Retroviruses cause cancers in a variety of animals and humans. Research on retroviruses has provided important insights into mechanisms of oncogenesis in humans, including the discovery of viral oncogenes and cellular proto-oncogenes. The subject of this review is the mechanisms by which retroviruses that do not carry oncogenes (non-acute retroviruses) cause cancers. The common theme is that these tumors result from insertional activation of cellular proto-oncogenes by integration of viral DNA. Early research on insertional activation of proto-oncogenes in virus-induced tumors is reviewed. Research on non-acute retroviruses has led to the discovery of new proto-oncogenes through searches for common insertion sites (CISs) in virus-induced tumors. Cooperation between different proto-oncogenes in development of tumors has been elucidated through the study of retrovirus-induced tumors, and retroviral infection of genetically susceptible mice (retroviral tagging) has been used to identify cellular proto-oncogenes active in specific oncogenic pathways. The pace of proto-oncogene discovery has been accelerated by technical advances including PCR cloning of viral integration sites, the availability of the mouse genome sequence, and high throughput DNA sequencing. Insertional activation has proven to be a significant risk in gene therapy trials to correct genetic defects with retroviral vectors. Studies on non-acute retroviral oncogenesis provide insight into the potential risks, and the mechanisms of oncogenesis.

Lung cancer is the leading cause of cancer deaths worldwide. While most cases are associated with cigarette smoking, 15% of cases in men and 53% in women occur in nonsmokers (39). Lung cancer in nonsmokers is most commonly diagnosed as adenocarcinoma (21). Jaagsiekte sheep retrovirus (JSRV) is the etiological agent of a contagious neoplasm in sheep termed ovine pulmonary adenocarcinoma (OPA) (35). OPA is derived from secretory epithelial cells, type II pneumocytes, and Clara cells and closely resembles bronchioloalveolar carcinoma (BAC) in humans (36,41). The similarities between OPA and BAC make JSRV and OPA a useful animal model for studying lung carcinogenesis.JSRV is unique because the envelope protein (Env, encoded by the env gene) is the oncogene. Expression of Env can transform cells in culture (2, 30, 43) as well as induce tumors in animals (38, 51). Initial studies illustrated the importance of the phosphatidylinositol 3-kinase (PI3K)-Akt-mTOR pathway in JSRV Env transformation. It is now clear that there are PI3K-dependent and -independent mechanisms of Akt-mTOR signaling. PI3K-dependent signaling was evident because JSRV Env-transformed cell lines have constitutively active Akt and inhibiting PI3K prevented transformation and caused reversion of the transformed phenotype (24,25,37,52). On the other hand, PI3K-independent Akt activation was later demonstrated, since cells in which PI3K was disabled could still be transformed by JSRV and, under these conditions, there was still activation of Akt (29).More recently, the H/N-Ras-MEK-mitogen-activated protein kinase (MAPK) pathway was found to play a more important role in JSRV Env transformation, since inhibiting MEK1 and H/N-Ras prevented transformation in NIH 3T3 and RK3E cell monolayers (28). Note that p38 MAPK has a negative role in JSRV Env transformation, as inhibiting p38 MAPK increases transformation. The finding that JSRV Env does not induce transformation solely through the PI3K-Akt-mTOR pathway is supported by the fact that not all OPA tissues demonstrate activated Akt (46). Together, these results underscore the complexity of JSRV Env transformation and the need to further understand the signaling pathways involved in transformation.Madin-Darby canine kidney (MDCK) epithelial cells grown in three-dimensional (3-D) culture by being embedded in Engelbreth-Holm-Swarm tumor extract (Matrigel) or collagen readily form spherical structures termed "acini." Acini grow as a single layer of polarized cells that are attached to the underlying basement membrane and enclose a central hollow lumen (7,26,33,34). Acinar structure and cell-cell and cell-environment interactions mimic what occurs in vivo. Maintenance of this highly ordered structure is critical for proper differentiated cell function, and when it is disrupted, malignancy can ensue. The events of MDCK acinus formation have been well defined and include cell polarization, secretion of basement membrane, formation of tight junctions, and responsiveness to apoptotic and proliferative suppressive si...

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