Vascular Control of Organ Function
Regulation of the tumor microenvironment by chronic β‑adrenergic stress in the tumor vasculature
Clinical and pre-clinical data show that chronic stress, characterized by elevated levels of catecholamines, sustains tumor progression by acting on cancer and stromal cells. Furthermore, important pathological observations linked the sympathetic innervation of the tumor stroma to tumor progression. Considering the importance of the β2-adrenoceptor (β2AR) in the physiological control of the vasculature, its role in the tumor vasculature remains largely elusive. Recent studies by us and others have identified that β2AR and its cAMP-dependent effectors as important regulators of tumor and endothelial cells (EC). Once activated, EC that comprise the tumor vasculature, are not passive bystanders but actively shape the tumor microenvironment by means of angiocrine signaling, creating a pro-inflammatory, pro-angiogenic and pro-metastatic niche that sustains tumor progression.
Our preliminary findings demonstrate a so far not detected interplay of catecholamine induced signaling and the canonical Wnt pathway mediator β-catenin. Importantly, this interaction results in enhanced nuclear translocation of transcriptionally active β-catenin and regulation of angiocrine signaling. Within this CRC, we study the role of chronic β2AR activation in tumor EC by using ectopic and orthotopic in vivo models of melanoma and prostate carcinoma in combination with established chronic stress models previously used in heart failure research. We employ conditional EC-specific knockout models to probe the role of specific targets in tumor-associated vasculature and tumor progression.