Breen, M and Modiano, JF. Evolutionarily conserved cytogenetic changes in hematological malignancies of dogs and humans-man and his best friend share more than companionship. Chromosome Res 16: 145-154

Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC, 27606, USA.
Chromosome Research (Impact Factor: 2.48). 02/2008; 16(1):145-54. DOI: 10.1007/s10577-007-1212-4
Source: PubMed


The pathophysiological similarities shared by many forms of human and canine disease, combined with the sophisticated genomic resources now available for the dog, have placed 'man's best friend' in a position of high visibility as a model system for a variety of biomedical concerns, including cancer. The importance of nonrandom cytogenetic abnormalities in human leukemia and lymphoma was recognized over 40 years ago, but the mechanisms of genome reorganization remain incompletely understood. The development of molecular cytogenetics, using fluorescence in situ hybridization (FISH) technology, has played a significant role in our understanding of cancer biology by providing a means for 'interrogating' tumor cells for a variety of gross genetic changes in the form of either numerical or structural chromosome aberrations. Here, we have identified cytogenetic abnormalities in naturally occurring canine hematopoietic tumors that are evolutionarily conserved compared with those that are considered characteristic of the corresponding human condition. These data suggest that humans and dogs share an ancestrally retained pathogenetic basis for cancer and that cytogenetic evaluation of canine tumors may provide greater insight into the biology of tumorigenesis.

