Comparative animal models for the study of lymphohematopoietic tumors: strengths and limitations of present approaches

Abstract

The lymphomas probably represent the most complex and heterogenous set of malignancies known to cancer medicine. Underneath the single term lymphoma exist some of the fastest growing cancers known to science (i.e Burkitt's and lymphoblastic lymphoma), as well as some of the slowest growing (i.e. small lymphocytic lymphoma [SLL] and follicular lymphoma). It is this very biology that can dictate the selection of drugs and treatment approaches for managing these patients, strategies that can range from very aggressive combination chemotherapy administered in an intensive care unit (for example, patients with Burkitt's lymphoma), to watch and wait approaches that may go on for years in patients with SLL. This impressive spectrum of biology emerges from a relatively restricted number of molecular defects. The importance of these different molecular defects is of course greatly influenced by the intrinsic biology that defines the lymphocyte at its different stages of differentiation and maturation. It is precisely this molecular understanding that is beginning to form the basis for a new approach to thinking about lymphoma, and novel approaches to its management. Unfortunately, while our understanding of human lymphoma has blossomed, our ability to generate appropriate animal models reflective of this biology has not. Most preclinical models of these diseases still rely upon sub-cutaneous xenograft models of only the most aggressive lymphomas like Burkitt's lymphoma. While these models clearly serve an important role in understanding biology, and perhaps more importantly, in identifying promising new drugs for these diseases, they fall short in truly representing the broader, more heterogenous biology found in patients. Clearly, depending upon the questions being posed, or the types of drugs being studied, the best model to employ may vary from situation to situation. In this article, we will review the numerous complexities associated with various animal models of lymphoma, and will try to explore several alternative models which might serve as better in vivo.

Subcutaneous passage increases cell aggressiveness in a xenograft model of diffuse large B cell lymphoma

“…The difficulty of DLBCL cells to engraft and disseminate after intravenous injection in immunodeficient mice has been described by other authors [16]. As a consequence of this difficulty, new drugs against DLBCL are generally tested in subcutaneous DLBCL xenografts [3] or in disseminated lymphoma models generated with intravenous injection of the aggressive Burkitt's lymphoma cells [5][6][7]. Genetically engineered mice (GEM) can also develop disseminated DLBCL [17][18][19] and they are very useful to evaluate the function of particular genes in tumour progression.…”

“…Approximately 60% of patients with DLBCL present a widespread disease at diagnosis [2]. Most animal models that are used to test new drugs against DLBCL, however, still rely on subcutaneous xenografts [3], that mainly show only localized tumours. More disseminated xenograft lymphoma models are achieved after intravenous administration of the aggressive human Burkitt's lymphoma cells in SCID mice [4].…”

Dissecting the Regulatory Microenvironment of a Large Animal Model of Non-Hodgkin Lymphoma: Evidence of a Negative Prognostic Impact of FOXP3+ T Cells in Canine B Cell Lymphoma

“…There is thus an urgent need to develop novel, targeted therapies for this group of diseases, driven by advances in our understanding of their pathogenesis and specific prognosis. Current rodent models of lymphoma are far from predictive of the natural course of the human disease, relying either on the subcutaneous implantation of xenogeneic lymphoma cells into immune-compromised mice, or on genetic manipulations that artificially increase the likelihood of lymphoma in a monogenic fashion [4]. Key to advancing the field will be the development of natural, polygenic animal models of NHL, allowing the further interrogation of molecular and cellular pathogenesis, as well as trials of novel anti-cancer agents.…”

Association of Morphology and Immunophenotype in Diffuse Large B-Cell Lymphomas with Bone Marrow Infiltration in a Sample Mexican Population

“…These alterations are observed at the origin of the errors occurring during physiological events involved in the diversification repertoire of the germinal center, during class switch recombination (CSR) or somatic hypermutation (SHM) [28,29]. Experimental studies on animal models have confirmed the critical roll played by the induced activation of the cytidine deaminase enzyme in the physiology of CSR and SHM in the development of lymphoid tumors [30,31].…”