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posted on 2024-06-11, 14:20 authored by Jong Hyuk Kim, Ashley J. Schulte, Aaron L. Sarver, Donghee Lee, Mathew G. Angelos, Aric M. Frantz, Colleen L. Forster, Timothy D. O'Brien, Ingrid Cornax, M. Gerard O'Sullivan, Nuojin Cheng, Mitzi Lewellen, LeAnn Oseth, Sunil Kumar, Susan Bullman, Chandra Sekhar Pedamallu, Sagar M. Goyal, Matthew Meyerson, Troy C. Lund, Matthew Breen, Kerstin Lindblad-Toh, Erin B. Dickerson, Dan S. Kaufman, Jaime F. Modiano Hematopoietic support and stromal regulation of canine hemangiosarcoma cells. A, Flow cytometric data depict populations of cells expressing CD43 and CD45 differentiated from CD34+ hUCB cells. CD34+ hUCB cells were pooled from 2 patients. M2-10B4, hBM-MSCs, and canine hemangiosarcoma cells (DHSA-1426 and EFB) were seeded on gelatin-coated 24-well plates at a density of 1 × 105 cells/well. Gelatin-coated wells without stroma served as a negative control. Surface antigens CD34, CD43, and CD45 were analyzed at week 5. B and C, Bar graphs illustrate number of different colonies formed by hUCB CD34+ cells cocultured with feeder cells. Both DHSA-1426 and EFB canine hemangiosarcoma cell lines expanded hUCB CD34+ cells similarly to the M2-10B4 and hBM-MSC positive control lines, while gelatin-coated wells alone failed to support expansion. Burst-forming unit-erythroid (BFU-E), CFU (colony-forming unit)-Erythroid (CFU-E), CFU-granulocyte/macrophage (CFU-GM), CFU-macrophage (CFU-M), and CFU-granulocyte/erythroid/macrophage/megakaryocyte (CFU-GEMM) were determined for CFU assay.
Funding
HHS | NIH | National Cancer Institute (NCI)
American Kennel Club Canine Health Foundation (CHF)
National Canine Cancer Foundation (NCCF)
Morris Animal Foundation (MAF)
Cancerfonden (Swedish Cancer Society)
U.S. Department of Defense (DOD)
History
ARTICLE ABSTRACT
Hemangiosarcoma and angiosarcoma are soft-tissue sarcomas of blood vessel–forming cells in dogs and humans, respectively. These vasoformative sarcomas are aggressive and highly metastatic, with disorganized, irregular blood-filled vascular spaces. Our objective was to define molecular programs which support the niche that enables progression of canine hemangiosarcoma and human angiosarcoma. Dog-in-mouse hemangiosarcoma xenografts recapitulated the vasoformative and highly angiogenic morphology and molecular characteristics of primary tumors. Blood vessels in the tumors were complex and disorganized, and they were lined by both donor and host cells. In a series of xenografts, we observed that the transplanted hemangiosarcoma cells created exuberant myeloid hyperplasia and gave rise to lymphoproliferative tumors of mouse origin. Our functional analyses indicate that hemangiosarcoma cells generate a microenvironment that supports expansion and differentiation of hematopoietic progenitor populations. Furthermore, gene expression profiling data revealed hemangiosarcoma cells expressed a repertoire of hematopoietic cytokines capable of regulating the surrounding stromal cells. We conclude that canine hemangiosarcomas, and possibly human angiosarcomas, maintain molecular properties that provide hematopoietic support and facilitate stromal reactions, suggesting their potential involvement in promoting the growth of hematopoietic tumors.
We demonstrate that hemangiosarcomas regulate molecular programs supporting hematopoietic expansion and differentiation, providing insights into their potential roles in creating a permissive stromal-immune environment for tumor progression.
