represents the advanced tumor entity and frequently develops from AK, overabundance of Staphylococcus aureus, a known skin pathogen, was noted. Moreover, S. aureus overabundance was significantly associated with increased human β-defensin-2 (hBD-2) expression in SCC. By challenging human SCC cell lines with S. aureus, a specific induction of hBD-2 expression and increased tumor cell growth was seen. Increased proliferation was also induced by directly challenging SCC cells with hBD-2. Together, our data indicate that a changed microbial community composition in SCC, specified by S. aureus overabundance, might promote tumor cell growth via modulation of hBD-2 expression.

Invasive and in situ lesions of squamous cell carcinoma are independent factors for postoperative surgical‐site infection after outpatient skin tumors surgery: A retrospective study of 512 patients

“…Madhusudhan et al demonstrated that the microscopic score of bacterial structures was higher in iSCC and AK than in BCC and normal skin samples. 3 Similarly, Wood et al showed that S. aureus, one of the predominant pathogens causing SSI, was relatively abundant in AK and iSCC lesions than in the patients' non-lesional skin. 4 Although the precise mechanism remains unclear, the presence of abundant bacteria in invasive and in situ SCC lesions might have contributed to the high incidence of SSI observed in our study.…”

“…Madhusudhan et al demonstrated that the microscopic score of bacterial structures was higher in iSCC and AK than in BCC and normal skin samples 3 . Similarly, Wood et al showed that S. aureus , one of the predominant pathogens causing SSI, was relatively abundant in AK and iSCC lesions than in the patients’ non‐lesional skin 4 .…”

“…Although the precise mechanism remains unclear, the presence of abundant bacteria in invasive and in situ SCC lesions might have contributed to the high incidence of SSI observed in our study. Given that the bacterial structures are frequently observed in the thickened stratum corneum of iSCC and AK, 3 hyperkeratotic condition may lead to an abundance of bacterial colonization in invasive and in situ lesions of SCC. Therefore, careful disinfection together with removal of the scales in these lesions is thought to be useful for reducing SSI incidence.…”

Human β-Defensin 2 and Its Postulated Role in Modulation of the Immune Response

“…Evidently, in skin cancers accompanied by significant changes in the composition of the bacterial communities present on the skin, the microbiome may be associated with the proliferation of tumor cells. In biopsies from patients with a keratinocyte skin tumor, overabundance of Staphylococcus aureus was associated with overexpression of hBD-2 and, importantly, with increased tumor proliferation [ 116 ]. It can be presumed that the overproduction of defensins has an indirect influence on the progression of neoplastic processes.…”

Identification of key genes in cutaneous squamous cell carcinoma: a transcriptome sequencing and bioinformatics profiling study

“…Recent studies demonstrate correlations between a particular composition of microbiome and a broad spectrum of diseases, including lung cancer, obesity, and even breast cancer (59,60). Microbiome-related pathways were also enriched in both AK and cSCC, especially the human papilloma virus (HPV), which has been shown to be positively correlated with keratinocyte cell proliferation, inflammation, and the immune response (34,61), suggesting that HPV is closely related to the occurrence of AK and cSCC and the transformation of AK to cSCC (62)(63)(64). In addition, a group of EMT-and autophagy-related genes involved in cSCC was identified, and most of the DEGs related to autophagy were downregulated.…”