The Human Microbiota and Skin Cancer

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The role of the human microbiota has recently been a focus of research interest in numerous cutaneous diseases including psoriasis and atopic dermatitis as well as skin cancer. The skin microbiota is increasingly thought to play an integral role in maintaining the homeostasis of the skin and its important barrier function. A recent review study¹ looked at the human microbiota, particularly the skin microbiota, and the potential role it may have in the development of skin cancer.

“Given the emphasis on microbial composition and its involvement in human disease in recent years, the question arises as to how an individual’s distinct microbiota, which outnumbers human cells by a factor of 10, may influence skin cancer risk and subsequent response to therapy. Since microbial dysbiosis is linked with chronic inflammation, inflammation-mediated carcinogenesis processes, and immune evasion, it is not surprising that microbes are associated with the development of specific cancers,” wrote Hei Sung Kim, MD, and fellow colleagues, of the department of dermatology at Incheon St. Mary’s Hospital of the Catholic University of Korea, in Seoul, Korea.

For many years now, the incidence of skin cancer including melanoma, T cell lymphoma, and nonmelanoma skin cancers (NMSC) including basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) has been on the rise and has become a major health issue in medical practice. The majority of NMSCs are BCC and SCC with approximately 70% and 25% constituting total cases, respectively.²

Most NMSCs are caused by excessive ultraviolet (UV) radiation via sun exposure, resulting in DNA damage, reactive oxygen species (ROS), and inflammatory cytokines leading to immunosuppression and cancer development. However, other risk factors including immunosuppression, chronic inflammation, and the use of antibiotics suggest the microbiome as another unexplored risk for the development of skin cancer.³

The skin microbiome consists of a collection of microbes including bacteria, archaea, fungi, viruses, and mites, all of which reside in and on the skin. The coexistence of these commensal microbes in an established healthy balance plays a central role in the normal barrier function of the skin and ensures skin homeostasis. The secretion of protease enzymes by resident skin microbes is integrally involved in the desquamation process and renewal of the stratum corneum. When dysbiosis of the skin microbiota occurs, it is possible that that the disarray can be in part responsible for the development of skin cancers.

The skin microbiota is always in a state of flux, witnessed by the increases in Staphylococcus aureus, Streptococcus pyogenes and Pseudomonas aeruginosa bacteria strains, as well as modifications in the mutual quantity of β-Human papillomavirus genotypes, Epstein Barr Virus and Malassezia or candidiasis, which all may contribute to a state of chronic self-maintaining inflammation, leading to cancer.⁴

In one study⁵ of Staphylococcus aureus (S. aureus) that included biopsies of SCC, BCC, actinic keratosis (AK), seborrheic keratosis, and healthy control skin specimens, researchers discovered a strong association between S. aureus and SCC when evaluating the tumor biopsies and swab samples. Study results showed a higher colonization of S. aureus in SCC biopsies (29.3%) when compared to healthy skin biopsies (5.7%). In PCR testing, they found that an increased prevalence of S. aureus DNA was strongly associated with AKs (a known precursor of SCC) and SCC, while no association was seen for BCC or seborrheic keratosis. Although the results seem to indicate that the presence of S. aureus may play a role in malignant transformation, there is no evidence of their causal association.

Researchers have also explored the association between melanoma and the skin microbiota. In one study⁶, a culture-based microbial analysis using skin swabs was conducted in patients with acral melanoma. Here, it was found that Corynebacterium was strongly associated with stage III/IV melanoma patients compared to stage I/II melanoma patients. Results showed a higher number of interleukin (IL)-17 positive cells in the genus Corynebacterium-positive sampled patients when compared to Corynebacterium-negative patients. In mouse model studies^7-8, researchers found that Corynebacterium can up-regulate IL-17 cells which according to Kim, suggest that the Corynebacterium species could influence the development of melanoma through an IL-17-dependent pathway.

A potential causal association of S. epidermidis to melanoma skin cancer has also been studied.⁹ Here, researchers found that the injection of 6-HAP derived from the S. epidermidis bacteria can inhibit the growth of the B16F10 melanoma cell line, which according to Kim, could suggest a protective function of the bacteria against melanoma. However, another study¹⁰ suggested that S. epidermidis and lipoteichoic acid from S. epidermidis can enhance the survival of melanocytes by upregulating TRAF1, CASP14, CASP5, and TP73 during UVB irradiation.

“Activation of the skin immune system, production of microbial metabolites and toxins, barrier disruption, and UV radiation altogether may be associated with alterations of skin microbiota, leading to the initiation and progression of skin cancer, and its response to therapy,” wrote Kim and fellow colleagues.

References

1. Woo YR, Cho SH, Lee JD, Kim HS. The Human Microbiota and Skin Cancer. Int. J. Mol.Sci.2022,23,1813. https:// doi.org/10.3390/ijms23031813

2. Ciuciulete AR, Stepan AE, Andreiana BC, Simionescu CE. Non-melanoma skin cancer: statistical associations between clinical parameters. Curr Health Sci J. 2022 Jan-Mar; 48(1): 110-115. Published online 2022 Mar 31. doi: 10.12865/CHSJ.48.01.16

3. Voigt AY, Emiola A, Johnson JS, Fleming ES, Nguyen H, Zhou W, Tsai KY, Fink C, Oh J. Skin Microbiome variation with cancer progression in human cutaneous squamous cell carcinoma. J Invest Dermatol. 2022 Oct;142(10):2773-2782.e16. doi: 10.1016/j.jid.2022.03.017. Epub 2022 Apr 4.

4. Squarzanti DF, Zavattaro E, Pizzimenti S, et al. Nonmelanoma skin cancer: news from the microbiota research. Crit Rev Microbiol. 2020 Aug;46(4):433-449. doi: 10.1080/1040841X.2020.1794792.

5. Kullander J, Forslund O, Dillner J. Staphylococcus aureus and squamous cell carcinoma of the skin. Cancer Epidemiol Biomarkers Prev. 2009;18(2):472-478. doi:10.1158/1055-9965.

6. Mizuhashi S, Kajihara I, Sawamura S. Skin microbiome in acral melanoma: Corynebacterium is associated with advanced melanoma. J Dermatol. 2021 Jan;48(1):e15-e16. doi: 10.1111/1346-8138.15633. Epub 2020 Oct 5.

7. Wang L, Yi T, Kortylewski M, et al. IL-17 can promote tumor growth through an IL-6-Stat3 signaling pathway. J Exp Med. 2009;206(7):1457-1464. doi:10.1084/jem.20090207

8. Ridaura VK, Bouladoux N, Claesen J, et al. Contextual control of skin immunity and inflammation by Corynebacterium. JExpMed.2018;215(3):785-799. doi:10.1084/jem.20171079

9. Nakatsuji T, Chen TH, Butcher AM, et al. A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Sci Adv. 2018 Feb 28;4(2):eaao4502. doi:10.1126/sciadv.aao4502

10. Wang Z, Choi JE, Wu CC, DiNardo A. Skin commensal bacteria Staphylococcus epidermidis promote survival of melanocytes bearing UVB-induced DNA damage, while bacteria Propionibacterium acnes inhibit survival of melanocytes by increasing apoptosis. PhotodermatolPhotoimmunolPhotomed. 2018;34(6):405-414. doi:10.1111/phpp.12411

Disclosures

This study was supported by a Grant of Translational R&D Project through the Institute for Bio-Medical convergence, Incheon St. Mary’s Hospital, The Catholic University of Korea.