The induction of plasmacytomas (PCTs) in the peritoneal cavity of BALB/cAn mice by plastics, paraffin oils or silicone gels is a model system for identifying the steps and stages of neoplastic development. The initial oncogenic event in this process is a chromosomal translocation that illegitimately recombines c-myc with an Ig locus gene resulting in deregulation of c-myc transcription. The focus of the work in the last year has been on determining when the initiating oncogenic mutation (a chromosomal translocation that deregulates c-myc transcription) takes place. Recent evidence from a highly sensitive nested PCR detection method indicates this step probably takes place before the introduction of the peritoneal inducing agent. Peritoneal PCT formation is dependent upon a susceptible genotype. Previous work has shown that genes on chromosome 4 contribute to this susceptibility by acting during the progression phase of the process. We have found evidence that DBA/2 genes located on chromosomes 5 and 15 also are associated with resistance to PCT induction by pristane. We seek to find the mechanism of action of these genes. Using PCR we now can ask whether there is also a genetic basis for developing the illegitimate recombinations of c-myc and Ig switch region sequence, or for influencing the number of these translocation events in normal B cell development. Continuing studies on the pathogenesis of PCT development initiated by different inducing agents have shown that silicone gels are highly efficient inducers of the microenvironment that permits progression. We are attempting to identify the active components and properties of the silicone gel that are responsible for PCT progression and have evidence that it is the chronic release of low molecular weight dimethylpolysiloxanes from the gel that is the plasmacytomagenesis principal. We have continued to investigate the mechanism of indomethacin inhibition of PCT induction by pristane and plastic discs and conclude that this treatment affects the stages of PCT development after the development of the T(12;15) myc deregulating translocation and the acquisition of autonomy. We continue to identify antigens that may be involved in PCT development and have found that silicones induce antibodies to cholesterol.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005596-27
Application #
2468437
Study Section
Special Emphasis Panel (LG)
Project Start
Project End
Budget Start
Budget End
Support Year
27
Fiscal Year
1996
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Casellas, Rafael; Yamane, Arito; Kovalchuk, Alexander L et al. (2009) Restricting activation-induced cytidine deaminase tumorigenic activity in B lymphocytes. Immunology 126:316-28
Potter, Michael (2007) The early history of plasma cell tumors in mice, 1954-1976. Adv Cancer Res 98:17-51
Park, Eun Sung; Shaughnessy Jr, John D; Gupta, Shalu et al. (2007) Gene expression profiling reveals different pathways related to Abl and other genes that cooperate with c-Myc in a model of plasma cell neoplasia. BMC Genomics 8:302
Kim, Byung-Gyu; Li, Cuiling; Qiao, Wenhui et al. (2006) Smad4 signalling in T cells is required for suppression of gastrointestinal cancer. Nature 441:1015-9
Potter, Michael (2003) Neoplastic development in plasma cells. Immunol Rev 194:177-95
Janz, Siegfried; Potter, Michael; Rabkin, Charles S (2003) Lymphoma- and leukemia-associated chromosomal translocations in healthy individuals. Genes Chromosomes Cancer 36:211-23
Potter, M; Jones, G; Dubois, W et al. (2000) Myeloma proteins that bind Hsp65 (GroEL) are polyreactive and are found in high incidence in pristine induced plasmacytomas. Curr Top Microbiol Immunol 252:265-71
Potter, M; Melchers, F (2000) Opinions on the nature of B-1 cells and their relationship to B cell neoplasia. Curr Top Microbiol Immunol 252:307-24
Potter, M (1999) Indomethacin inhibition of pristane plasmacytomagenesis in genetically susceptible inbred mice. Adv Exp Med Biol 469:151-6
Potter, M; Wax, J S; Hansen, C T et al. (1999) BALB/c.CBA/N mice carrying the defective Btk(xid) gene are resistant to pristane-induced plasmacytomagenesis. Int Immunol 11:1059-64

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