Paraneoplastic Syndromes in Experimental Animal Model Systems*

Abstract

Altered physiological states observed in tumor-bearing animals that involve a variety of changes in various organ systems are well known to the laboratory investigator and are usually referred to as "tumor-host relationships." Although a rather impressive literature that documents these relationships has accumulated, investigators who utilize experimental animals have usually focused relatively little attention on the "clinical course" of cancer in these laboratory animals. Instead, their attention has been directed primarily toward etiological factors. The clinical oncologist, conversely, must realistically concentrate on how to control growth of the neoplasm and the accompanying systemic physiological alterations that are expressed in the form of signs and symptoms. Thus, the documentation, in this monograph, of the numerous elegant studies and observations on tumor-host relationships in man has been long expected. Furthermore, the identification and focus of attention on these physiological alterations by defining them as "paraneoplastic syndromes" will undoubtedly create a greater awareness and hopefully provide additional information as to the mechanisms involved.In this regard, however, clinical investigative studies are hampered, in part, by the real and apparent spectrum of host responses that occur with tumors that arise in the same or different tissues, thus presumably reflecting the limited numbers and heterogeneity of the population being studied. Perhaps, herein lies the major contribution of animal studies in attempting to elucidate the nature of paraneoplastic syndromes, namely, the opportunity provided by the use of genetically inbred strains of mice and rats to maintain a controlled and defined genetic background upon which a given tumor-host relationship can be studied. By maintaining a constant host genetic substrate upon which a given tumor cell population of similar genetic constitution (at least originally) can interact with subsequent expressions of definable and consistent responses of both host and tumor, one can establish reproducible model systems for a given tumor-host interaction. This, in turn, permits for a more thorough dissection of a given phenomenon at all levels of structural and functional integration. Thus, questions can be posed that pertain to a given paraneoplastic syndrome with respect to altered cellular and subcellular functions, in addition to the possible development of diagnostic techniques and therapy.One can, at this point, raise a question about the usefulness of experimental animal studies in attempting to understand the nature of paraneoplastic syndromes, because in man these altered physiological events basically represent clinical manifestations of the response of the host to an autochthonous neoplasm. This is in contrast, of course, to the majority of tumor-host animal studies that 547 548 Annals New York Academy of Sciences have utilized the transplanted tumor system, that is, the abrupt imposition upon essentially young healthy animals of the challenge of a...

Trials, Tribulations, and Trends in Tumor Modeling in Mice

“…Paraneoplastic syndromes typically result in clinical manifestations of altered physiological responses to autochthonous (spontaneous) neoplasms. These syndromes in mouse models of neoplasia have been seldom described (Liebelt et al, 1974) even though they exist. This oversight is brought on by the focused and short-term nature of most studies.…”

“…This type of study design neglects important interactions of the host with tumor receptor expression and secretions produced by tumor cells or by stimulation of host cells by the tumor. Paraneoplastic syndromes include extramedullary hematopoiesis, bone marrow hyperplasia, peripheral granulocytosis and leukocytosis (leukemoid reactions), thrombocytosis, anemia, altered lipid metabolism, hypercalcemia of malignancy, hypoglycemia, cachexia and organomegaly in nontumor-bearing tissues (Liebelt et al, 1974;Castillo et al, 1982;Yoneda et al, 1991;Tanaka et al, 1996;Diament et al, 1998, Schuh, unpublished data). Paraneoplastic syndromes represent potential models for similar syndromes in humans but causation are poorly characterized and effects of these syndromes on pharmacology, safety, and efficacy studies using experimental tumors are unknown.…”