Plasmacytomas in Mice

Abstract

A number of years ago it was fortuitously discovered that BALB/c mice carrying intraperitoneally implanted Millipore diffusion chambers containing C3H mammary tumor tissue developed plasmacytomas. Thinking that this process was a form of chronic immunization, we sought to find other means to chronically immunize BALB/c mice and this led us to use various immunologic adjuvant mixtures containing antigens. The best known of these was Freund’s Adjuvants (FA), a mineral oil in water emulsion. It was shown that adjuvants like FA (Lieberman’s Adjuvant containing staphylococcal antigens) also induced plasmacytomas. Later mineral oil alone was shown to be an effective inducing agent and no antigen needed to be added. The chronic immunization hypothesis appeared to be incorrect. Because of the ease of administration, mineral oils or chemically defined components of mineral oils such as pristane (2, 6, 10, 14 tetramethylpentadecane) became commonly used plasmacytoma inducing agents, even though the underlying mechanism of plasma cell tumor development remained obscure. Pristane is now the best studied agent. Although pristane can be found in fossil mineral oils, it is also generated biologically. Marine copepods metabolically convert the alkane phytane (of plant origin) into pristane.’ These organisms are consumed by filter feeding fishes and mammals. Whale livers consequently contain large amounts of pristane and are a source of the material used today. Pristane, like mineral oils is probably not effectively metabolized by mammals and for this reason it is regarded as an unlikely mutagen or carcinogen. The action of pristane as a plasma cell tumor inducing agent is indirect and appears to be related to its inflammatory properties in the peritoneal cavity. The presence of the oil in the peritoneal space stimulates the influx of large numbers of cells of the monocyte-macrophage series and neutrophils for the purpose of containing the foreign material. This influx is chronic and persists as long as there is free oil in the peritoneum. The mineral oils or pristane in the peritoneal cavity are emulsified into variable sized globules. Some of these are small enough to be phagocytized but other larger globules are surrounded by several cells5 The phagocytic cells that have engulfed or adhered to oil droplets in turn adhere to peritoneal surfaces on the mesentery, omentum, abdominal wall, diaphram, and pelvic fat. They provoke an angiogenic reaction from mesenteric blood vessels that leads to vascularization of much of the accumulating oil laden cells. The vascularized tissue is called an oil granuloma (OG).5 OG formation begins within a few days of the injection of pristane and continues to accumulate. Most of the surfaces of OG are covered by mesothelial cells. The importance of the OG to plasma cell tumor development is demonstrated by the fact that these tumors originate in this tissue, ie, the fully developed plasmacytoma and a series of progressive preneoplastic plasma cell proliferations are found within the OG. To cope with the continuous demand for phagocytic cells both in the peritoneal space and for renewal of cells in the fixed OG, there are probably major changes in hematopoiesis in the bone marrow. However, there have only been a few studies of the increased production of bone marrow precursors. Pietrangeli et al7 have described increased proliferation of B lymphocytes in the bone marrow after intraperitoneal (IP) mineral oil injection and it is assumed that macrophages and