The conundrum of causality in tumor virology: The cases of KSHV and MCV

Abstract

Controversy has plagued tumor virology since the first tumor viruses were described over 100 years ago. Methods to establish cancer causation, such as Koch’s postulates, work poorly or not at all for these viruses. Kaposi’s sarcoma herpesvirus (KSHV/HHV8) and Merkel cell polyomavirus (MCV) were both found using nucleic acid identification methods but they represent opposite poles in the patterns for tumor virus epidemiology. KSHV is uncommon and has specific risk factors that contribute to infection and subsequent cancers. MCV and Merkel cell carcinoma (MCC), in contrast, is an example in which mutations to our normal viral flora contribute to cancer. Given the near-ubiquity of human MCV infection, establishing cancer causality relies on molecular evidence that does not fit comfortably within traditional infectious disease epidemiological models. These two viruses reveal some of the challenges and opportunities for inferring viral cancer causation in the age of molecular biology.

Common Commensal Cancer Viruses

“…Unlike acute viral infections, in which common sense and simple epidemiology provide an answer as to whether or not an agent causes a disease, viral cancers have complex patterns of infection that reveal fundamental weaknesses in current epidemiologic theory [5,6]. …”

Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC

“…Furthermore, expression of the early viral proteins, i.e. the T antigens consisting of small T-Antigen (sT) and large T-Antigen (LT), can be detected in tumor tissues [23–26]. While both sT and LT are necessary for maintaining the oncogenic phenotype of MCPyV + MCC cell lines, sT appears to be more potent in transforming model cell lines such as rodent fibroblast cell lines [27–29].…”

“…To understand early events of viral integration and cellular transformation, an in vitro MCPyV replication model was developed which will allow to mimic these early events of virus-induced transformation [23, 26]. To understand MCC pathogenesis and in particular MCC metastasis formation, a spontaneous metastasis xenograft mouse model was used.…”

Large T and small T antigens of Merkel cell polyomavirus

“…Merkel cell polyomavirus (MCV) is the newest member of the short list of human cancer viruses [1,2], and is the only known human polyomavirus confirmed to be oncogenic [3–17]. While MCV was only discovered in 2008, polyomavirus research dates back over a half-century, beginning with the isolation of murine polyomavirus (MuPyV) [18] and later simian vacuolating virus 40 (SV40) [19,20].…”