Specific chromosomal abnormalities characterize fibrosarcomas of bovine papillomavirus type 1 transgenic mice.

Abstract

In the BPV1.69 line of transgenic mice, the bovine papillomavirus type 1 genome elicits both benign dermal fibroblastic proliferation (fibromatoses) and malignant fibrosarcomas. Because these lesions arise only with time, nonviral factors appear to be involved. We have karyotyped several primary tumors as well as a series of low-passage cell lines derived both from fibromatoses and from fibrosarcomas. The fibrosarcomas, but not the preneoplastic fibromatoses, show consistent abnormalities of one or both of two chromosomes, chromosome 8 (trisomy or duplication) and chromosome 14 (monosomy or translocation). The chromosomal abnormalities are not a direct consequence of the viral integration, which we have mapped to chromosome 15 by in situ hybridization. These results suggest that transgenic mice can be used to study the role(s) of cytogenetic changes in tumorigenesis and may direct the search for genes involved in tumor progression.Papillomaviruses are thought to play important roles in the etiology of a variety of human malignancies, most notably in cervical cancers (1, 2). Studies of bovine papillomavirus type 1 (BPV-1) have provided much knowledge of the molecular biology of this group of DNA viruses (3). In its natural host BPV-1 induces benign fibropapillomas of the skin. In the laboratory BPV-1 transforms cultured mouse cells (4), and the products of two early viral genes, E5 and E6, have transforming properties (5,6). One recent approach to the systematic study of the multistep genesis of cancer has been to introduce oncogenes into the mouse genome with the purpose of reducing the number of steps required for tumor induction. Tumorigenesis in transgenic mice models the natural process in that different oncogenes heritably elicit specific types of tumors, and the tumors occur with a pattern that implies oncogenes are necessary but not sufficient for tumor formation (7).To dissect the relative participation of papillomaviruses and cellular factors in oncogenesis, Lacey et al. (8) produced a line of transgenic mice (BPV1.69 mice) using a plasmid containing a partial tandem duplication (1.69 copies) of the BPV-1 genome. At 8 or 9 mo of age, mice in this lineage develop two types of skin lesions, fibromatoses and fibrosarcomas (8, 9). The fibromatoses are characterized by dramatic, but benign, thickening of the dermis with concomitant atrophy of the epidermis and loss of hair. The fibrosarcomas are protuberant dermal tumors that invade locally but have not been seen to metastasize. Both the fibromatoses and the tumors contain extrachromosomal BPV-1 DNA and express viral RNA (10). In contrast, unaffected skin of the transgenic mice contains only integrated viral DNA that is not expressed (10). The state of the viral DNA and its expression thus distinguish normal skin from the fibromatoses and the fibrosarcomas but do not differentiate the two pathologic entities. These observations imply that alterations in cellular genes and/or their expression are involved in the development of malignant fibrosarcomas...

Loss of Mitotic Spindle Checkpoint Activity Predisposes to Chromosomal Instability at Early Stages of Fibrosarcoma Development

“…30 Importantly, although NF cells are diploid, fibromatoses may already present random chromosomal aberrations. 14 It might be possible that BPV-1 coded genes play a role in MSCCC inactivation in this tumor progression model. The transforming properties of BPV-1 reside in two genes, E5 and E6, that are transcribed already in MF cells, but not in NF cells, 13 correlating with the early alterations of mitotic checkpoint detected in MF cells.…”

“…These are normal fibroblast (NF) cells, two histological grades of hyperplasia, mild fibromatosis (MF) and aggressive fibromatosis (AF) cells, and dermal fibrosarcoma (FS) cells. 13 FS cells are characterized by consistent abnormalities of one or both of chromosomes 8 and 14, which correlate with tumorigenic potential and increased glucocorticoid receptor activity, 14,15 while random aneuploidy is already exhibited by fibromatoses cells. 14 We show here that activity of the mitotic checkpoint is altered at early stages of fibrosarcoma progression, that this results from unscheduled cyclin B metabolism and is associated with deregulated expression of Cks1, but that it is independent of p53 mutation.…”

“…13 FS cells are characterized by consistent abnormalities of one or both of chromosomes 8 and 14, which correlate with tumorigenic potential and increased glucocorticoid receptor activity, 14,15 while random aneuploidy is already exhibited by fibromatoses cells. 14 We show here that activity of the mitotic checkpoint is altered at early stages of fibrosarcoma progression, that this results from unscheduled cyclin B metabolism and is associated with deregulated expression of Cks1, but that it is independent of p53 mutation. These results demonstrate that loss of mitotic spindle checkpoint activity predisposes to chromosomal instability at early stages of fibrosarcoma development.…”

Strain‐dependency of Chromosomal Abnormalities in Lymphomas Developed in Eμ‐myc Transgenic Mice

“…[33][34][35] Transgenic or knockout mouse models of human carcinogenesis, together with advanced techniques of FISH analysis, such as spectral karyotyping (SKY), 36) may prove to be attractive tools for the study of genetic instability.…”

Transcription factors junB and c-jun are selectively up-regulated and functionally implicated in fibrosarcoma development.

“…A cytogenetic analysis revealed two types of karyotypic defects in fibrosarcoma but not fibromatosis cells: Chromosome 14 is monosomic or involved in translocations (in 60% of fibrosarcomas), and/or chromosome 8 is trisomic or partially duplicated (in 70% of fibrosarcomas) (Lindgren et al 1989). These observations imply a recessive locus on mouse chromosome 14, and genes with dominant properties on mouse chromosome 8.…”