Viruses may lead to skin disease, cancer

Caption of photo above: Photomicrograph of Merkel cell carcinoma Invasive skin Merkel cell carcinoma caused by Merkel cell polyomavirus (MCV T antigen, brown).

Over the last several years, the understanding of various cancers and their etiologies has gone viral. Literally. Advances in genetics research resulted in discovery of 11 new human polyomaviruses over the past eight years, including those causing Merkel cell carcinoma, trichodysplasia spinulosum, HPyV7-related hyperplasia/dyskeratosis, necrotic skin lesions and other skin diseases.

READ: Advances in understanding, treating MCC

In his plenary session at the 23rd World Congress of Dermatology in Vancouver, June 2015, Patrick Moore, M.D., M.P.H., discussed lessons researchers have learned from studying Kaposi’s sarcoma and Merkel cell Carcinoma. He is distinguished professor, Department of Molecular Microbiology and Genetics, University of Pittsburgh; director, Cancer Virology Program, Hillman Comprehensive Cancer Institute.

Dr. Moore, who together with Yuan Chang, discovered two of the seven known human cancer viruses: Kaposi’s sarcoma herpesvirus (KSHV/HHV8) and Merkel cell polyomavirus (MCPyV), notes that researchers are only beginning to understand the range of viruses resident in skin that may be the cause of long-established idiopathic (and perhaps common) dermatologic disorders. New technologies, such as genomic sequencing, have helped illuminate hundreds of new viruses. It’s believed that viruses cause 15-20% of all cancer cases worldwide; as researchers uncover the connections between viruses and malignancies, the diagnosis, prognosis, and treatment of skin cancers caused by viruses are rapidly changing.

Moore’s Research Lab studies Kaposi’s sarcoma-associated herpesvirus (KSHV), the viral cause of Kaposi’s sarcoma; Merkel cell  polyomavirus (MCV), the viral cause of Merkel cell carcinoma; and methods to search for undiscovered human tumor viruses.

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To search for new human tumor viruses, the lab developed a technique called digital transcriptome subtraction (DTS) to sample tumor mRNA profiles for foreign transcripts. Unlike other new pathogen discovery techniques, DTS is quantitative so researchers can rule out infection if no foreign transcripts are found. Moore’s Research Lab has successfully used DTS to measure KSHV transcription in infected cell lines, and researchers have demonstrated that an AIDS-related cancer, squamous cell conjunctival carcinoma, is unlikely to be caused by an exogenous infection.

NEXT: Uncovering the virus to cancer route

Caption of photo above: Photomicrograph of Merkel cell carcinoma Invasive skin Merkel cell carcinoma caused by Merkel cell polyomavirus (MCV T antigen, brown).

Uncovering the virus to cancer route

Researchers have recently been able to associate viruses with various diseases, particularly in immunocompromised patients. This suggests ongoing exposure to many of these viruses may cause some idiopathic dermatologic diseases, and possibly not only rare cancers but also common diseases.

READ: Reprogramming cancer with a code

“Over the past decade, we’ve learned that our skin and other organs are teeming with previously unknown viruses, such as MCV,” Dr. Moore says. “MCV and Merkel cell carcinoma is a new example in which mutations to our flora (rather than the host cell) lead to an invasive cancer. It seems likely that some of these newly found viruses will ultimately be found to cause skin diseases and cancers.” 

Moore’s lab’s recent studies on KSHV have shown that its major latency protein evades typical protein processing pathways to avoid provoking a cell-mediated immune response. They also found that both KSHV and Epstein-Barr virus (EBV) undergo programmed frameshifting to generate novel latent proteins, allowing these viruses to increase their phenotypic diversity within tight biological constraints on their genome size.

Dr. Moore says the role of viruses in causing cancer is frequently overlooked – and particularly so for cancers of the skin, an organ continually exposed to environmental pathogens, tumor viruses are exceedingly important. Both Kaposi’s sarcoma herpesvirus (KSHV or HHV8) and Merkel cell polyomavirus (MCV) were first discovered in skin cancers. KSHV, the cause of KS and some B cell lymphomas and lymphoproliferative disorders was discovered in 1994 by physically isolating viral DNA from a KS lesion.

“If someone is infected with this virus and is also immunodeficient, there is a very high rate of KS,” Dr. Moore says. “In Europe and North America, where the general prevalence of KSHV is low, there is a low rate of KS. For some risk groups, however, such as gay and bisexual men – particularly those also infected with HIV – the risk of KS is high. In Africa and parts of South America where KSHV infection is common, KS can be the most commonly reported cancer. This is a terribly underappreciated public health problem.”

