1759: Disrupting the Differentiation of Cancer Stem Cells to Prevent the Spread of Hemangiosarcoma

Grant Status: Closed

Grant Amount: $233,914
Dr. 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 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, United States Australian Shepherd Foundation, Versatility in Poodles, Inc., Vizsla Club of America Welfare Foundation, White Shepherd Genetics Project
Breed(s): -All Dogs
Research Program Area: Oncology - Hemangiosarcoma

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.

Publication(s)

Abstracts:

1. Graef AJ, Kim JH, Sarver AL, Frantz AM, O'Brien TD, Sharkey LC, Dickerson EB, Modiano JF (2013). Gene expression profiling reveals a role of CXCR4/7 in canine hemangiosarcoma. Proceedings of the 2013 International Conference on Advances in Canine and Feline Genomics and Inherited Diseases

2. Kim JH, Sarver AL, Frantz AM, Scott MC, Graef AJ, Tonomura N, Elvers I, Thomas R, Lewellen M, Dickerson EB, Breen M, Lindblad-Toh K, Modiano JF (2013). Germ-line risk factors are associated with upregulation of genes mediating cell cycle arrest and stem cell activity in canine hemangiosarcoma. Proceedings of the 2013 International Conference on Advances in Canine and Feline Genomics and Inherited Diseases

3. Kim JH, Anderson KL, Frantz AM, Graef AJ, Dickerson EB, Modiano JF (2013). IL-8 and Slug regulate cancer cell self-renewal and microenvironment interactions in hemangiosarcoma. Proceedings of the 2013 Veterinary Cancer Society Meeting

4. Graef AJ, Kim JH, Modiano JF. Inhibition of CXCR4 in canine hemangiosarcoma. Proceedings Masonic Cancer Center Research Symposium, Minneapolis, MN

Papers

1. Gorden BH, Kim JH, Frantz A, Sarver AL, Breen M, Lindblad-Toh K, O'Brien TD, Sharkey LC, Modiano JF, Dickerson EB. (2013). Gene expression profiling and progenitor cell characterization identify three molecular and functional signatures in canine hemangiosarcoma. Am J Pathol, Accepted for Publication

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