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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 Immune cell infiltration and comparative immune signatures between canine hemangiosarcoma and human angiosarcoma. A, A total of 461 upregulated genes were identified in immune-high (N = 8) compared with immune-low (N = 5) groups in human angiosarcomas (FDR P value < 0.05). B, 567 immune gene signatures were identified among three molecular subtypes of canine hemangiosarcomas (N = 76; FDR P value < 0.001; fold change > 3). The heat maps show upregulated (red) and downregulated (green) genes by unsupervised hierarchical clustering (average linkage; mean-centered; log2 transformed). C, Venn diagram shows 58 common genes associated with signaling pathways of immune cell functions between human and canine tumors. Representative photomicrographs of H&E and IHC staining showing histologic morphology and immune cell infiltration in canine hemangiosarcoma (D) and human angiosarcoma tissues (E) using anti-CD3, anti-PAX5, anti-MAC387, and anti-Iba1 (for canine) or anti-CD163 (for human) antibodies for detecting T cell, B cell, and macrophages. Horseradish peroxidase (counterstain = hematoxylin) or alkaline phosphate (for Iba1; counterstain = methylene blue). Bar = 50 µm. Scatter plots display correlation between transcriptional and IHC immune score in canine hemangiosarcoma (F) and human angiosarcoma (G). Spearman correlation coefficient (R) was calculated.
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.
