Tumor induction by human adenovirus type 12 in hamsters: loss of the viral genome from adenovirus type 12-induced tumor cells is compatible with tumor formation.

Abstract

The patterns of integration of adenovirus type 12 (Ad12) DNA in 39 virus‐induced hamster tumors were determined. Both the amount of Ad12 DNA persisting and the apparent sites of insertion differed from tumor to tumor. In 30 tumors, the intact Ad12 genome persisted in colinear arrangement and in multiple copies. In nine tumors, only the left‐ or the left‐ and right‐hand parts of the Ad12 genome persisted in the tumor cells. In three other cell lines the Ad12 genomes were lost completely during continuous passage in culture. A shift from epithelioid to fibroblastic morphology correlated with loss of Adl2 genomes. The cell line H1111(1) derived from an Ad12‐induced tumor had lost all viral DNA by the thirteenth subpassage, but was still oncogenic when reinjected into animals. This finding raises the question, to what extent persistence of the Ad12 genome is essential for the oncogenic phenotype. Tumor cells could be detected histologically inside local lymphatic vessels. In those experiments in which Ad12 preparations were used which contained sizeable proportions of the symmetric recombinant between Ad12 and KB cellular DNA (Deuring et al., 1981), tumors were observed in the nuchal region of the animals.

Plasmid-induced "hit-and-run" tumorigenesis in Chinese hamster embryo fibroblast (CHEF) cells.

“…Furthermore, there is no conclusive evidence that initiation of neoplasia is mediated by a viral protein (15). In the case of adenovirus, tumorigenicity can still be maintained despite the loss of all viral DNA from tumor-derived adenovirus-transformed cells (14). Another possible avenue of explanation for our results lies in the promoter-insertion model of tumorigenesis.…”

“…More recently, examples of hit-and-run transformation have been described following infection with herpes simplex virus (13) and with adenovirus 12 (14). In transformation by herpes simplex virus DNA, no unique set of viral genes seems to be consistently retained or expressed in the transformed cells, and similar results have been obtained with human cervical carcinoma, suggesting that viral DNA is not needed to maintain the transformed phenotype (13).…”

“Hit-and-Run” Transformation by Adenovirus Oncogenes

“…Consistent with the conventional concept of viral oncogenesis, it has been reported that cells transformed by E1A and E1B continuously express the whole set of viral oncoproteins (7,10,35). However, evidence from earlier work suggested that the permanent presence and stable expression of E1 gene products are not absolutely required to maintain the transformed phenotypes of some cells, implying that hit-and-run mechanisms may play a role during adenoviral oncogenesis (12,24). Moreover, Shenk and coworkers recently demonstrated that adenovirus E1A proteins can cooperate with the major immediate-early gene products (IE1 and IE2) of human cytomegalovirus (CMV) to mediate hit-and-run transformation of primary rat cells (28).…”

Lack of correlation between DNA methylation and transcriptional inactivation: the chicken lysozyme gene.

“…This last observation may be related to the general finding that cell lines have become more methylated upon passaging. Thus, the HD-11 cells may not be a reliable guide as to how methylation states relate to transcriptional activity (24,25).…”