Suppression of beta 2 adrenergic receptor actions prevent UVB mediated cutaneous squamous cell tumorigenesis through inhibition of VEGF‐A induced angiogenesis

Abstract

Although beta 2 adrenergic receptors (β2ADR) are present in the keratinocytes, their role in cutaneous squamous cell tumorigenesis needs to be ascertained. For the first time, we report here that selective β2ADR antagonists by inhibiting β2ADR actions significantly retarded the progression of ultraviolet B (UVB) induced premalignant cutaneous squamous cell lesions. These antagonists acted by inhibiting vascular endothelial growth factor‐A (VEGF) mediated angiogenesis to prevent UVB radiation‐induced squamous cell carcinoma of the skin.

β‐Adrenergic signaling in skin cancer

“…Adrenergic blockade has also been shown to inhibit tumorigenesis in nonmelanoma skin cancers. 22 For example, in cutaneous squamous cell carcinoma, carvedilol suppressed the progression of UV‐B–induced premalignant cutaneous squamous cell lesions by inhibiting VEGF‐mediated angiogenesis. 22 Thus, adrenergic blockade has therapeutic potential against all skin cancers, not only melanoma.…”

The Immunohistochemical Assessment of Neoangiogenesis Factors in Squamous Cell Carcinomas and Their Precursors in the Skin

“…Mice exposed to UVB showed an increased presence of VEGF and CD31 markers compared with healthy skin. An injection of butoxamine, a selective β2 adrenergic receptor antagonist, induced an inhibition of angiogenesis, lower CD31 and VEGF expression than in the control group, and a decrease in the number of tumors in treated mice [ 17 ].…”

“…Measuring VEGF levels could help estimate the likelihood of metastatic risk [ 10 , 13 , 14 ]. The role of β2 adrenergic receptor antagonist in reducing the development of UVB-induced cancer lesions, needs to be investigated as it may represent a new therapeutic opportunity [ 17 ].…”

Increased β 2 -adrenergic signaling promotes fracture healing through callus neovascularization in mice

“…For example, NE dose-and timedependently induces Vegfa transcription in brown adipocytes, which is reversible by the βblocker propranolol (53,54). Similarly, adrenergic signaling through ADRB2 has been shown to promote VEGFAdependent tumor vascularization in prostate, skin, and breast cancer cells (55)(56)(57). Together, these observations demonstrate that NE is capable of inducing VEGFA in a variety of different cell types and, in the case of bone healing, results in an overall promotion of type-H vessel formation required for osteogenesis.…”