Abstract
Human angiosarcomas and canine hemangiosarcomas are highly aggressive cancers thought to arise from cells of vascular origin. The pathological features, morphological organization, and clinical behavior of canine hemangiosarcomas are virtually indistinct from those of human angiosarcomas. Overall survival with current standard-of-care approaches remains dismal for both humans and dogs, and each is likely to succumb to their disease within a short duration. While angiosarcomas in humans are extremely rare, limiting their study and treatment options, canine hemangiosarcomas occur frequently. Therefore, studies of these sarcomas in dogs can be used to advance treatment approaches for both patient groups. Emerging data suggest that angiosarcomas and hemangiosarcomas utilize beta adrenergic signaling to drive their progression by regulating the tumor cell niche and fine-tuning cellular responses within the tumor microenvironment. These discoveries indicate that inhibition of beta adrenergic signaling could serve as an Achilles heel for these tumors and emphasize the need to design therapeutic strategies that target tumor cell and stromal cell constituents. In this review, we summarize recent discoveries and present new hypotheses regarding the roles of beta adrenergic signaling in angiosarcomas and hemangiosarcomas. Because the use of beta adrenergic receptor antagonists is well established in human and veterinary medicine, beta blockade could provide an immediate adjunct therapy for treatment along with a tangible opportunity to improve upon the outcomes of both humans and dogs with these diseases.
Highlights
Angiosarcomas represent a subgroup of soft tissue sarcomas, characterized by both their aggressive behavior and clinical heterogeneity [1,2,3]
We previously described the activation of Src in canine hemangiosarcoma cell lines [63]
CXCL12 promoted cell migration and invasion of hemangiosarcoma cells, and these responses were sensitive to the CXCR4 antagonist, AMD3100. These findings suggest CXCL12 potentiates the migration and invasion of canine hemangiosarcoma cells through CXCR4 signaling
Summary
Angiosarcomas represent a subgroup (approximately 2%–3%) of soft tissue sarcomas, characterized by both their aggressive behavior and clinical heterogeneity [1,2,3]. Alternative approaches to conventional single agent chemotherapy protocols, including combinations of cytotoxic drugs [19,21,22,23,24,25,26,27,28,29], metronomic dosing [30], autologous vaccines [31], and immune-based and antiangiogenic therapies [32] have been studied in dogs None of these have shown benefit over the current standard-of-care, leaving both human and canine patients to confront what is likely to be a bleak prognosis. We will discuss how these pathways can be disrupted by beta blockade for therapeutic intervention
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