Kim Jong Hyuk, Schulte Ashley J, Sarver Aaron L, Lee Donghee, Angelos Mathew G, Frantz Aric M, Forster Colleen L, O'Brien Timothy D, Cornax Ingrid, O'Sullivan M Gerard, Cheng Nuojin, Lewellen Mitzi, Oseth LeAnn, Kumar Sunil, Bullman Susan, Pedamallu Chandra Sekhar, Goyal Sagar M, Meyerson Matthew, Lund Troy C, Breen Matthew, Lindblad-Toh Kerstin, Dickerson Erin B, Kaufman Dan S, Modiano Jaime F
Animal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota.
Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota.
Cancer Res Commun. 2024 Jun 11;4(6):1467-1480. doi: 10.1158/2767-9764.CRC-23-0441.
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.
血管肉瘤和血管内皮肉瘤分别是犬类和人类中由血管形成细胞构成的软组织肉瘤。这些血管形成性肉瘤具有侵袭性且高度转移，具有杂乱无章、不规则的充满血液的血管腔隙。我们的目标是确定支持犬类血管肉瘤和人类血管内皮肉瘤进展的生态位的分子程序。犬源血管肉瘤移植到小鼠体内后，重现了原发性肿瘤的血管形成性和高度血管生成的形态及分子特征。肿瘤中的血管复杂且杂乱无章，由供体细胞和宿主细胞共同构成内壁。在一系列移植实验中，我们观察到移植的血管肉瘤细胞引发了旺盛的髓样增生，并导致了小鼠源性的淋巴增殖性肿瘤。我们的功能分析表明，血管肉瘤细胞产生了一个支持造血祖细胞群体扩增和分化的微环境。此外，基因表达谱数据显示血管肉瘤细胞表达了一系列能够调节周围基质细胞的造血细胞因子。我们得出结论，犬类血管肉瘤以及可能的人类血管内皮肉瘤维持着提供造血支持并促进基质反应的分子特性，这表明它们可能参与促进造血肿瘤的生长。
我们证明血管肉瘤调节支持造血扩增和分化的分子程序，为其在为肿瘤进展创造有利的基质 - 免疫环境中的潜在作用提供了见解。
