Neuroendocrine influences on cancer progression

“In this review, we will focus on chronic stress conditions that keep the body in a constant state of ‘‘overdrive’’, leading to deleterious downstream effects, deregulating the stress response and negatively affecting many organs systems (McEwen, 1998).”

“Tumor cells must perform these steps while evading immune system surveillance, and the cells that fail in any of these tasks cannot metastasize (Fidler, 2003).”

“Besides catecholamines, glucocorticoids are also involved in the stress response and can control many normal physiological activities such as circadian rhythms, immune function and restoration of homeostasis (Glaser and Kiecolt-Glaser, 2005).”

“Several studies have shown that the effect of stress hormones on cancer cell proliferation varies according to the specific hormone influences and the tumor type studied (as reviewed in Antoni et al., 2006).”

“…disease have shown that tumor incidence and progression can be exacerbated by chronic stressors, mainly through the reduction of type 1 cytokines and T cell and natural killer cell activity resulting in impaired antigen presentation and higher numbers of regulatory T cells (Webster et al., 2002).”

“Various approaches have been used to model disease (Frese and Tuveson, 2007).”

“ADRBs are the key components of the stress signaling pathway, and data now suggest that they also play a major role in protumoral signaling pathways (Cole and Sood, 2012).”

“Furthermore, it has been demonstrated that isoproterenol can promote ovarian cancer cell movement and adhesion via laminin-5 through an Epac1 dependent pathway (Bos, 2006).”

“Furthermore, recent studies have reported that beta-blocker use can improve the outcomes of breast cancer patient (Barron et al., 2011; Melhem-Bertrandt et al., 2011; Powe and Entschladen, 2011).”

“Furthermore, a rationale exists for the use of antidepressants, owing to their known antiinflammatory effects in the context of several types of cancer (Moreno-Smith et al., 2010).”

“Although there are promising data relating psychosocial interventions to survival (Andersen et al., 2010, 2008), additional work is needed to understand the efficacy of such interventions and the physiological mechanisms mediating such results.”

“Additionally, several in vivo and in vitro studies have shown that stress hormones can significantly increase the production of matrix metalloproteinase (MMP) 2 and 9 by ovarian cancer cells through ADRB-mediated pathways (Sood et al., 2006; Thaker et al., 2006).”

“Furthermore, recent studies have reported that beta-blocker use can improve the outcomes of breast cancer patient (Barron et al., 2011; Melhem-Bertrandt et al., 2011; Powe and Entschladen, 2011).”

“…report indicating that chronic stress, through ADRB2-mediated signaling, leads to the accumulation of DNA damage in murine and human cell lines (Hara et al., 2011) suggest that new research strategies may shed light on the question of whether and/or under what conditions biobehavioral states,…”

“Experiments using human head and neck cancer cells have shown similar results, demonstrating that MMP levels were substantially elevated in response to NE treatment in these cell lines (Yang et al., 2006).”

“…patients that underwent surgery demonstrated immune alterations such as lowered T cell mediated secretion of TH1 versus TH2 cytokines, a poorer T-cell response to mitogen stimulation and reduced natural killer cell activity (Andersen et al., 1998; Blomberg et al., 2009; Thornton et al., 2007).”

“Alternatively, in vivo mouse and in vitro studies have shown that DA can abrogate VEGF-induced angiogenesis by reducing the downstream activity mediated by one of its receptors, VEGFR-2 (Basu et al., 2001).”

“…suggests that hypothalamic brain-derived neurotrophic factor can be selectively upregulated by the enriched environment, while proposing that genetic or environmental activation of this brain-derived neurotrophic factor-leptin axis may have therapeutic significance for cancer (Cao et al., 2010).”

“…studies have reported that there is no relationship between stressful events (Duijts et al., 2003) or personality (Bleiker et al., 2008) and cancer incidence, while other reports seem to suggest that severe life stressors might induce cancer development (Lillberg et al., 2003; Price et al., 2001).”

“Moreover, in ovarian cancer patients, distress at the time of surgery was associated with decreased natural killer cell activity in tumor infiltrating lymphocytes (TIL) and lower T cell secretion of TH1 and TH2 cytokines in peripheral blood mononuclear cells and TIL (Lutgendorf et al., 2005).”

