β‐Adrenergic signaling in skin cancer

Batalla‐Covello, Jennifer; Ali, Shahrukh; Xie, Tongxin; Amit, Moran

doi:10.1096/fba.2021-00097

Cited by 7 publications

(5 citation statements)

References 39 publications

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“…Although the latter observation did not reach statistical significance, it is worth noting that the strongest signal of an enhanced response with combination ICI plus β-AR blockade was observed in a small subset (n = 19; 19%) of patients who were taking nonselective β-AR blockade compared to the majority (81%) of patients on a selective β-AR blocker, which further supports the previous observations regarding the importance of nonselective β-AR blockade (particularly targeting the β2-AR) as a means to fully optimize these therapeutically additive immunologic responses [92]. Several additional clinical trials utilizing nonselective β-AR blockade, with and without ICI, for patients with varying stages of melanoma are ongoing for which each trial's preliminary findings are highly anticipated [66].…”

Section: Impact Of ß-Adrenergic Immune Modulation In Melanoma: Clinic...supporting

confidence: 80%

“…Current clinical observations suggest that these pathways appear to be driven largely in part via expression of the β2-AR subtype, and increasing pre-clinical evidence suggests the β3-AR pathways may also be involved. Antagonism of β2-ARs has now exhibited repeated evidence of restoring anti-tumoral immunogenicity as well as enhancing effectiveness of ICI therapies within both pre-clinical and clinical melanoma models [28,66,71]. Our group's aforementioned multicenter phase II clinical trial observing the benefits of nonselective β-AR when combined with ICI (pembrolizumab) in patients with advanced melanoma is actively enrolling patients, and is expected to provide a more definitive answer regarding the clinical benefit of this combination in the setting of advanced melanoma [91].…”

Section: Discussionmentioning

confidence: 99%

“…A variety of translational and clinical models have suggested that the immunosuppressive patterns of chronic stress-induced β2-AR signaling can be mitigated via reduction of stressful stimuli as well as pharmacologic blockade of these receptors [66]. For example, the aforementioned tumorigenic upregulation of VEGF, IL-6, and IL-8 pathways associated with the neuroendocrine stress response in melanoma cell lines appears to be abrogated by a non-selective inhibitor of β-AR signaling (propranolol) [28,60].…”

Section: Impact Of ß-Adrenergic Immune Modulation In Melanoma: Pre-cl...mentioning

confidence: 99%

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Targeting beta-adrenergic receptor pathways in melanoma: how stress modulates oncogenic immunity

Switzer,

Puzanov,

Gandhi

et al. 2023

Melanoma Research

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The intricate pathways of the sympathetic nervous system hold an inherently protective role in the setting of acute stress. This is achieved through dynamic immunomodulatory and neurobiological networks. However, excessive and chronic exposure to these stress-induced stimuli appears to cause physiologic dysfunction through several mechanisms that may impair psychosocial, neurologic, and immunologic health. Numerous preclinical observations have identified the beta-2 adrenergic receptor (β2-AR) subtype to possess the strongest impact on immune dysfunction in the setting of chronic stressful stimuli. This prolonged expression of β2-ARs appears to suppress immune surveillance and promote tumorigenesis within multiple cancer types. This occurs through several pathways, including (1) decreasing the frequency and function of CD8 + T-cells infiltrating the tumor microenvironment (TME) via inhibition of metabolic reprogramming during T cell activation, and (2) establishing an immunosuppressive profile within the TME including promotion of an exhausted T cell phenotype while simultaneously enhancing local and paracrine metastatic potential. The use of nonselective β-AR antagonists appears to reverse many chronic stress-induced tumorigenic pathways and may also provide an additive therapeutic benefit for various immune checkpoint modulating agents including commonly utilized immune checkpoint inhibitors. Here we review the translational and clinical observations highlighting the foundational hypotheses that chronic stress-induced β-AR signaling promotes a pro-tumoral immunophenotype and that blockade of these pathways may augment the therapeutic response of immune checkpoint inhibition within the scope of melanoma.

