Src activation by β-adrenoreceptors is a key switch for tumour metastasis

Abstract

Norepinephrine (NE) can modulate multiple cellular functions important for cancer progression; however, how this single extracellular signal regulates such a broad array of cellular processes is unknown. Here, we identify Src as a key regulator of phosphoproteomic signaling networks activated in response to beta-adrenergic signaling in cancer cells. These results also identify a new mechanism of Src phosphorylation that mediates beta-adrenergic/PKA regulation of downstream networks, thereby enhancing tumor cell migration, invasion and growth. In human ovarian cancer samples, high tumoral NE levels were correlated with high pSrcY419 levels. Moreover, among cancer patients, the use of beta blockers was significantly associated with reduced cancer-related mortality. Collectively, these data provide a pivotal molecular target for disrupting neural signaling in the tumor microenvironment.

Targeting psychoemotional stress to treat prostate cancer

“…5 Data on reduced mortality among beta-blocker users across multiple cancers including 20% reduction in mortality from male reproductive neoplasms based on analysis of the United States Food and Drug Administration Adverse Events Reporting System were also recently presented. 6 These results are consistent with the generalized conclusion from multiple studies which have shown that stress does not affect cancer incidence, but contributes to increased mortality from already established cancers.…”

“…9 Earlier experiments in breast and ovarian cancer models demonstrated the importance of the tumor microenvironment (immune cells and angiogenesis) in mediating effects of stress on cancer progression. 6 Additional studies in mouse prostate cancer models will clarify whether these stressactivated mechanisms, identified in other cancers, operate in prostate cancer as well and whether anti-apoptotic signaling plays a leading role or is but one of several mechanisms through which stress influences prostate cancer.…”

Wnt3a Expression is Associated with MMP-9 Expression in Primary Tumor and Metastatic Site in Recurrent or Stage IV Colorectal Cancer

“…This secondary messenger, cAMP, regulates many cellular functions through its effectors, such as cAMP-dependent protein kinase (PKA) and EPAC (exchange proteins directly activated by cAMP) [69][70][71]. Preclinical studies have demonstrated that β-adrenergic signaling can regulate multiple fundamental biological processes underlying the progression and metastasis of tumors, including the promotion of inflammation [72][73][74], angiogenesis [75][76][77][78], migration [79], invasion [80,81] and resistance to programmed cell death [82][83][84][85]. Some evidence suggests that the stimulation of β-adrenergic signaling can also inhibit DNA damage repair and the cellular immune response [86,87] and promote surgery-induced metastasis [88,89].…”

Cancer’s got nerve: Schwann cells drive perineural invasion

“…Increasing evidence suggests that activation of nerve growth into tumors, termed neoneurogenesis, is another key driver of cancer progression. In addition, chronic activation of the sympathetic nervous system via increased norepinephrine levels has been observed in the tumor microenvironment (1,2), and this activation has been demonstrated to promote tumor growth and progression via β-adrenergic receptor signaling on tumor cells and subsequent upregulation of tumor-promoting chemokines (3)(4)(5)(6). However, it was the hallmark paper from Magnon et al (7) that clearly demonstrated that neuronal involvement promotes cancer progression.…”