“We found that NE and Epi can protect ovarian cancer cells from anoikis by inducing the activation of focal adhesion kinase (FAK) through an ADRB/ PKA/Src dependent pathway (Sood et al., 2010).”

“Another in vitro study reported that isoproterenol can stimulate cell adhesion to fibronectin in a cAMP-mediated Epac–Rap1 pathway (Rangarajan et al., 2003).”

“One study identified the genetic status at the interleukin 6 (IL6) locus as an important factor in ADRB activation of the transcriptional factor GATA1, potentially explaining how social adversity can affect health risk (Cole et al., 2010; Webster et al., 2002).”

“For example, mice exposed to ultraviolet radiation and undergoing chronic stress had an increased incidence of squamous cell carcinoma resulting from the reduction of type 1 cytokines and protective T-cell infiltrates (Saul et al., 2005).”

“BAD is known to have pro-apoptotic functions in its unphosphorylated form, but once phosphorylated it releases Bcl-2 and B-cell lymphoma-extra large (Bcl-xL), thereby inhibiting the apoptotic process (Sastry et al., 2007).”

“Interestingly, ovarian cancer patients who experience distress and poor social support have elevated IL-6 levels, which have been associated with shorter survival in epidemiologic studies (Costanzo et al., 2005; Lutgendorf et al., 2008c).”

“Recently, it was shown that cAMP, besides targeting PKA, can also signal through exchange protein activated by cAMP (EPAC), a widely expressed exchange factor for the small GTPases Ras-related protein (RAP) 1 and 2 (Mercurio and Rabinovitz, 2001).”

“Our analysis revealed that mortality was reduced by an average of 17% across all major cancer types if patients were treated with beta-blockers (Armaiz Pena et al., 2011).”

“Several studies have reported that there is no relationship between stressful events (Duijts et al., 2003) or personality (Bleiker et al., 2008) and cancer incidence, while other reports seem to suggest that severe life stressors might induce cancer development (Lillberg et al., 2003; Price et al.,…”

“Additionally, tumor-bearing mice undergoing chronic stress had increased levels of the pro-angiogenic factor, interleukin 8 (IL-8) that were mediated by FosB (Moreno-Smith et al., 2010; Shahzad et al., 2010).”

“…human ovarian cancer cells in vitro that showed that norepinephrine and the beta agonist isoproterenol were both capable of inducing VEGF expression and that this effect was largely mediated by the ADRB/cAMP/Protein Kinase A (PKA) signaling axis (Fredriksson et al., 2000; Lutgendorf et al., 2003).”

“Furthermore, rat ovarian catecholamine levels are augmented in response to increased sympathetic activity and this elevation has been associated with the appearance of precystic follicles (Lara et al., 2000).”

“Advanced breast cancer patients diagnosed with clinical depression exhibit decreased cellular immunity (Sephton et al., 2009).”

“For example, an epidemiological study found that patients who used beta-blockers had a reduced risk of developing prostate cancer, which suggests that ADRBs play a role in the development of prostate cancer (Perron et al., 2004).”

“Data now demonstrate a clear link between social support and elevated serum VEGF levels in ovarian cancer patients (Lutgendorf et al., 2002).”

“We have shown that NE can induce IL-6 production in ovarian cancer cells through a mechanism mediated by the Src kinase (Nilsson et al., 2007).”

“Although there are promising data relating psychosocial interventions to survival (Andersen et al., 2010, 2008), additional work is needed to understand the efficacy of such interventions and the physiological mechanisms mediating such results.”

“Interestingly, ovarian cancer patients who experience distress and poor social support have elevated IL-6 levels, which have been associated with shorter survival in epidemiologic studies (Costanzo et al., 2005; Lutgendorf et al., 2008c).”

“Chronic stress can result in the activation of signal transducer and activator of transcription 3 (STAT-3), which increases tumor-associated angiogenesis in an orthotopic model of ovarian cancer (Landen et al., 2007).”

“(Ben-Eliyahu et al., 1999; Pollock et al., 1991).”

“Interestingly, ovarian cancer patients who experience distress and poor social support have elevated IL-6 levels, which have been associated with shorter survival in epidemiologic studies (Costanzo et al., 2005; Lutgendorf et al., 2008c).”

“Another interesting approach could be the use of dopamine analogues since dopamine replacement abrogates chronic stress-induced cancer growth (Basu et al., 2004; Moreno-Smith et al., 2011).”

