Dr Lens's comment to our study, while underlining the hope for a new therapeutic option, fosters various hypotheses regarding the possible mechanisms of action of β-blockers to slow down the progression of melanoma and possibly other malignant diseases. The unprecedented ability of propranolol to treat infantile hemangiomas dictated the underlying hypothesis that led us to investigate the effect of β-blockers in patients with cutaneous malignant melanoma. The role of β-adrenoceptors to promote angiogenesis, supported by both basic and clinical evidence, represents the most robust working hypothesis explaining the beneficial effect of β-blockers in melanoma. The ability of β-adrenoceptors to enhance the VEGF pathway contributes to the identification of this mechanism as a primary target of β-blockers. The unique ability of propranolol to treat the disease and reduce VEGF levels in a child with diffuse lymphangiomatosis associated with chylothorax1 further strengthens this hypothesis. However, as appropriately underlined by Dr Lens, inhibition of additional pathways, such as the 2 metalloproteinases MMP-2 and MMP-9, which are markedly involved in angiogenesis, has also been shown for β-blockers. In addition, the proapoptotic action of β-blockers and the increased expression of the cytokines IL-6 and IL-8 by β-adrenoceptor stimulation should not be overlooked. If doubts exist regarding the mechanism responsible for the anticancer action of β-blockers, there is further uncertainty regarding the β-adrenoceptor subtype involved in cancer progression. A recent article reported that only the unselective β1/β2-antagonist propranolol, but not the selective β1 antagonist atenolol, had a protective effect in breast cancer.2 However, an article concurrently published in the same journal issue reported that patients who showed a reduced risk of relapse with triple-negative breast cancer (as in our patients with melanoma) mostly used selective β1-receptor antagonists.3 Thus, the underlying mechanism and the specific β-adrenergic receptor subtype(s) responsible for the anticancer activity of β-blockers remain unsettled issues in both breast cancer and melanoma. Finally, it should not be disregarded that the association between β-blocker use and cancer protection has not been unanimously recognized.4 Only randomized trials can answer the question whether β-blockers may offer a novel strategy to fight cancer, and the selection of the type of cancer and the right β-blocker is a matter of current, intense debate.
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