Thinking small can produce big results

Skin cancer is one of the most common diagnoses seen in dermatological practice and its worldwide prevalence continues to increase.1 Ultraviolet radiation is well established as a major risk factor in the development of skin cancer, but other risk factors may be influential. Since the cancer microenvironment – ​​which refers to non-cancerous cells – in the tumor environment is known to modulate cancer progression and response to treatment, recent research has begun to investigate the cancer microenvironment in cutaneous malignancy.2 One such cancerous microenvironment that is attracting interest is the human microbiota. The human body is colonized by a large number of microbes, commonly referred to as the human microbiota. The link between these microbes and our health is the subject of a growing number of research initiatives, particularly in dermatology. In fact, a recent review article summarized existing research on gut microbiome composition and function in psoriasis and psoriatic arthritis, exploring potential roles in disease pathogenesis, progression, and management.3

“This review highlights potentially important associations between the skin and gut microbiome and skin cancer,” said Wilson Liao, MD, board-certified dermatologist, professor of dermatology and co-director of the Psoriasis and Skin Treatment Center at the University of California, San Francisco. “The microbiome is well known to influence inflammatory skin diseases such as atopic dermatitis, psoriasis, and hidradenitis suppurativa.”

Given the recent focus on the human microbiota and its involvement in human health and disease, researchers have begun to explore whether a patient’s unique microbiota can influence skin cancer risk and response to treatment. Unfortunately, not much is known about the influence of human microbiota on skin cancer.

Since more research is needed on this topic, Woo et. al conducted a study on the human skin microbiota that is most closely associated with skin cancer and highlighted the mechanism of action and therapeutic potential.4 First, the authors discuss the link between the skin microbiome and skin-specific and skin-related malignancies.

Evidence has been presented on the association between Staphylococcus aureus (S. aureus) and squamous cell carcinoma (SCC), and a study was introduced by Kullander et. al who found that the colonization of S. aureus was higher in SCC biopsies (29.3%) than in healthy skin biopsies (5.7%).5 These same authors found a higher prevalence of S. aureus DNA in actinic keratoses and SCC of the skin using the polymerase chain reaction. Since actinic keratoses are well-known precursor lesions to cutaneous SCC, it is hypothesized that the bacterium may contribute to malignant transformation. Despite the observations of S. aureus in CSCs, there is no evidence of a causal association between the 2.

Various studies have also linked S. aureus and cutaneous T-cell lymphoma (CTCL). The colonization of S. aureus was found to be heaviest in erythrodermic Sézary syndrome whereas it was rare in mycosis fungoides without erythroderma.2.5 Another finding on this topic found that 58% of patients with CTCL showed clinical improvement with 4 weeks of antibiotic treatment against S. aureus and 8 patients with treatment-resistant CTCL disease achieved improvement with similar antibiotic treatment.6.7 Antibiotics have also been shown to modulate mRNA expression patterns in the CTCL, causing these signals to become more similar to those found in normal skin. The cytokine IL-2 was inhibited after treatment with antibiotics, as well as activation of STAT3.6 Other types of bacteria that have been implicated in CTCL are β-hemolytic streptococci, Enterobacteriaceae, Pseudomonas aeruginosaand Enterococcus species.8

Despite these interesting results, larger randomized controlled trials with antibiotic treatments are needed to better determine how these bacteria are associated with pathogenesis or clinical response in CTCL. Many studies of the skin microbiome and CTCL are limited by the fact that it has only been studied in a small number of patients.

Several studies on the protective and detrimental effects of specific bacteria on malignant melanoma (MM) were discussed such as Corynebacterium, S. epidermidis, Fusobacterium, and Trueprella. A study revealed that Corynebacterium is more strongly associated with patients with stage 3/4 MM, and in a mouse model, this bacterium has been shown to upregulate IL-17 cells.9-11 Since IL-17 can induce melanoma growth, these results may suggest that Corynebacterium may promote MM growth through an IL-17-dependent pathway. There are studies that show that S. epidermidis both promotes and inhibits the growth of MM. Nakatsuji et al found that intravenous injection of 6-HAP (derived from S. epidermidis) can inhibit the growth of the B16F10 melanoma cell line and Wang et. al suggested that S. epidermidis may improve its survival by upregulating TRAF1, CASP14, CASP5 and TP73 during UVB irradiation.12.13

