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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 expansion derived from adoptive transplantation of canine hemangiosarcoma in immunodeficient mice. A and B, Xenotransplantation of canine hemangiosarcoma cell lines created exuberant myeloid hyperplasia in mouse spleens. Representative photomicrographs show histopathology by H&E staining of spleens from NSG mice transplanted with hemangiosarcoma cell lines SB (A) and EFB (B). C, Immunoreactivity of anti-mouse Ki-67 (Tec-3) antibody shows strongly positive signal in proliferating cells in the spleen. D, Immunostaining of anti-human (and canine cross-reactive) Ki-67 (MiB-1) antibody shows lack of positive staining among proliferating cells. E, The proliferating cells are immunoreactive with anti-mouse Ter-119 antibody. F, SB cells expressing Luciferase are detected in mouse spleen (arrows). Images shown in C, D, E, and F are from IHC staining done in mice inoculated with SB cells modified to express GFP and firefly Luciferase. Horseradish peroxidase (for Ki-67 stains) and alkaline phosphatase (for Ter-119 and Luciferase) conjugates were used. Counterstain = hematoxylin. A–D: Bar = 200 µm; E–F: Bar = 50 µm.
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.
