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. An early oncogenic event in plasmacytomagenesis (PCTgenesis) 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 and where the chromosomal translocations take 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, i.e., in active B lymphocyte populations, e.g., Peyer's patches. Many of the steps in PCTgenesis take place in the chronic inflammatory microenvironment of the oil granuloma. Silicone gels are highly efficient inducers of the microenvironment that permits progression. In contrast, silicone fluids containing long chains are virtually ineffective. We are attempting to identify the active components and properties of silicone gels 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 plasmacytomagenic principal. A relatively high incidence of polyreactive myeloma proteins have been in silicone gel evoked PCTs. A second consistent tumor suppressor phenotype, i.e., loss of functional TGF-beta receptors has been identified. Pursuing the basis for the dramatic inhibition of PCTgenesis by the NSAID, indomethacin, we have found that PCT cells possess functional PGE2 receptors, but only develop modest elevations in intracellular cAMP, further PGE2 alone does not initiate cell death in PCTs, but PGE2 plus IBMX, or forskolin alone, both of which raise cAMP 2-3 fold higher do trigger cell death. We are using plasma cells that accumulate in lymph nodes of IL-6 transgenic mice as normal plasma cells which have functional TGF-beta receptors and develop elevated cAMP responses to PGE2.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC005596-29
Application #
6100827
Study Section
Special Emphasis Panel (LG)
Project Start
Project End
Budget Start
Budget End
Support Year
29
Fiscal Year
1998
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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