For 40 years following the discovery of the first tumor virus by Peyton Rous in 1911, viruses were viewed as peculiar infectious agents capable of inducing cancer in animals but having no relevance to humans. However, by the end of the 20th century, compelling evidence had accumulated that six different human viruses, including EBV, HBV, HPV, HTLV-1, HCV, and KSHV, were bona fide etiologic agents of human cancer and caused 15% to 20% of all human tumors worldwide (refs. 57
; ). During this time, tumor viruses also proved their worth as powerful tools for revealing fundamental molecular events that trigger the development of all human cancers, regardless of etiology. Both RNA and DNA tumor viruses contributed distinct insights into this disease process by revealing central roles for cellular oncogene activation and tumor suppressor gene inactivation, respectively. Most known cellular oncogenes have been identified through studies of RNA tumor viruses, whereas identification of the p53 tumor suppressor and many functions of the Rb tumor suppressor were gleaned through studies of DNA tumor viruses. Without these seminal contributions of tumor virology, it is difficult to envision that our understanding of cancer would be revealed at the depth that we appreciate today. In the 21st century, it is expected that tumor viruses will continue to serve as tools for discovery. As one example, findings indicate that oncoproteins encoded by adenovirus, HPV, and HTLV-1 commonly target and block the function of cellular factors required for the establishment of proper cell polarity (Dlg1, Scribble, PATJ, ZO-2; ), a property lost in nearly all epithelial-derived cancer cells (106
). Thus, given accumulating evidence suggesting that loss of cell polarity directly contributes to malignant progression (107
), studies of tumor viruses may aid in revealing how this common defect contributes to the development of many human cancers.
We anticipate that the list of human tumor viruses will grow considerably longer in the future. This will include recognition of known viruses having a role in human cancer, as well as identification of new candidate cancer viruses through the use of modern molecular technology. In particular, there is emerging interest in the polyomaviruses as possible human carcinogens (refs. 108
; ). SV40, which naturally infects the rhesus monkey, was inadvertently introduced into the human population as a contaminant of early poliovirus vaccines, whereas the BK and JC polyomaviruses are natural human pathogens associated with disease processes in the urinary tract or brain, respectively. DNA sequences of these three polyomaviruses, which are tumorigenic under experimental conditions, have been detected in mesothelioma, osteosarcoma, non–Hodgkin lymphoma, brain tumors, and prostate cancer. In addition, an integrated form of a new polyomavirus, Merkel cell polyomavirus, was recently observed in Merkel cell carcinoma, a rare but aggressive human skin cancer of neuroendocrine origin (110
Several other candidate human tumor viruses have also been documented (105
). Although early investigations failed to associate adenovirus with human cancer, a recent study found adenoviral DNA in pediatric brain tumors. Human endogenous retroviruses, which are sequences resembling infectious retroviruses in the human genome, have been shown to display increased viral mRNA and protein expression as well as retrovirus-like particle production in seminomas, breast cancer, myeloproliferative disease, ovarian cancer, melanoma, and prostate cancer. Likewise, particles of human mammary tumor virus, a retrovirus similar to mouse mammary tumor virus, were detected in primary human breast cancer cells. Finally, protein expression by a newly discovered xenotropic murine leukemia virus–related virus was found in the stroma of human prostate tumors, and DNA sequences of torque teno virus were observed in myeloma and cancers of the gastrointestinal tract, lung, and breast. As the mere presence of viral sequences is insufficient to conclude that a virus contributes to tumor formation, the causal role of these viruses in human cancer remains unresolved. It is challenging and usually requires years of research to achieve wide acceptance of the viral causation for a given human cancer (31
). The challenge is even greater if only a subset of the cancers in question have a viral etiology. Nonetheless, we predict that, in the 21st century, viruses will be associated with substantially more than the current estimate of 15% to 20% of all human cancers.
Many tumor viruses play an essential role in both the early initiation and subsequent progression of cancer, as evidenced by a requirement for viral oncogene functions at all stages of the neoplasm. Nonetheless, in the future, more consideration must be given to the possibility that viral functions required for early tumor initiation may occasionally become dispensable upon the selection of more growth-autonomous tumor cells, thereby permitting the loss of viral sequences during progression to late stage tumors. Although this so-called “hit-and-run” mechanism for carcinogenesis is intrinsically difficult to prove, the recent demonstration that certain viral oncoproteins (e.g., HPV E7 and HTLV-1 Tax) induce mutations and reduce genomic stability by impairing the cellular DNA repair system support this concept (105
). Such effects could conceivably increase the rate at which mutations accumulate in growth-regulatory genes, thereby promoting tumor formation independent of a need for the continued presence of viral sequences. Another scenario that must also be considered is that viral sequences and viral gene expression are maintained in only a small fraction of cancer cells, which secrete factors that promote abnormal proliferation of surrounding uninfected cells in a tumor. These proposed mechanisms challenge the widely held belief that viral sequences will be found in every cell if the virus is etiologically important in the genesis of the tumor.
Prophylactic vaccines are the most effective approach in the prevention of viral disease because they induce antibodies that efficiently neutralize viruses prior to the establishment of an acute or chronic infection. Prophylactic vaccination also offers the potential to prevent cancers having a viral etiology, as has been shown for both HBV-associated and HPV-associated diseases. The latter successes warrant that a major emphasis be placed on the development of new vaccines against other human tumor viruses, given that such efforts represent an opportunity to decrease the incidence of cancer worldwide. It is possible that new targets will be identified from viral pathogenesis studies to prompt the development of antiviral drugs to treat chronic infections by human tumor viruses. If such infections could be controlled or eliminated, the subsequent development of virus-induced cancer in the host would be reduced.
Viruses have also been used as therapeutic tools to augment conventional cancer chemotherapy or immunotherapy. One approach has been the use of oncolytic viruses capable of killing cancer cells but not normal cells. A virus that has already shown some therapeutic promise is the oncolytic adenovirus mutant Onyx-015 (111
). The ability of the adenovirus to replicate lytically in normal cells depends on the viral E1B
gene and its ability to promote late viral gene expression required for progeny virus production and to shut off host cell gene expression. Onyx-015 carries an E1B
gene mutation that prevents lytic replication in normal cells but permits selective lytic replication in cancer cells, which in general, conveniently complement the Onyx-015 E1B
replication deficiency. In a phase II trial for patients with head and neck tumors, intratumoral injection of Onyx-015 combined with systemic chemotherapy caused 19 out of 30 tumors to decrease in size by 50% or more and 8 tumors to completely regress. Other types of oncolytic viruses in development include vaccinia, herpes simplex virus type 1, reovirus, and Newcastle disease virus (112
). Viral vectors are likewise being used to deliver therapeutic genes designed to kill or block the growth of tumor cells or boost the immune system to target and destroy such cells. Although oncolytic viruses and viral vectors are at early stages of development and many limitations must still be solved, these approaches are expected to yield significant therapeutic benefits in the treatment and prevention of human cancers in the 21st century.
In sum, tumor virology has played a central role in cancer research since the middle of the 20th century. Viruses have been identified as infectious causes of specific human cancers and have advanced our general understanding of the molecular basis of carcinogenesis. We predict that tumor virology will continue to be an invaluable partner in cancer research efforts in the 21st century.