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Available from: Matthew Breen, Oct 09, 2015
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    • "As for such human cancers, canine HS involves the proliferation of members of both histiocytic lineages; dendritic cells and macrophages [5], [6]. The dog is genetically closer related to man than mice [7], [8] and the study of genetic changes of spontaneous cancers in the dog therefore has high comparative value [3], [9], in particular for cancers that are rare in the human such as histiocytic malignancies [10], [11]. Research could lead to more insight in the pathogenesis of this disease and could facilitate the identification of therapeutic targets valuable for both species [4], [7], [12]–[15]. "
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    ABSTRACT: Examination of gene functions in specific tumor types improves insight in tumorigenesis and helps design better treatments. Due to the rarity of histiocytic/dendritic cell sarcoma in humans, it is difficult to accrue such knowledge. Therefore, comparative research of these cancers in predisposed dog breeds, such as the Flatcoated retriever, can be of value. Histiocytic sarcoma in the dog can be grouped into a soft tissue- and visceral form. The soft tissue form at first is localized, while the visceral form progresses more quickly to a terminal state, which might be related to variations in gene expression. Microarray analyses were performed on fresh-frozen tissue from Flatcoated retrievers with either soft tissue- or visceral histiocytic sarcoma. Expression differences of ten most significantly differentially expressed genes were validated with quantitative real-time PCR (q PCR) analyses. Q PCR analyses confirmed the significantly aberrant expression of three of the selected genes: C6 was up-regulated; CLEC12A and CCL5 were down-regulated in the visceral histiocytic sarcoma compared to the soft tissue form. The findings of our study indicate that these two forms of histiocytic sarcoma in the dog display a variation in gene expression and warrant analysis of functional changes in the expression of those genes in these rare sarcomas in man.
    PLoS ONE 06/2014; 9(6):e98258. DOI:10.1371/journal.pone.0098258 · 3.23 Impact Factor
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    • "Pet dogs that develop Non-Hodgkins Lymphoma (NHL) are recognized as a clinically relevant, spontaneous large animal model of the human disease [25], [27]–[31]. Gene expression analysis of primary canine B cell lymphoma tissue has revealed germinal center and post-germinal center, ABC-like DLBCL subsets with the latter characterized by the presence of phosphorylated p65 and increased expression of NF-κB target genes [29]. Furthermore, tissue microarrays from lymphomatous canine tissue confirmed the presence of constitutive NF-κB activity and pharmacological inhibition of IKK leads to increased cytotoxicity in canine B cell lines [28]. "
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    ABSTRACT: Activated B-Cell (ABC) Diffuse Large B-Cell Lymphoma (DLBCL) is a common, aggressive and poorly chemoresponsive subtype of DLBCL, characterized by constitutive canonical NF-κB signaling. Inhibition of NF-κB signaling leads to apoptosis of ABC-DLBCL cell lines, suggesting targeted disruption of this pathway may have therapeutic relevance. The selective IKK inhibitor, NEMO Binding Domain (NBD) peptide effectively blocks constitutive NF-κB activity and induces apoptosis in ABC-DLBCL cells in vitro. Here we used a comparative approach to determine the safety and efficacy of systemic NBD peptide to inhibit constitutive NF-κB signaling in privately owned dogs with spontaneous newly diagnosed or relapsed ABC-like DLBCL. Malignant lymph nodes biopsies were taken before and twenty-four hours after peptide administration to determine biological effects. Intravenous administration of <2 mg/kg NBD peptide was safe and inhibited constitutive canonical NF-κB activity in 6/10 dogs. Reductions in mitotic index and Cyclin D expression also occurred in a subset of dogs 24 hours post peptide and in 3 dogs marked, therapeutically beneficial histopathological changes were identified. Mild, grade 1 toxicities were noted in 3 dogs at the time of peptide administration and one dog developed transient subclinical hepatopathy. Long term toxicities were not identified. Pharmacokinetic data suggested rapid uptake of peptide into tissues. No significant hematological or biochemical toxicities were identified. Overall the results from this phase I study indicate that systemic administration of NBD peptide is safe and effectively blocks constitutive NF-κB signaling and reduces malignant B cell proliferation in a subset of dogs with ABC-like DLBCL. These results have potential translational relevance for human ABC-DLBCL.
    PLoS ONE 05/2014; 9(5):e95404. DOI:10.1371/journal.pone.0095404 · 3.23 Impact Factor
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    • "Based upon a fundamental and evolutionarily conserved association between cytogenetic abnormalities and tumor phenotype in different species [10], [57] these genes may be of major interest in the study of histiocytic malignancies in the human as well. There exists a great difference in incidence of histiocytic malignancies between this specific dog breed as compared to the human. "
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    ABSTRACT: The determination of altered expression of genes in specific tumor types and their effect upon cellular processes may create insight in tumorigenesis and help to design better treatments. The Flatcoated retriever is a dog breed with an exceptionally high incidence of histiocytic sarcomas. The breed develops two distinct entities of histiocytic neoplasia, a soft tissue form and a visceral form. Gene expression studies of these tumors have value for comparable human diseases such as histiocytic/dendritic cell sarcoma for which knowledge is difficult to accrue due to their rare occurrence. In addition, such studies may help in the search for genetic aberrations underlying the genetic predisposition in this dog breed. Microarray analysis and pathway analyses were performed on fresh-frozen tissues obtained from Flatcoated retrievers with localized, soft tissue histiocytic sarcomas (STHS) and disseminated, visceral histiocytic sarcomas (VHS) and on normal canine spleens from various breeds. Expression differences of nine genes were validated with quantitative real-time PCR (qPCR) analyses. QPCR analyses identified the significantly altered expression of nine genes; PPBP, SpiC, VCAM1, ENPEP, ITGAD (down-regulated), and GTSF1, Col3a1, CD90 and LUM (up-regulated) in the comparison of both the soft tissue and the visceral form with healthy spleen. DAVID pathway analyses revealed 24 pathways that were significantly involved in the development of HS in general, most of which were involved in the DNA repair and replication process. This study identified altered expression of nine genes not yet implicated in histiocytic sarcoma manifestations in the dog nor in comparable human histiocytic/dendritic sarcomas. Exploration of the downside effect of canine inbreeding strategies for the study of similar sarcomas in humans might also lead to the identification of genes related to these rare malignancies in the human.
    PLoS ONE 08/2013; 8(8):e71094. DOI:10.1371/journal.pone.0071094 · 3.23 Impact Factor
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