Merkel cell carcinomaWe know that viruses cause a significant minority of human cancers, but we don’t know quite how many, or which, cancers are viral. It’s not as easy as you might think to tell.

The link between viruses and cancer was one of the major breakthroughs in cancer biology, but you could also make a case that that link set cancer research back several years. (Cancer viruses were shown, in chickens, in 19111, but it wasn’t until the 1960s that interest in the concept took off, with Epstein’s demonstration of Epstein-Barr virus (EBV)2 in some human tumors. ) Studying viral oncogenesis has led to huge advances in our understanding of the fundamental biology of cancers. The problem was that there was a general assumption, in the 1960s and 1970s, that viruses were directly responsible for the vast majority of human tumors. If so, all we needed to do was to identify the viruses, develop vaccines against them, and voila! No more cancer!

Of course, it wasn’t that easy. For all the fundamental advances from this concept, it’s been relatively unproductive as far as the bedside is concerned. Most human tumors are not caused by viruses,3 and even those that are, have been really resistant to treatment via direct anti-viral approaches.4 The research units that were established in the 1970s to look at the virus/tumor connection have mostly either disbanded, or taken a different direction now.

Mouse polyomavirus
Mouse polyomavirus

In spite of that, there’s still new and exciting stuff coming out. Most recently,5 Yuan Chang and Patrick Moore identified a new cancer-causing virus of humans. (This was their second breakthrough virus; in 19946 they also found the second-most recent cancer-causing virus of humans, Kaposi’s Sarcoma Herpesvirus.)) This brings to six the number of clearly-linked human cancer viruses: papillomaviruses, HTLV-1, hepatitis B virus, EBV, Kaposi’s Sarcoma Herpesvirus, and the new one, Merkel cell polyomavirus.

I keep meaning to talk about the discovery of Merkel cell polyomavirus, but I’ll set that aside for now. Very briefly, last fall Chang and Moore showed that the presence of the virus is linked to a fairly rare tumor, Merkel cell carcinoma, and they and others have now confirmed the epidemiological association and demonstrated a mechanism for causing tumors. We’re at the stage now of trying to understand the normal biology of the virus. As with most (and all human) cancer viruses, the virus is much more widespread than the tumor. How widespread it is? How does it spread? Does it cause other disease — in particular, is it involved in other tumors?

That last is a particularly interesting question, because although Merkel cell tumors are rare, there are a number of common tumors that could, conceivably, also be caused by the virus; and if the virus causes even a subset of those, then it could be a common cause of cancer rather than an unusual one. So far, though, I think the evidence suggests that the virus is fairly limited in the damage it causes; quite a few groups have looked for the virus in other types of cancer, and although it may be occasionally found7, that most likely reflects general background infection with the virus rather than a causative role.

One exception is a recent paper8 which suggested that the virus might be associated with a subset of squamous cell carcinomas. SCC are a pretty common form of skin tumor, so if MCPyV is a cause of even a subset of SCC it might be a significant cause of cancer.

The problem is that the other studies on MCPyV have shown that it’s out there even in normal, non-diseased humans9 — as you’d expect; the virus must be able to spread and circulate within the human population somehow, and the version of the virus found in Merkel cell tumors is damaged and likely can’t spread, so there must be virus replicating in normal tissues. In this paper, the authors find the virus in a subset of SCC cancers, but I would like to know how many they’d find in normal human skin using the same techniques —  the 15% of positive tumor samples may or may not be significantly different. On the other hand, the SCC-associated virus did show a similar molecular signature to that found in Merkel cell cancer,10 suggesting a causative role. Right now, I’m not completely convinced, but am definitely intrigued.

One really interesting point to add is that — if MCPyV really does cause a significant number of tumors — then it’s been missed all these years, despite high interest in searching for human cancer viruses, until new techniques were applied to the right samples in the right way. Are there other human cancer viruses out there, waiting for the right technique? Is it still possible that most human cancers are caused by viruses? I think that’s pretty unlikely, but the door is still open a crack.

  1. A sarcoma of the fowl transmissible by an agent separable from the tumor cells. Rous, P. 1911. J. Exp. Med. 13:397–411.[]
  2. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. MA Epstein, BG Achong and YM Barr. Lancet 1 (1964), pp. 702–703.[]
  3. The usual educated guess is 20%[]
  4. One major exception, of course, being papilloma virus vaccines, which are a direct outcome of this line of research. But it’s taken a long time to come to fruition. You could also point to vaccination against hepatitis B virus, and a number of veterinary vaccines, as clinical advances arising from the virus/cancer research. But I think it’s fair to say that the energy put into this has been fundamentally, but not clinically, well spent.[]
  5. Feng, H., Shuda, M., Chang, Y., & Moore, P. (2008). Clonal Integration of a Polyomavirus in Human Merkel Cell Carcinoma Science, 319 (5866), 1096-1100 DOI: 10.1126/science.1152586[]
  6. Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi’s sarcoma.
    Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS.
    Science. 1994 Dec 16;266(5192):1865-9.[]
  7. For example, Human Merkel cell polyomavirus infection I. MCV T antigen expression in Merkel cell carcinoma, lymphoid tissues and lymphoid tumors.
    Shuda M, Arora R, Kwun HJ, Feng H, Sarid R, Fernández-Figueras MT, Tolstov Y, Gjoerup O, Mansukhani MM, Swerdlow SH, Chaudhary PM, Kirkwood JM, Nalesnik MA, Kant JA, Weiss LM, Moore PS, Chang Y.
    Int J Cancer. 2009 Sep 15;125(6):1243-9[]
  8. Dworkin, A., Tseng, S., Allain, D., Iwenofu, O., Peters, S., & Toland, A. (2009). Merkel Cell Polyomavirus in Cutaneous Squamous Cell Carcinoma of Immunocompetent Individuals Journal of Investigative Dermatology DOI: 10.1038/jid.2009.183[]
  9. Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays.
    Tolstov YL, Pastrana DV, Feng H, Becker JC, Jenkins FJ, Moschos S, Chang Y, Buck CB, Moore PS.
    Int J Cancer. 2009 Sep 15;125(6):1250-6[]
  10. Shuda, M., Feng, H., Kwun, H., Rosen, S., Gjoerup, O., Moore, P., & Chang, Y. (2008). T antigen mutations are a human tumor-specific signature for Merkel cell polyomavirus Proceedings of the National Academy of Sciences, 105 (42), 16272-16277 DOI: 10.1073/pnas.0806526105 []