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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 Establishment of xenografts derived from canine hemangiosarcoma in immunodeficient mice. A, Schematic illustration depicts process of tumor xenografts in BNX mice. B, DHSA-1426 tumor cell line was established from a canine patient diagnosed with hemangiosarcoma (A). Cells from DHSA-1426 passages 5 (p5) and 14 (p14) formed tumors histologically classified as hemangiosarcoma (B and C). Cells cultured from xenograft-derived tumors developed histologically identical tumors after serial transplantation (D). Both the primary tumor (E) and the xenograft tumor (F) were positive for CD31 IHC staining. A–D, Hematoxylin and eosin (H&E) stain. E and F, IHC with an anti-CD31 antibody (alkaline phosphatase conjugates; counterstain = hematoxylin). Bar = 200 µm. C, FISH images using canine-specific (CXCL8, red) and mouse-specific (X chromosome, green) probes in a canine hemangiosarcoma xenograft transplanted into receptive immunodeficient female mouse hosts. Red and green arrows point to representative xenograft canine tumor cells and mouse stromal cells, respectively, to aid in identification. D, Individual points on graph represent relative quantity of donor (dog) and host (mouse) cells in each tumor type. 10–12 fields of pictures at high magnification (400X) per slide were acquired. A total of approximately 1,000 cells in individual xenograft tumor was counted, and the percentages for each species-specific cells are presented. E, Dot plot shows microenvironment scores for 76 primary hemangiosarcoma tissues, estimated using RNA-seq data and xCell algorithm. The red dot indicates a DHSA-1426 tumor tissue used for xenograft.
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.