NEXT: the majoy factor determining whether cancer occurs

Caption of photo above: Photomicrograph of Merkel cell carcinoma Invasive skin Merkel cell carcinoma caused by Merkel cell polyomavirus (MCV T antigen, brown).

Dr. Moore notes that for KSHV, the major factor determining whether cancer occurs is whether or not the virus is present. “Thus, development of a vaccine to prevent KSHV would be the most effective weapon to control KS,” he says. “Unfortunately, little progress is being made on this front because the people afflicted by KSHV are those who are least able to pay for a new vaccine.” 

READ: Hh inhibitors a less invasive tx for BCC

Kaposi’s sarcoma and Merkel cell carcinoma represent two different poles in the spectrum of viral skin cancers, and the causative viruses behind these malignancies differ widely in prevalence, geographic distribution, UV-susceptibility, and other factors. Using DTS, Moore’s lab discovered Merkel cell polyomavirus (MCV), the likely cause of ~80% of Merkel cell carcinomas.

“MCV and Merkel cell carcinoma have an entirely different pattern from KSHV,” Dr. Moore explains.

MCV is the first polyomavirus to be found that is a likely cause of human cancer.

“We found MCV in 2008 by first sequencing a Merkel cell tumor and then subtracting all of the known human sequences using a computer, the central feature of DTS. This is very similar to the way that we found KSHV-except that we substituted a computer analysis for a biological technique.  Analyzing what was left revealed a new human polyomavirus, distantly related to the BK and JC viruses. Unlike KSHV, MCV is a near-ubiquitous asymptomatic skin infection that naturally occurs in children and young adults. Approximately 80% of people 50 years or older harbor this otherwise harmless infection. It causes no symptoms and it is part of our healthy skin flora. Under rare circumstances when MCV undergoes mutation, it will drive cell proliferation to form tumors. Again, those who lose immune control over the virus are at highest risk for development of a cancer.”

Lab researchers are characterizing the basic biology of this virus in host cell transformation, and are searching for other diseases that may be related to MCV infection. They are developing monoclonal antibodies and serologic tests that will be useful diagnostic markers for infection, and have recently found a unique mutation in tumor-derived MCV that sheds light on tumor cell evolution and the fundamental mechanism for Merkel cell carcinogenesis.

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Dr. Moore says that development of tests for early diagnosis and new approaches to therapy are most likely to be important in controlling Merkel cell carcinoma. He notes that while clinical trials using immune checkpoint inhibitors are at an early stage, they are highly encouraging, “since reawakening the immune system to target foreign viral antigens in these tumors is especially promising.”

NEXT: Foundation for future treatment

Caption of photo above: Photomicrograph of Merkel cell carcinoma Invasive skin Merkel cell carcinoma caused by Merkel cell polyomavirus (MCV T antigen, brown).

Foundation for future treatment

Discoveries are evolving rapidly, changing the face of current understanding and informing ongoing research. What we know today will surely influence how medicine is practiced in the immediate future, not to mention 10 or 20 years from now.

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“Finding the fundamental cause for a cancer is the first step in ultimately treating and curing it,” Dr. Moore says. Today’s understanding is the foundation for discovering those treatments and cures. “For the cancers I’ve mentioned, we now know the viral cause and scientists are working on new ways to target the virus rather than the cancer cell.” Dr. Moore is hopeful that this will result in new diagnostics, new therapeutics and in some cases new vaccines. Testing for MCV proteins in clinical tissues and sentinel biopsies of suspected MCC patients is now commonly used.

“When I was in medical school there were only two known human polyomaviruses, BK and JC,” Dr. Moore says. “Now there are at least 12 known human polyomaviruses. In addition to MCV, a research group in Holland has discovered one of these viruses to cause a rare skin disorder called trichodysplasia spinulosis. Our group at Pittsburgh have shown another one, HPyV7, to be the cause of a dyskeratosis and hyperplasia syndrome in transplant patients (resulting in the so-called keratinocyte ‘peacock plummage pattern’). We are only at the beginning stage in exploring when and how these ‘harmless’ viruses can cause disease.”  

Scientists are bound to find additional viral causes for many long-standing dermatologic disorders, Dr. Moore says. The future is white bright with potential. Dr. Moore believes that with breakthroughs in new immunologics and antiviral therapies, the next decade is poised for a revolution in diagnosis and treatment of previously intractable skin disorders.