01113: Canine Non-Hodgkin Lymphoma: Characterization and Prognostic Value of Cancer Stem Cells
Grant Status: Closed
Project Summary
Stem cells are cells which, in general, have the ability to give rise to multiple different (differentiated) cell types while at the same time maintaining their own population of undifferentiated stem cells. Embryonic stem cells are the quintessential stem cell and have the ability to form any tissue of the embryo, fetus, and adult. However, in the adult animal, most tissues or organs also have a stem cell population (adult stem cells) with a more limited repertoire, which can give rise to any of the mature cell types of that organ or tissue (e.g., skin, brain, liver, or blood and lymphocyte stem cells). Recently, cells have also been identified in several human and animal cancers that have the essential features of stem cells (cancer stem cells) and which are thought to be responsible for the growth and spread of the tumor. In this-completed study, the researchers investigated a unique population of cells within canine lymphomas which had features highly suggestive of a cancer stem cell. The researchers extended their initial findings to show that the cells they identified (lymphoid progenitor cells; LPCs) are consistently present in all canine lymphomas. During the project, the researchers specifically assessed the expression of several genes known to be characteristic of stem cells. The findings indicate that LPCs more closely resemble a hematopoietic stem cell (ie. an adult stem cell) than a pluripotent stem cell such as embryonic stem cells. The researchers also used microarray analysis to assess the expression of tens of thousands of genes, comparing the LPCs to the bulk tumor cells. This analysis showed a consistent significant difference in expression of genes between the LPC and bulk tumor cells. The findings of this study suggest canine lymphoma has a cancer stem cell (LPCs) which give rise to the rest of the tumor cells, and elimination of which, would be sufficient and necessary to cure the disease. These findings represent an important conceptual step forward in the understanding of the basic pathobiology of canine lymphoma and will serve to inform further studies into effective therapeutic approaches to this common and devastating disease. Specifically, further knowledge of the biology of the lymphoma cancer stem cell may reveal novel therapeutic approaches specifically targeting the lymphoma cancer stem cell, and by reducing or eliminating these cells, enable prolonged remissions or complete cures of this disease.
Publication(s)
Frantz, A. M., Sarver, A. L., Ito, D., Phang, T. L., Karimpour-Fard, A., Scott, M. C., … Modiano, J. F. (2013). Molecular Profiling Reveals Prognostically Significant Subtypes of Canine Lymphoma. Veterinary Pathology, 50(4), 693–703. https://doi.org/10.1177/0300985812465325
Ito, D., Endicott, M. M., Jubala, C. M., Helm, K. M., Burnett, R. C., Husbands, B. D., … Modiano, J. F. (2011). A Tumor-Related Lymphoid Progenitor Population Supports Hierarchical Tumor Organization in Canine B-Cell Lymphoma: Canine B-Cell Lymphoma. Journal of Veterinary Internal Medicine, 25(4), 890–896. https://doi.org/10.1111/j.1939-1676.2011.0756.x
Ito, Daisuke, Frantz, A. M., Williams, C., Thomas, R., Burnett, R. C., Avery, A. C., … Modiano, J. F. (2012). CD40 ligand is necessary and sufficient to support primary diffuse large B-cell lymphoma cells in culture: a tool for in vitro preclinical studies with primary B-cell malignancies. Leukemia & Lymphoma, 53(7), 1390–1398. https://doi.org/10.3109/10428194.2011.654337
Ito, Daisuke, O’Brien, T. D., & Modiano, J. F. (2010). Exclusion of cytoplasmic fragments in flow cytometric analysis of lymph node samples from dogs with lymphoma using membrane-permeable violet laser-excitable DNA-binding fluorescent dye (DyeCycle Violet). Veterinary Clinical Pathology, 39(4), 494–498. https://doi.org/10.1111/j.1939-165X.2010.00252.x
Kim, J.-H., Frantz, A. M., Sarver, A. L., Gorden Klukas, B. H., Lewellen, M., O’Brien, T. D., … Modiano, J. F. (2018). Modulation of fatty acid metabolism and immune suppression are features of in vitro tumour sphere formation in ontogenetically distinct dog cancers. Veterinary and Comparative Oncology, 16(1), E176–E184. https://doi.org/10.1111/vco.12368
Help Future Generations of Dogs
Participate in canine health research by providing samples or by enrolling in a clinical trial. Samples are needed from healthy dogs and dogs affected by specific diseases.
