A novel canine lymphoma cell line: A translational and comparative model for lymphoma research
Introduction
Spontaneously occurring lymphoma in the dog has many of the same histopathological, molecular, and clinical features as non-Hodgkin's lymphoma (NHL) in people [1], [2], [3]. Most of the lymphoma subtypes recognized in humans have histopathologically identical counterparts in the dog [4] and recent investigations show similar molecular characteristics in the two species [1], [5] (Kisseberth et al., submitted; Fosmire et al., submitted). Likewise, spontaneous lymphoma in the dog has a similar clinical presentation, response to chemotherapy, and clinical progression compared to NHL in people [1], [2], [3]. Until recently, utilization of spontaneous cancers in dogs as a model for human cancers was limited by the unavailability of reagents and techniques that could be used in the dog. However, recent advances in canine genomics, including sequencing of the dog genome, availability of gene microarrays, development of advanced cytogenetic and comparative genomic hybridization techniques and development of species-specific flow cytometry, FISH, and other antibody techniques now makes possible most of the experimental techniques that are routinely available for in vitro and in vivo use in humans and mice. Given these similarities and the advantage of larger subject size and presence of spontaneous disease (in contrast to small subject size and experimentally induced disease in xenograft and genetically modified mouse models of lymphoma); spontaneously occurring lymphoma in the dog represents an excellent large animal model for the study of lymphoma in people, including investigation of new therapeutic agents [1], [2], [3].
Laboratory study of spontaneous canine lymphoma has been severely limited by the lack of validated, well characterized, and widely disseminated cell lines. Those previously reported were either only partially characterized, were not widely distributed, or were established from leukemias, rather than lymphomas [6], [7], [8], [9], [10]. These canine hematopoietic cell lines include: 17–71, established from the lymph node of a dog with multicentric lymphoma, GL-1 established from a dog with B-cell leukemia, CL-1 established from the pleural fluid of a dog with thymic lymphoma, DLC-01 established from the lymph node of a dog with cutaneous lymphoma, and DLC-02 established from peripheral lymphocytes of a dog with large granular lymphocyte (LGL) leukemia [6], [7], [8], [9], [10]. As in humans, establishment of new lymphoma cell lines is difficult. To further accelerate the use of spontaneous cancers in dogs as a model system for new anticancer drug development and cancer cell biology, we established a novel T-cell lymphoma cell line. The cell line OSW was established from the malignant pleural effusion of a dog with peripheral T-cell lymphoma. The comparative molecular and biological properties of OSW, grown as a cell line and xenograft, are the subject of this study. The OSW cell line grows rapidly in vitro and is tumorigenic as a xenograft in SCID/NOD mice. The cell line has an oligoclonal TCRγ gene rearrangement, but does not express T-cell differentiation antigens. OSW contains several of the more common chromosomal aberrations reported previously in canine lymphoma [5], [11], [12] resulting in decreased copy number of p16/INK4a (also known as CDKN2A), RB1, and PTEN and increased copy number of MYC. As canine lymphoma has many similarities, both clinically and molecularly, to NHL in people, this cell line and xenograft will be useful for translational studies of novel therapeutics using spontaneous lymphoma in the dog as a model for human disease.
Section snippets
Case report
A 5.5-year-old male Airedale Terrier was referred to The Ohio State University Veterinary Teaching Hospital in February 2004 for evaluation of lethargy and mandibular lymphadenopathy. Thoracic radiographs showed severe pleural effusion with hilar lymphadenopathy. Thoracocentesis was performed and 1000 mL of serosanguinous fluid was removed. An abdominal ultrasound showed multicentric lymphadenopathy, small hypoechoic nodules throughout the spleen, and a diffusely hyperechoic and enlarged liver.
Morphology of primary lymphoma (peripheral lymph node, mediastinal mass, and malignant effusion)
The histopathological diagnosis of a peripheral lymph node biopsy from the dog was peripheral T-cell lymphoma. Immunohistochemical staining of the lymph node biopsy showed that the majority of neoplastic cells stained positive for CD3 and CD18 and were negative for CD20, CD79a, and BLA36, consistent with a T-cell origin. Twenty to thirty percent of the round cells stained positive for CD79a. These cells were morphologically distinct from the neoplastic cells and were interpreted as normal
Discussion
In this report we describe the establishment and characterization of a novel canine lymphoma cell line derived from the malignant pleural effusion of a dog with peripheral T-cell lymphoma. The dog initially presented with peripheral lymphadenopathy and pleural effusion and had a partial response to combination chemotherapy; however, the disease progressed rapidly, typical of most intermediate- and high-grade T-cell lymphomas seen commonly in the dog. The morphology of OSW cells was similar to
Acknowledgements
Canine lymphoma research at The Ohio State University is generously supported by grants from the American Kennel Club Canine Health Foundation and the Morris Animal Foundation (awarded to WCK). Canine molecular cytogenetics research at North Carolina State University is generously supported by grants from the National Institutes of Health, the American Kennel Club Canine Health Foundation and the Morris Animal Foundation (awarded to MB). The authors thank Jeremiah Meeks (cell culture), Marc
References (62)
- et al.
Spontaneous and genetically engineered animal models; use in preclinical cancer drug development
Eur J Cancer
(2004) - et al.
