01759: Disrupting the Differentiation of Cancer Stem Cells to Prevent the Spread of Hemangiosarcoma

Grant Status: Closed

Grant Amount: $233,914
Jaime F Modiano, VMD, PhD; University of Minnesota
January 1, 2013 - December 31, 2015

Sponsor(s): American Belgian Tervuren Club, Inc., American Bouvier des Flandres Club - Bouvier Health Foundation, American German Shepherd Dog Charitable Foundation, Inc., American Pointer Club, American Spaniel Club Foundation, Australian Shepherd Health & Genetics Institute, Australian Terrier Club of America, Bearded Collie Club of America, Bernese Mountain Dog Club of America, Briard Club of America/ BCA Health & Education Trust, Clumber Spaniel Health Foundation, Dachshund Club of America, Inc., English Setter Association of America, Inc., Flat-Coated Retriever Foundation, German Shorthaired Pointer Club of America, Inc., Golden Retriever Foundation, Great Dane Club of America, Great Pyrenees Club of America, Irish Setter Club of America Foundation, Irish Water Spaniel Club of America, Italian Greyhound Club of America, Keeshond Club of America, Keeshond Donors Circle Trust, Leonberger Health Foundation, Mastiff Club of America, Norwegian Elkhound Association of America, Inc., Old English Sheepdog Club of America, Poodle Club of America Foundation, Portuguese Water Dog Club of America, Inc., Portuguese Water Dog Foundation, Rottweiler Health Foundation, Saluki Health Research, Inc., Starlight Fund, TarTan Gordon Setter Club, University of Minnesota - DAF for EIC Royalties, Versatility in Poodles, Inc., Vizsla Club of America Welfare Foundation, White Shepherd Genetics Project

Breed(s): -All Dogs
Research Program Area: Oncology - Hemangiosarcoma
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Project Summary

We completed progress to achieve the aims. Our results confirm and extend the notions that interactions between the tumor and its local environment regulate hemangiosarcoma progression. Yet, variability in cells within tumors can reduce the predictability of hemangiosarcoma behavior, and possibly contribute to therapy resistance. For example, hemangiosarcomas respond to the degradation of their supporting matrix by recruiting inflammatory cells and blood vessels. But the magnitude of this effect is variable among different hemangiosarcomas, which requires us to consider that these tumors might adapt efficiently to very different microenvironments. The hemangiosarcoma microenvironment also tends to be rich in a molecule called CXCL12, which is used as a means of communication between the tumor cells and the normal supporting cells. Only some of the tumor cells have the receptors that transmit the signals from CXCL12. These cells help to support the tumor, and also can be efficient mediators of metastasis. But in their absence, other mechanisms might perform these functions. Attenuating inflammation and modulating the metabolic activity of the cells shows modest effects on hemangiosarcoma cell growth, but neither approach is completely effective to eliminate the tumor. This suggests that blocking specific pathways might have positive therapeutic effects in selected patients, but managing this disease will require combining strategies that lower the capacity of cells to simply switch their behavior to use alternate pathways to survive and thrive.


Dickerson, E., & Bryan, B. (2015). Beta Adrenergic Signaling: A Targetable Regulator of Angiosarcoma and Hemangiosarcoma. Veterinary Sciences, 2(3), 270–292. https://doi.org/10.3390/vetsci2030270

Gorden, B. H., Kim, J.-H., Sarver, A. L., Frantz, A. M., Breen, M., Lindblad-Toh, K., … Dickerson, E. B. (2014). Identification of Three Molecular and Functional Subtypes in Canine Hemangiosarcoma through Gene Expression Profiling and Progenitor Cell Characterization. The American Journal of Pathology, 184(4), 985–995. https://doi.org/10.1016/j.ajpath.2013.12.025

Im, K. S., Graef, A. J., Breen, M., Lindblad-Toh, K., Modiano, J. F., & Kim, J.-H. (2015). Interactions between CXCR4 and CXCL12 promote cell migration and invasion of canine hemangiosarcoma: CXCR4/CXCL12 in HSA migration and invasion. Veterinary and Comparative Oncology, 15(2), 315–327. https://doi.org/10.1111/vco.12165

Im, K. S., Kim, J. H., Graef, A. J., Cornax, I., Seelig, D. M., O’Sullivan, M. G., … Modiano, J. F. (2017). Establishment of a Patient-Derived Xenograft of Canine Enteropathy-Associated T-Cell Lymphoma, Large Cell Type. Journal of Comparative Pathology, 156(1), 37–41. https://doi.org/10.1016/j.jcpa.2016.11.271

Kim, J.-H., Frantz, A. M., Anderson, K. L., Graef, A. J., Scott, M. C., Robinson, S., … Modiano, J. F. (2014). Interleukin-8 promotes canine hemangiosarcoma growth by regulating the tumor microenvironment. Experimental Cell Research, 323(1), 155–164. https://doi.org/10.1016/j.yexcr.2014.02.020

Kim, J.-H., Graef, A., Dickerson, E., & Modiano, J. (2015). Pathobiology of Hemangiosarcoma in Dogs: Research Advances and Future Perspectives. Veterinary Sciences, 2(4), 388–405. https://doi.org/10.3390/vetsci2040388

Rodriguez, A. M., Graef, A. J., LeVine, D. N., Cohen, I. R., Modiano, J. F., & Kim, J.-H. (2015). Association of Sphingosine-1-phosphate (S1P)/S1P Receptor-1 Pathway with Cell Proliferation and Survival in Canine Hemangiosarcoma. Journal of Veterinary Internal Medicine, 29(4), 1088–1097. https://doi.org/10.1111/jvim.13570

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