To summarize, high-risk HPVs encode oncogenic proteins that inactivate RB and p53, activate cyclin/ CDK complexes, and combat cellular senescence. Thus, it is evident that HPV proteins promote many of the hallmarks of cancer. The primacy of HPV infection in the causation of cervical cancer is confirmed by the effectiveness of HPV vaccines in preventing it. However, infection with HPV itself is not sufficient for carcinogenesis, and full-blown transformation requires the acquisition of mutations in host cancer genes, such as RAS. A high proportion of women infected with HPV clear the infection by immunologic mechanisms, but others do not, some because of acquired immune abnormalities, such as those that result from HIV infection. As might be expected, women who are coinfected with high-risk HPV types and HIV are at particularly high risk for developing cervical cancer.
EBV, a member of the herpesvirus family, was the first virus linked to a human tumor, Burkitt lymphoma. Burkitt lymphoma is an aggressive tumor that is endemic in certain parts of Africa and occurs sporadically elsewhere. In endemic areas, the tumor cells in virtually all affected patients carry the EBV genome. Since its initial discovery in Burkitt lymphoma some 50 years ago, EBV has been detected within the cells of a surprisingly diverse list of other tumors, including most nasopharyngeal carcinomas and a subset of T cell lymphomas, NK cell lymphomas, gastric carcinomas, and even, in rare instances, sarcomas, mainly in the immunosuppressed.
The manner in which EBV causes B cell tumors such as Burkitt lymphoma is complex and incompletely understood, but best appreciated by considering its effects on normal B cells. EBV uses the complement receptor CD21 to attach to and infect B cells. In vitro, such infection leads to polyclonal B cell proliferation and generation of immortal B lymphoblastoid cell lines. One EBV-encoded gene, LMP1 (latent membrane protein 1), acts as an oncogene, as proven by its ability to induce B cell lymphomas in transgenic mice. LMP1 promotes B cell proliferation, mimicking
Etiology of Cancer: Carcinogenic Agents233 the effects of a key surface receptor known as CD40. CD40 is normally activated by interaction with CD40 ligands expressed mainly on T cells. By contrast, LMP1 is constitutively active and stimulates signaling through the NF-κB and JAK/STAT pathways, both of which promote B cell proliferation and survival. Thus, the virus “borrows” a normal B cell activation pathway to promote its own replication by expanding the pool of infected cells. Another EBV-encoded protein, EBNA2, transactivates several host genes, including cyclin D and the SRC family of protooncogenes. In addition, the EBV genome contains a viral cytokine, vIL-10, that was pirated from the host genome. This viral cytokine can prevent macrophages and monocytes from activating T cells and killing virally infected cells. In immunologically normal persons, the EBV-driven polyclonal B cell proliferation is readily controlled by cytotoxic T cells, and the affected patient either remains asymptomatic or experiences a self-limited episode of infectious mononucleosis. However, a small number of EBV-infected B cells downregulate expression of immunogenic viral proteins such as LMP-1 and EBNA2 and enter a long-lived pool of memory B cells that persist  throughout life.
Given these observations, how then does EBV contribute to the genesis of endemic Burkitt lymphoma? One possibility is shown in
Fig. 6.34 . In regions of the world where
OUTGROWTH OF NEOPLASTIC CLONE: BURKITT LYMPHOMA