PMC

Venn diagram demonstrating miRNAs differentially expressed between hemangiosarcoma, nodular hyperplasia, and normal spleen (fold change ≥ ± 2, significance set a p < 0.05). Eighteen miRNAs were differentially expressed solely between hemangiosarcoma and normal spleen samples. Fourteen miRNAs were differentially expressed solely between nodular hyperplasia and normal spleen samples. Three miRNAs were differentially expressed solely between hemangiosarcoma and nodular hyperplasia samples. Four miRNAs were determined to be potential markers of hemangiosarcoma as they were differentially expressed between hemangiosarcoma and nodular hyperplasia samples and also hemangiosarcoma and normal spleen samples. Four miRNAs were determined to be potential markers of nodular hyperplasia as they were differentially expressed between hemangiosarcoma and nodular hyperplasia samples and also nodular hyperplasia and normal spleen samples. Eight miRNAs were determined to be potential markers of normal splenic tissue as they were differentially expressed between hemangiosarcoma and normal spleen samples and also nodular hyperplasia and normal spleen samples

(A) Liver, hemangiosarcoma. Neoplastic cells are arranged in cords, forming blood-filled, vascular channels. The parenchyma is diffusely expanded, effaced, and replaced by hemangiosarcoma. (B) Liver, hemangiosarcoma. Plump spindloid neoplastic cells line vascular channels that contain RBC. (C) Lung, hemangiosarcoma. (D) Skin, hemangiosarcoma. (E) Bone, zygomatic arch, hemangiosarcoma. (F) Bone, zygomatic arch, hemangiosarcoma. Hematoxylin and eosin stain; magnification: 2× (A, C, D, E); 10× (F); 40× (B).

Overview of the relationships between biological signaling molecules and the tumor microenvironment in canine hemangiosarcoma. Canine hemangiosarcoma is thought to originate from hematopoietic progenitor cells in the bone marrow. Chromosome translocations and a reactive microenvironment are suggested as potential genetic and biological events that may transform the hemangiosarcoma progenitor cells. Interleukin (IL)-8, produced by hemangiosarcoma cells, is thought to modulate the tumor microenvironment, promoting the growth and survival of tumor cells. CXCR4 and its ligand, CXCL12, found to be abundant in hemangiosarcoma tissue, transduce biological signaling, causing tumor cells to increase their motility to migrate and invade into the other sites for metastasis. Canine hemangiosarcoma cells that consume Sphingosine-1-phosphate (S1P) from the tumor microenvironment induce intracellular signaling through S1P receptor-1 (S1P₁), increasing cell growth and survival. It is suggested that these chemokines and modified biolipids are key regulators for hemangiosarcoma behavior, and their signaling pathways are potential therapeutic targets.

(A, B) Liver; rhesus macaque. Multifocal 5 mm to 4 cm in diameter blood-filled neoplastic masses compressing adjacent normal hepatic parenchyma. (C) Liver; rhesus macaque. Hepatic hemangiosarcoma: coalescing foci of an invasive neoplasm that compresses and replaces the hepatic parenchyma with blood-filled spaces lined by neoplastic endothelial cells. Hematoxylin and eosin. (D) Liver; rhesus macaque. Hepatic hemangiosarcoma: markedly pleomorphic spindle to round endothelial cells forming variable sized, blood-filled vascular channels. Hematoxylin and eosin. (E) Liver; rhesus macaque. Hepatic hemangiosarcoma: densely cellular areas with neoplastic sarcomatous cells forming whorls of ‘kaposi-form’ spindle cells consistent with PHAS. Hematoxylin and eosin. (F) Liver; rhesus macaque. Hepatic hemangiosarcoma: strong cytoplasmic reactivity for CD31 in the neoplastic epithelial cells surrounding entrapped normal hepatocytes and portal areas. DAB with Mayer’s hematoxylin counterstain. (G) Liver; rhesus macaque. Hepatic hemangiosarcoma: endothelial neoplastic cells exhibit weak immunoreactivity for vWF antigen. DAB with Mayer’s hematoxylin counterstain. (H) Liver; rhesus macaque. Hepatic hemangiosarcoma: neoplastic endothelial cells express increased aberrant nuclear p53 protein. DAB with Mayer’s hematoxylin counterstain. (I) Liver; rhesus macaque. Hepatic hemangiosarcoma: endothelial cells express the proliferation marker MIB-1/Ki-67. DAB with Mayer’s hematoxylin.