Secreted Toxins From Staphylococcus aureus Strains Isolated From Keratinocyte Skin Cancers Mediate Pro-tumorigenic Inflammatory Responses in the Skin

Abstract

Squamous cell carcinoma (SCC) is a common type of skin cancer that typically arises from premalignant precursor lesions named actinic keratoses (AK). Chronic inflammation is a well-known promoter of skin cancer progression. AK and SCC have been associated with an overabundance of the bacterium Staphylococcus aureus (S. aureus). Certain secreted products from S. aureus are known to promote cutaneous pro-inflammatory responses; however, not all S. aureus strains produce these. As inflammation plays a key role in SCC development, we investigated the pro-inflammatory potential and toxin secretion profiles of skin-cancer associated S. aureus. Sterile culture supernatants (“secretomes”) of S. aureus clinical strains isolated from AK and SCC were applied to human keratinocytes in vitro. Some S. aureus secretomes induced keratinocytes to overexpress inflammatory mediators that have been linked to skin carcinogenesis, including IL-6, IL-8, and TNFα. A large phenotypic variation between the tested clinical strains was observed. Strains that are highly pro-inflammatory in vitro also caused more pronounced skin inflammation in mice. Proteomic characterization of S. aureus secretomes using mass spectrometry established that specific S. aureus enzymes and cytolytic toxins, including hemolysins, phenol-soluble modulins, and serine proteases, as well as currently uncharacterized proteins, correlate with the pro-inflammatory S. aureus phenotype. This study is the first to describe the toxin secretion profiles of AK and SCC-associated S. aureus, and their potential to induce a pro-inflammatory environment in the skin. Further studies are needed to establish whether these S. aureus products promote SCC development by mediating chronic inflammation.

Targeting Staphylococcus aureus dominated skin dysbiosis in actinic keratosis to prevent the onset of cutaneous squamous cell carcinoma: Outlook for future therapies?

“…Patients with AK lesions often present with Staphylococcus as the dominant taxon on the skin, and a high portion of this taxon are S. aureus. S. aureus secrete toxins on the skin which can cause human keratinocytes to overexpress inflammatory factors that may promote skin carcinogenesis (21)(22)(23)(24). While no causative relationship between S. aureus colonization and AK to cSCC progression has been established to date, this hypothesis presents an interesting interdisciplinary avenue to explore in the fields of oncology and microbiology.…”

Skin Microbiome and Treatment-Related Skin Toxicities in Patients With Cancer: A Mini-Review

“…Healthy skin is primarily characterized with Firmicutes, in which Staphylococcus, Streptococcus, and Lactobacillus are dominant (26). Although the mechanism of bacteria-inducing tumor proliferation is not well understood, there are several contributing processes, such as the production of toxins and inflammation, which leads to DNA damage and induce a proinflammatory environment in the skin (25,(29)(30)(31)(32).…”

“…Besides skin cancer, recent preliminary work showed a high abundance of some skin Staphylococcus species linked with breast cancer and metastases, in which microbial transfer to underlying tissue is proposed, including retrograde transfer via ductal systems, skin barrier breakdown, and migration through nipple-aspirate fluid (37). As a summary, skin morphology is significantly changed during carcinogenesis and consequently the microbial communities are altered, inhabiting potentially pro-tumorigenic microbes (29). To fully evaluate the skin microbiome, we encourage future researchers to further confirm alterations in microbial profiles across the continuum of cancer care trajectory.…”

Microbiome modulates immunotherapy response in cutaneous squamous cell carcinoma

“…We and others have found skin microbiome alterations in SCC, predominantly manifesting as a concomitant depletion of the potentially protective Cutibacterium acnes together with enrichment of Staphylococcus aureus , a skin pathobiont 14-17 . Correspondingly, first insights have been identified into how microbes may affect SCC progression, for example by induction of inflammatory pathways by organisms such as S. aureus 18 .…”