Establishment and characterization of a canine T-lymphoblastoid cell line derived from malignant lymphoma
Vet Immunol Immunopathol
(1997) - et al.
An immunophenotypic study of canine leukemias and preliminary assessment of clonality by polymerase chain reaction
Vet Immunol Immunopathol
(1999) - et al.
Genomic organization of the T-cell receptor gamma gene and PCR detection of its clonal rearrangement in canine T-cell lymphoma/leukemia
Vet Immunol Immunopathol
(2007) - et al.
Frequent T and B cell oligoclones in histologically and immunophenotypically characterized angioimmunoblastic lymphadenopathy
Am J Pathol
(2000) - et al.
Molecular and flow cytometric analysis of the Vbeta repertoire for clonality assessment in mature TCRalphabeta T-cell proliferations
Blood
(2001) - et al.
Recent advances in flow cytometry: application to the diagnosis of hematologic malignancy
Blood
(1997) - et al.
Peripheral T-cell lymphoma with aberrant expression of CD79a and CD20: a diagnostic pitfall
Mod Pathol
(2001) - et al.
Reciprocal chromosome painting reveals detailed regions of conserved synteny between the karyotypes of the domestic dog (Canis familiaris) and human
Genomics
(1999) - et al.
A complete comparative chromosome map for the dog, red fox, and human and its integration with canine genetic maps
Genomics
(1999)
Role of KIT and platelet-derived growth factor receptors as oncoproteins
Semin Oncol
Disruption of the multiple tumor suppressor gene MTS1/p16(INK4a)/CDKN2 by illegitimate V(D)J recombinase activity in T-cell acute lymphoblastic leukemias
Blood
Loss of p16/INK4A protein expression in non-Hodgkin's lymphomas is a frequent finding associated with tumor progression
Am J Pathol
From centrocytic to mantle cell lymphoma: a clinicopathologic and molecular review of 3 decades
Hum Pathol
Deletions and loss of expression of p16INK4a and p21Waf1 genes are associated with aggressive variants of mantle cell lymphomas
Blood
Continuous hematopoietic cell lines as model systems for leukaemia–lymphoma research
Leuk Res
The dog as a cancer model
Nat Biotechnol
Spontaneously occurring tumors of companion animals as models for human cancer
Cancer Invest
Classification of hematopoietic tumors of domestic animals
Chromosome aberrations in canine multicentric lymphomas detected with comparative genomic hybridisation and a panel of single locus probes
Br J Cancer
Canine lymphoma-associated antigens defined by murine monoclonal antibodies
Cancer Immunol Immunother
Establishment and characterization of a new canine B-cell leukemia cell line
J Vet Med Sci
Characterization of a canine long-term T cell line (DLC 01) established from a dog with Sezary syndrome and producing retroviral particles
Leukemia
Canine large granular lymphocyte leukemia and its derived cell line produce infectious retroviral particles
Vet Pathol
Diagnostic and prognostic importance of chromosomal aberrations identified in 61 dogs with lymphosarcoma
Vet Pathol
Predictive value of p16 or Rb inactivation in a model of naturally occurring canine non-Hodgkin's lymphoma
Leukemia
Lymphoma in the cat and dog
Comparison of tyrosinase-related protein-2, S-100, and Melan A immunoreactivity in canine amelanotic melanomas
Vet Pathol
Diagnosis of canine lymphoid neoplasia using clonal rearrangements of antigen receptor genes
Vet Pathol
The DAPI banded karyotype of the domestic dog (Canis familiaris) generated using chromosome-specific paint probes
Chromosome Res
Construction of a 2-Mb resolution BAC microarray for CGH analysis of canine tumors
Genome Res
Cited by (49)
Advanced diagnostic techniques
2022, Canine and Feline Cytopathology: A Color Atlas and Interpretation GuideEstablishment of a Patient-Derived Xenograft of Canine Enteropathy-Associated T-Cell Lymphoma, Large Cell Type
2017, Journal of Comparative PathologyEpithelial Cell Adhesion Molecule Expression in Canine Tumours
2016, Journal of Comparative PathologyCharacterization of a novel canine T-cell line established from a spontaneously occurring aggressive T-cell lymphoma with large granular cell morphology
2016, ImmunobiologyCitation Excerpt :Therefore, the opportunity to develop a preclinical spontaneous canine model or to obtain canine NK/T-cell line to assess novel therapeutic approaches for such lymphomas constitutes a major challenge. To date, twelve still available canine cell lines have been described and characterized according to their morphology, immunophenotype, pattern of TCR genes status and ability to induce tumours in mice (Kisseberth et al., 2007; Momoi et al., 1997; Nakaichi et al., 1996; Rutgen et al., 2010; Steplewski et al., 1987; Suter et al., 2005; Umeki et al., 2013; Yamazaki et al., 2008). Importantly, cell phenotype may change either from the primary material to the establishment of the cell line (Rutgen et al., 2010) or during in vitro maintenance (Umeki et al., 2013), leading to differences in the pattern of expression of specific markers.
Stearidonic acid, a plant-based dietary fatty acid, enhances the chemosensitivity of canine lymphoid tumor cells
2015, Biochemical and Biophysical Research CommunicationsAdvanced Diagnostic Techniques
2015, Canine and Feline Cytology: A Color Atlas and Interpretation Guide