In the review, the authors propose a mechanistic link between the skin microbiota and skin cancer and take into account key factors such as the skin immune system, microbial metabolites on the skin, barrier breakdown, UV radiation and the intratumoral microbiota. Their main hypothesis was that all of these distinct factors are synergistic in enabling tumor progression through immunosuppression, cell proliferation and inflammation in the skin microenvironment.4

Considering these various factors, suggestions for therapeutic interventions are reviewed by the authors and data are presented on the role of prebiotics and probiotics in other dermatological diseases. For example, topical application of Roseomonas mucosa leads to clinical improvement of atopic dermatitis.14 Similarly, there is evidence to show that topical application with enterocins of Enterococcus Faecalis SL-5 improved acne over an 8 week course.

Although no studies have tested the effect of topical probiotics on skin cancer, the mechanism of action of topical probiotics may modulate the skin microenvironment and result in tumor suppression. The authors concluded that recent research on the role of skin microbiota has contributed to our understanding of skin cancer pathogenesis, but further studies are needed to further elucidate its exact role in skin cancer.4

“It is exciting that these findings are now being extended to skin cancer, which has significant morbidity for our patients,” Liao said.

References:

  1. Christenson LJ, Borrowman TA, Vachon CM, et al. Incidence of basal cell and squamous cell carcinomas in a population under 40 years old. JAMA. 2005;294(6):681-690. doi:10.1001/jama.294.6.681
  2. Woo YR, Cho SH, Lee JD, Kim HS. The human microbiota and skin cancer. Int J Mol Sci. 2022;23(3):1813. doi:10.3390/ijms23031813
  3. Myers B, Brownstone N, Reddy V, et al. Gut microbiota in psoriasis and psoriatic arthritis. Best Practice Res Clin Rheumatol. 2019;33(6):101494. doi:10.1016/j.berh.2020.101494
  4. Woo YR, Cho SH, Lee JD, Kim HS. The human microbiota and skin cancer. IJMS. 2022;23(3):1813.
  5. Kullander J, Forslund O, Dillner J. Staphylococcus aureus and squamous cell carcinoma of the skin. Biomarkers of cancer epidemiol Previous. 2009;18(2):472-478. doi:10.1158/1055-9965.EPI-08-0905
  6. Talpur R, Bassett R, Duvic M. Prevalence and treatment of Staphylococcus aureus colonization in patients with mycosis fungoides and Sézary syndrome. Br J Dermatol. 2008;159(1):105-112. doi:10.1111/j.1365-2133.2008.08612.x
  7. Lindahl LM, Willerslev-Olsen A, Gjerdrum LMR, et al. Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma. Blood. 2019;134(13):1072-1083. doi:10.1182/blood.2018888107
  8. Axelrod PI, Lorber B, Vonderheid EC. Infections complicating mycosis fungoides and Sézary syndrome. JAMA. 1992;267(10):1354-1358.
  9. Mizuhashi S, Kajihara I, Sawamura S, et al. Skin microbiome in acral melanoma: Corynebacterium is associated with advanced melanoma. J-Dermatol. 2021;48(1):e15-e16. doi:10.1111/1346-8138.15633
  10. Ridaura VK, Bouladoux N, Claesen J, et al. Contextual control of cutaneous immunity and inflammation by Corynebacterium. J Med Exp. 2018;215(3):785-799. doi:10.1084/jem.20171079
  11. Wang L, Yi T, Kortylewski M, Pardoll DM, Zeng D, Yu H. IL-17 can promote tumor growth via an IL-6-Stat3 signaling pathway. J Med Exp. 2009;206(7):1457-1464. doi:10.1084/jem.20090207
  12. Wang Z, Choi JE, Wu CC, Di Nardo A. Commensal skin bacteria Staphylococcus epidermidis promote survival of melanocytes bearing UVB-induced DNA damage, while Propionibacterium acnes bacteria inhibit melanocyte survival by increasing apoptosis. Photodermatol Photoimmunol Photomed. 2018;34(6):405-414. doi:10.1111/phpp.12411
  13. Nakatsuji T, Chen TH, Butcher AM, et al. A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Science Adv. 2018;4(2):eaao4502. doi:10.1126/sciadv.aao4502
  14. Myles IA, Earland NJ, Anderson ED, et al. First human topical microbiome transplant with Roseomonas mucosa for atopic dermatitis. JCI Overview. 2018;3(9):120608. doi:10.1172/jci.insight.120608

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