Transcriptional and Functional Activity of Hemangiosarcoma Support Bone Marrow Nurse Cell Ontogeny

Hemangiosarcoma and angiosarcoma are soft tissue sarcomas of malignant 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 that support the niche, enabling progression of canine hemangiosarcoma and human angiosarcoma. Here, we show that the transcriptional landscape of canine hemangiosarcoma and human angiosarcoma included comparable angiogenic and inflammatory programs. 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, a trait that was not observed in xenografts from canine osteosarcoma and lymphoma. In some cases, the xenografted hemangiosarcoma cells created exuberant myeloid hyperplasia and gave rise to lymphoproliferative tumors of mouse origin. We did not uncover a definitive transmissible etiology, but our data indicate that transcriptional programs of hemangiosarcoma cells resemble those of hematopoietic nurse cells, and these malignant cells support expansion and differentiation of human hematopoietic progenitors. We conclude that canine hemangiosarcoma, and possibly human angiosarcoma, originate from nurse cells that make up the stromal bone marrow niche, and that these cells may also support the growth of hematopoietic tumors. ### Competing Interest Statement The authors have declared no competing interest. * BM : Bone marrow CAR : CXCL12-abundant reticular HSPC : hematopoietic stem and progenitor cell IACUC : Institutional Animal Care and Use Committee hBM-MSC : Human BM-derived mesenchymal stromal cell hUCB : Human umbilical cord blood NSG : NOD-Scid-Gamma BNX : Beige-Nude-Xid RAR : Research Animal Resources FISH : fluorescence in situ hybridization EFB : Emma-brain CPDX : canine patient-derived xenograft MuLV : murine leukemia virus PCR : Polymerase chain reaction LTC-IC : long-term culture initiating cell HPC : hematopoietic progenitor cell MSC : mesenchymal stromal cell CFU : colony-forming unit