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Section: Impact Of ß-Adrenergic Immune Modulation In Melanoma: Clinic...supporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Impact Of ß-Adrenergic Immune Modulation In Melanoma: Pre-cl...mentioning

confidence: 99%

See 1 more Smart Citation

Targeting beta-adrenergic receptor pathways in melanoma: how stress modulates oncogenic immunity

Switzer,

Puzanov,

Gandhi

et al. 2023

Melanoma Research

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“…In skin cancers, especially in melanoma, all ß1, ß2, and ß3-ARs are expressed, of which ß1 appears to be the most significant. It is worth noting that among all tumor types studied, ß-ARs showed the highest expression in melanoma, which provided convincing evidence for the relationship between the adrenergic system and this skin cancer type [ 53 , 54 ].…”

Section: Review Of the Literaturementioning

confidence: 98%

ß-Adrenoreceptors in Human Cancers

Kraboth

Kálmán

2023

IJMS

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Cancer is the leading cause of death and represents a significant economic burden worldwide. The numbers are constantly growing as a result of increasing life expectancy, toxic environmental factors, and adoption of Western lifestyle. Among lifestyle factors, stress and the related signaling pathways have recently been implicated in the development of tumors. Here we present some epidemiological and preclinical data concerning stress-related activation of the ß-adrenoreceptors (ß-ARs), which contributes to the formation, sequential transformation, and migration of different tumor cell types. We focused our survey on research results for breast and lung cancer, melanoma, and gliomas published in the past five years. Based on the converging evidence, we present a conceptual framework of how cancer cells hijack a physiological mechanism involving ß-ARs toward a positive modulation of their own survival. In addition, we also highlight the potential contribution of ß-AR activation to tumorigenesis and metastasis formation. Finally, we outline the antitumor effects of targeting the ß-adrenergic signaling pathways, methods for which primarily include repurposed ß-blocker drugs. However, we also call attention to the emerging (though as yet largely explorative) method of chemogenetics, which has a great potential in suppressing tumor growth either by selectively modulating neuronal cell groups involved in stress responses affecting cancer cells or by directly manipulating specific (e.g., the ß-AR) receptors on a tumor and its microenvironment.

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“…This was linked to over-activation of the β2-adrenergic receptor (ADRB2)-cAMP-PKA pathway and increased angiogenesis in the stressed situation. There is now a large body of data from animals showing that adrenergic signaling is involved in tumor growth, metastasis, and overall mortality associated with multiple cancers, such as melanoma [ 17 ], colorectal cancer [ 141 ], breast cancer [ 222 ], and many more. In line with the rodent data, an early cohort study investigating over 10,000 women found significantly increased breast cancer risk in patients who had experienced a stressful life event, such as a divorce or death of a close family member [ 139 ].…”

Section: Adrenergic Signaling Linking Obesity and Cancermentioning

confidence: 99%

Obesity and cancer—extracellular matrix, angiogenesis, and adrenergic signaling as unusual suspects linking the two diseases

Pellegata

Díaz

Rohm

et al. 2022

Cancer Metastasis Rev

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Obesity is an established risk factor for several human cancers. Given the association between excess body weight and cancer, the increasing rates of obesity worldwide are worrisome. A variety of obesity-related factors has been implicated in cancer initiation, progression, and response to therapy. These factors include circulating nutritional factors, hormones, and cytokines, causing hyperinsulinemia, inflammation, and adipose tissue dysfunction. The impact of these conditions on cancer development and progression has been the focus of extensive literature. In this review, we concentrate on processes that can link obesity and cancer, and which provide a novel perspective: extracellular matrix remodeling, angiogenesis, and adrenergic signaling. We describe molecular mechanisms involved in these processes, which represent putative targets for intervention. Liver, pancreas, and breast cancers were chosen as exemplary disease models. In view of the expanding epidemic of obesity, a better understanding of the tumorigenic process in obese individuals might lead to more effective treatments and preventive measures.

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β‐Adrenergic signaling in skin cancer

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 7 publications

References 39 publications

Targeting beta-adrenergic receptor pathways in melanoma: how stress modulates oncogenic immunity

Targeting beta-adrenergic receptor pathways in melanoma: how stress modulates oncogenic immunity

ß-Adrenoreceptors in Human Cancers

Obesity and cancer—extracellular matrix, angiogenesis, and adrenergic signaling as unusual suspects linking the two diseases

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