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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 Gene expression analysis in DHSA-1426 hemangiosarcoma cells and xenograft tumors using RNA-seq data. A, The volcano plot visualizes 2,391 significant DEGs (1,034 upregulated and 1,357 downregulated) in DHSA-1426 cells (n = 3) compared with nonmalignant endothelial cells (n = 4; q-value < 0.01; log2 fold change > |2|). The DEGs are indicated by red dots. NS = not significant; log2FC = log2 fold change. B, Gene Ontology enrichment analysis depicts biological processes associated with significant DEGs. P, adjust = adjusted P-value. C, Bar graphs present normalized gene expression values of CSF3, IL6, and IL8 in RNA-seq data generated from canine nonmalignant endothelial cells (n = 4) and DHSA-1426 hemangiosarcoma cells (n = 3). D, Schematic illustration visualizes the experimental steps for species-specific gene expression analysis of xenograft tumors using RNA-seq data. E, Bar graphs show the expression of mouse-specific genes in RNA-seq data generated from xenograft tumor tissues of canine hemangiosarcoma (n = 4) and mouse lymphoma (n = 7). A two-way ANOVA test was conducted to compare the means between groups. ****, P < 0.0001
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.
