1759: Disrupting the Differentiation of Cancer Stem Cells to Prevent the Spread of Hemangiosarcoma
Grant Status: Closed
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.
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
-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.
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