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Abadías-Granado et al. Plast Aesthet Res 2021;8:27 https://dx.doi.org/10.20517/2347-9264.2020.199 Page 7 of 10

[46]
Focusing on skin cancer, Mrázek et al. conducted a study on pigs, showing that the bacterial diversity was
significantly different between normal skin and melanoma surface. They found that Trueperella and
Fusobacterium genera were present in the microbiome of melanoma samples, which also had an increased
amount of Streptococcus and Staphylococcus compared to the microbiome of normal skin. Moreover,
Fusobacterium nucleatum increased with age in animals with progressive melanoma, whereas it diminished
when animals had regressive disease. The authors concluded that Fusobacteria might be associated with
tumor progression, and, as a possible mechanism, they proposed a tumor-based immune evasion: F.
nucleatum - bound tumors are protected against the immune system, inhibiting natural killer cell
cytotoxicity through the interaction of the fusobacterial protein Fap2 with the inhibitory receptor TIGIT of
[46]
the immune cells. F. nucleatum can bind to different tumor types, including melanoma .

[47]
Recent studies suggest that some microorganisms of the skin microbiome can suppress tumor growth . In
this sense, dysbiosis would be potentially harmful because the host microbiota loses its protective function
and/or gains a harmful microbial community. This study describes a strain of Staphylococcus epidermidis
common in the microbiota of the skin that produces 6-N-hydroxyaminopurine (6-HAP), a molecule that
inhibits DNA polymerase activity . In culture, 6-HAP selectively inhibited the proliferation of tumor cell
[47]
lines but did not inhibit normal keratinocytes. Intravenous injection of 6-HAP in mice suppressed
melanoma growth without evidence of systemic toxicity. Colonization of mice with a strain of S. epidermidis
producing 6-HAP reduced the chronic ultraviolet radiation skin damage and developing of tumors
[47]
compared to mice colonized by a control strain that did not produce 6-HAP . S. epidermidis strains
producing 6-HAP have been found in the metagenome from the skin of multiple healthy human subjects,
suggesting that the microbiome of some individuals may protect against skin cancer . These findings show
[47]
a new role for skin commensal bacteria in host defense against skin cancer induced by ultraviolet radiation.

Wang et al. proposed an in vitro model irradiating with co-cultures of human melanocytes and
[48]
commensal skin bacteria containing Propionibacterium acnes and S. epidermidis. Commensal S. epidermidis
and its byproduct lipoteic acid (LPA or TLR2 ligand, which has specific anti-inflammatory action on
keratinocytes, increasing UVB resistance) promote melanocyte survival after UVB irradiation; this effect is
due to an upregulation of TRAF1, CASP5, CASP14, and TP73; however, P. acnes induces apoptosis of UVB-
irradiated melanocytes mediated by TNF-alpha production. The apparently opposite effects can be
explained by the different location and concentration of P. acnes in the normal skin. P. acnes is found
primarily in hair follicles, whose environment is critical for the maintenance of stem cells. Considering that
DNA damage in these cells can result in severe mutations, P. acnes may have been accepted during
evolution in the hair follicle niche to contribute to the health of the stem cell niche. By contrast, S.
epidermidis is more present in dry areas of the body, especially on the inter-follicular epidermis. As
mentioned above, LTA helps melanocytes to escape from UVB-induced apoptosis, which is crucial to
preserve viable inter-follicular melanocytes during sun exposure, preventing their transformation into
[48]
tumoral cells . Other studies that support this perspective include previous observations from the
intestinal microbiome probing that microbes may suppress tumor growth by the production of short-chain
free fatty acids [49,50] . Additionally, skin microbiota potentially produce cis-urocanic acid by degrading L-
histidine, which plays a role in the immunosuppression induced by UV radiation and suppresses melanoma
growth .
[47]

To our knowledge, there are few human studies investigating the relationship between the skin microbiome
and skin cancer. One of them did not find significant differences in the diversity or abundance of bacterial
genera between the microbiome of cutaneous melanomas and melanocytic nevi, although the cohort was
relatively small (17 nevi and 15 melanoma) .
[51]