“For example, in the rat, it is well known that SNS-induced catecholamine release can play a role in the regulation of peripheral organs, such as the ovary, where stress hormones affect ovarian hormone production and menstrual cycle (Aguado and Ojeda, 1984; Ben-Jonathan et al., 1984).”

“Another interesting approach could be the use of dopamine analogues since dopamine replacement abrogates chronic stress-induced cancer growth (Basu et al., 2004; Moreno-Smith et al., 2011).”

“…on the effects of catecholamines on normal cell proliferation indicates that catecholamines are suppressors of cell proliferation, as it has been shown that stress hormones can delay wound healing, mainly by decreasing keratinocyte proliferation (Flaxman and Harper, 1975; Merritt et al., 2008).”

“…element binding (CREB)mediated expression of viral oncogenes and growth factors that are known to promote tumor growth, and Epstein-Barr virus and high-risk variants of the human papilloma virus are similarly subject to activation by glucocorticoids (Cacioppo et al., 2002; Glaser et al., 1995).”

“Furthermore, recent studies have reported that beta-blocker use can improve the outcomes of breast cancer patient (Barron et al., 2011; Melhem-Bertrandt et al., 2011; Powe and Entschladen, 2011).”

“Catecholamine levels are also elevated in the murine bone marrow, as nerve endings and bone marrow cells possess the ability to secrete them into the bone marrow microenvironment (Maestroni, 2000).”

“…patients that underwent surgery demonstrated immune alterations such as lowered T cell mediated secretion of TH1 versus TH2 cytokines, a poorer T-cell response to mitogen stimulation and reduced natural killer cell activity (Andersen et al., 1998; Blomberg et al., 2009; Thornton et al., 2007).”

“…element binding (CREB)mediated expression of viral oncogenes and growth factors that are known to promote tumor growth, and Epstein-Barr virus and high-risk variants of the human papilloma virus are similarly subject to activation by glucocorticoids (Cacioppo et al., 2002; Glaser et al., 1995).”

“…patients that underwent surgery demonstrated immune alterations such as lowered T cell mediated secretion of TH1 versus TH2 cytokines, a poorer T-cell response to mitogen stimulation and reduced natural killer cell activity (Andersen et al., 1998; Blomberg et al., 2009; Thornton et al., 2007).”

“A second study found that the use of beta-blockers by patients with cardiovascular disease significantly reduced their risk of cancer (Algazi et al., 2004).”

“For example, human herpesvirus 8, which induces Kaposi’s sarcoma, possesses a cyclic adenosine monophosphate (cAMP) response element in the promoter of an important viral transcription factor (Chang et al., 2005).”

“Several studies have reported that there is no relationship between stressful events (Duijts et al., 2003) or personality (Bleiker et al., 2008) and cancer incidence, while other reports seem to suggest that severe life stressors might induce cancer development (Lillberg et al., 2003; Price et al.,…”

“For example, in a rat model of breast cancer, ADRB activation was associated with increased tumor growth (Marchetti et al., 1991).”

“For example, in the rat, it is well known that SNS-induced catecholamine release can play a role in the regulation of peripheral organs, such as the ovary, where stress hormones affect ovarian hormone production and menstrual cycle (Aguado and Ojeda, 1984; Ben-Jonathan et al., 1984).”

“It has been shown that NE can inhibit neuroblastoma cell growth, primarily in cells that express the DA transporter (Pifl et al., 2001).”

“Several in vitro and in vivo studies have demonstrated that NE can increase the migratory and metastatic potential of several types of cancers by inducing the activation of ADRB-mediated signaling cascades (Voss and Entschladen, 2010).”

“Conversely, in human melanoma and neuroblastoma cells, catecholamines appear to inhibit tumor cell proliferation, a process that may be mediated by alpha adrenergic receptors (ADRA) (Bleiker et al., 2008; Lutgendorf et al., 2002; Pifl et al., 2001; Scarparo et al., 2004).”

“The immune system is a crucial mediator through which stress affects the course of cancer,(2,6) although many immune-independent mechanisms also are critical mediators of cancer-related effects of stress.(7) In the current review, we focus on the effects of stress and stress management (SM) on immune function in relat…”

“beta-adrenergic receptors on tumor and stromal cells [34].”