Pathogenic mechanisms and etiologic aspects of Mycobacterium avium subspecies paratuberculosis as an infectious cause of cutaneous melanoma

Abstract

Infectious etiologies have previously been proposed as causes of both melanoma and non-melanoma skin cancer. This exploratory overview explains and presents the evidence for the hypothesis that a microorganism excreted in infected ruminant animal feces, Mycobacterium avium subspecies paratuberculosis (MAP), is the cause of some cases of cutaneous melanoma (CM). Occupational, residential, and recreational contact with MAP-contaminated feces, soil, sand, and natural bodies of water may confer a higher rate of CM. Included in our hypothesis are possible reasons for the differing rates and locations of CM in persons with white versus nonwhite skin, why CM develops underneath nails and in vulvar skin, why canine melanoma is an excellent model for human melanoma, and why the Bacille Calmette-Guérin (BCG) vaccine has demonstrated efficacy in the prevention and treatment of CM. The pathogenic mechanisms and etiologic aspects of MAP, as a transmittable agent underlying CM risk, are carefully deliberated in this paper. Imbalances in gut and skin bacteria, genetic risk factors, and vaccine prevention/therapy are also discussed, while acknowledging that the evidence for a causal association between MAP exposure and CM remains circumstantial.

Keywords: animal bacteria; infectious cancers; melanomagenesis; nonsolar; paratuberculosis; skin cancer; zoonotic etiology.

FIGURE 1

Mycobacterium avium subspecies paratuberculosis (MAP) exposure and related risk factors for cutaneous melanoma. Cutaneous melanoma is hypothesized to result from the interplay of MAP exposure, genetics, chemical exposures, and ultraviolet (UV) radiation. This combination leads to inflammation, oxidative stress, and infected melanocytes, setting the stage for cutaneous melanoma to develop.

FIGURE 2

Concentration of Mycobacterium avium subspecies paratuberculosis (MAP) associated with cattle manure. Emphasis is placed on the relationship between the amount of manure and doses of MAP. With more manure it is expected that increasing doses of MAP are present.

FIGURE 3

Potential alternative pathways for Mycobacterium avium subspecies paratuberculosis (MAP) exposure. Although MAP infection predominantly results from exposure to cattle manure where MAP is present, MAP infection can also occur from exposure to water or dirt contaminated by these bacteria. As illustrated above, both recreational and occupational activities can increase the risk of MAP exposure such as swimming, surfing, welding, cleaning chimney sweeps, and printing.

FIGURE 4

Importance of the gut–skin axis in the development of cutaneous melanoma. Patients with high levels of inflammatory cytokines, for example, interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-12 (IL-12), tumor necrosis factor (TNF), and interferon-γ (IFN-γ) may result from the “challenging to clear” Mycobacterium avium subspecies paratuberculosis (MAP) in the gut. This manifests as decreased integrity of the gut epithelium and microbiota imbalance (dysbiosis). Chronic inflammation, disruption of the gut–skin axis, and dysbiosis are important etiologic determinants of cutaneous melanoma risk.

FIGURE 5

The role of genetics in cutaneous melanoma development. Genetics have an indirect role in melanoma susceptibility, suggesting an interaction with environmental exposures (e.g., Mycobacterium avium subspecies paratuberculosis [MAP]). Many genes are independent of ultraviolet (UV) radiation such as phosphatase and tensin homolog (PTEN), breast cancer type 1 susceptibility protein (BRCA1), breast cancer type 2 susceptibility protein (BRCA2), retinoblastoma protein 1 (RB1), transformation-related protein 53 (TP53), BRCA1 associated protein 1 (BAP1), and glutamine synthetase gene-B (glnB). Typically, most variants associated with melanoma are somatic; however, a polygenic mode of inheritance involving the interplay of multiple low-risk alleles or rare mutations in high-penetrance genes such as adrenocortical dysplasia protein homolog (ACD), BAP1, cyclin-dependent kinase 4 (CDK4), cyclin-dependent kinase inhibitor 2A (CDKN2A/p16INK4a), protection of telomeres 1 protein (POT1), telomeric repeat binding factor 2 interacting protein (TERF2IP), and telomerase reverse transcriptase (TERT) should not be ruled out. In non-pigment pathways, DNA repair, as suggested for melanocortin 1 receptors (MC1R), may underlie melanoma predisposition. Additionally, in vitro growth genes important to melanoma development include ribonucleic acid (RNA) polymerase sigma subfactor A (sigA), phosphoribosylaminoimidazole-succinocarboxamide synthase (PurC), phosphoribosylformylglycinamidine synthase subunit (PurL), and phosphoribosylglycinamide formyltransferase 1 (PurN). The significant genome-wide association with rs28986343 at the human leukocyte antigen (HLA) locus and the association between rs408825 and expression of the innate immunity gene interferon-induced guanosine triphosphate (GTP)-binding protein (MX2) supports an immunologic role for melanoma development.

FIGURE 6

Immune system role in cutaneous melanoma risk and therapy. BCG vaccination potentially may act through the simulation of heterologous or trained immunity against Mycobacterium avium subspecies paratuberculosis (MAP). However, antigens vary among melanoma patients, presenting an obstacle to the development of individualized immune-related therapies.