Skin bacteria may fuel cancer cell progression

Staphylococcal enterotoxins activate oncogenic pathways in cutaneous T cell lymphoma (CTCL), suggesting microbes drive disease progression, according to a new study.¹

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In CTCL, malignant T cells proliferate in a chronic inflammatory environment. Bacteria colonize these patients’ compromised skin barriers as the disease progresses, causing half of CTCL patients with severe disease to die not directly from the malignancy, but rather from infection.

But patients’ frequent bacterial infections might not be a mere disease side effect. On the contrary, toxins in the bacteria actually benefit cancer cells, according to the study’s senior author Niels Ødum, M.D., D.M.Sc., professor in the department of immunology and microbiology at The University of Copenhagen.

“Bacteria like staphylococcus and their toxins may fuel this malignancy by creating a bad inflammatory environment,” Dr. Ødum tells Dermatology Times. “Disease progression of cutaneous T cell lymphoma, and perhaps other cancers, is not a preprogrammed event but a dynamic process influenced by local inflammatory events, which, again, are modulated by a multitude of factors, such as bacteria, which might flip the balance towards an environment supporting cancer progression.”

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In other words, he says, it seems to matter how doctors treat not just the malignant cells, but also the disease as a whole, including surrounding cells and microbes.

NEXT: Findings

The researchers found that bacterial isolates containing staphylococcal enterotoxin-A (SEA) from the affected CTCL patients’ skin, as well as recombinant SEA, stimulate activation of Signal Transducer And Activator of Transcription 3 (STAT3) and up-regulation of Interleukin 17 (IL-17) in immortalized and primary patient-derived malignant and non-malignant T cells, according to the study.

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They concluded, based on their study: SEA induces cell cross-talk-dependent activation of STAT3 and expression of IL-17 in malignant T cells, suggesting a mechanism where SEA-producing bacteria promote activation of an established oncogenic pathway.

This finding could impact what dermatologists and others do today to treat these patients, according to Dr. Ødum.

Lesional skin of CTCL patients often gets colonized with Staphylococcus aureus - which is not a surprise as the skin barrier is damaged, he says.

“Accordingly, following antibiotic treatment, it is often seen that the bacteria come back after some time. As we have a great awareness and concern about methicillin-resistant Staphylococcus aureus (MRSA), there is an understandable [reluctance] to use antibiotics to CTCL patients,” Dr. Ødum says.

Doctors rationalize that if the bacteria relapse rapidly and the treatment increases the risk of antibiotic resistance, it might be safer to be conservative and avoid antibiotic use in these patients.

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“Dr. Madelene Duvic in Texas and her colleagues, have been pioneers taking a more active approach to antibiotic treatment and other antimicrobial measures and have reported in small cohorts on a beneficial effect, at least in some CTCL patients,” Dr. Ødum says. “As CTCL is a rare disease, the societal risk of promoting MRSA by a more active approach to antibiotic treatment is very little. Therefore, if we can confirm in new studies that antibacterial measures halt disease progression and even improve the disease, then antibiotics might become a cornerstone in future therapy of patients with toxin producing Staphylococcus aureus … our present findings that such toxins may activate oncogenic pathways in the cancer cells provide a rationale for a novel aggressive treatment with antibiotics in selected patients.”

NEXT: Future impact

Dr. Ødum says the future impact of the study’s findings might help to improve treatment - not cure - CTCL. As yet, there is no proof that bacteria are etiological agents, or a direct cause, of the disease. However, he s­ays, these new findings strongly indicate the possibility that toxin-producing bacteria may fuel the disease. So, treatment of the bacteria, could prevent an indolent, slowly progressing disease of a low malignancy from turning into a highly aggressive and uncontrollable disease in some patients.

“If our ongoing studies confirm clear beneficial effects of antibiotics on the disease progression and severity of this malignancy, then we anticipate it will become a new standard in CTCL treatment and care. But one step at a time,” he says.

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Dr. Ødum says that he and his colleagues are pursuing this research field in collaboration with dermatologists and researchers in United States, Canada, and Denmark. They hope to have important news later this year, both regarding the effects of bacteria on the disease pathogenesis and the effect of antibiotics.

Disclosure: Dr. Ødum reports no disclosures.

References:

1 Willerslev-olsen A, Krejsgaard T, Lindahl LM, et al. Staphylococcus aureus enterotoxin A (SEA) stimulates STAT3 activation and IL-17 expression in cutaneous T-cell lymphoma. Blood. 2016;:blood-2015-08-662353.