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Barnard ME, Poole EM, Huang T, Sood AK, Kubzansky LD, Tworoger SS. Caregiver burden and risk of epithelial ovarian cancer in the Nurses' Health Studies. Am J Epidemiol 2025; 194:362-369. [PMID: 38973733 PMCID: PMC11815502 DOI: 10.1093/aje/kwae185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 05/09/2024] [Accepted: 07/02/2024] [Indexed: 07/09/2024] Open
Abstract
Psychosocial stress may increase ovarian cancer risk and accelerate disease progression. We examined the association between caregiver burden, a common stressor, and risk of epithelial ovarian cancer. We prospectively followed 67 724 women in the Nurses' Health Study (1992-2012) and 70 720 women in the Nurses' Health Study II (2001-2009) who answered questions on informal caregiving (ie, caregiving outside of work). Women who reported no informal caregiving were considered noncaregivers, while, among women who provided care outside of work, caregiver burden was categorized by time spent caregiving and perceived stress from caregiving. For the 34% of women who provided informal care for ≥15 hours per week, 42% described caregiving as moderately to extremely stressful. Pooled multivariate analyses indicated no difference in ovarian cancer risk for women providing ≥15 hours of care per week compared to noncaregivers (hazard ratio [HR] = 0.96; 95% confidence interval [CI], 0.79-1.18), and no association was evident for women who reported moderate or extreme stress from caregiving compared to noncaregivers (HR = 0.96; 95% CI, 0.75-1.22). Together with prior work evaluating job strain and ovarian cancer risk, our findings suggest that, when evaluating a stressor's role in cancer risk, it is critical to consider how the stressor contributes to the overall experience of distress. This article is part of a Special Collection on Gynecological Cancer.
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Affiliation(s)
- Mollie E Barnard
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
- Slone Epidemiology Center, Boston University Chobanian & Avedisian School of Medicine, Boston, MA 02118, United States
| | - Elizabeth M Poole
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, United States
| | - Tianyi Huang
- Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, United States
| | - Anil K Sood
- Departments of Gynecologic Oncology and Reproductive Medicine, MD Anderson Cancer Center, Houston, TX 77054, United States
| | - Laura D Kubzansky
- Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
| | - Shelley S Tworoger
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, United States
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL 33612, United States
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2
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Itami T, Kurokawa Y, Hagi T, Nagano S, Nakamoto R, Kamakura Y, Takahashi T, Saito T, Yamamoto K, Momose K, Yamashita K, Tanaka K, Makino T, Nakajima K, Eguchi H, Doki Y. Sympathetic innervation induced by nerve growth factor promotes malignant transformation in gastric cancer. Sci Rep 2025; 15:3824. [PMID: 39885251 PMCID: PMC11782669 DOI: 10.1038/s41598-025-87492-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2024] [Accepted: 01/20/2025] [Indexed: 02/01/2025] Open
Abstract
Sympathetic nerves regulate nearly all human organs. Their peripheral nerves are present in tumor tissue. Activation of the sympathetic nervous system promotes malignant transformation in several cancers. This study aimed to quantify sympathetic nerve density (SND) in gastric cancer and investigate the relationship between SND and nerve growth factor (NGF) in human clinical samples using immunohistochemistry. Patients with high SND in tumor tissue had significantly shorter survival. High NGF expression in tumor tissue was significantly associated with increased SND and poorer prognosis. In vitro studies demonstrated that nerve elongation of PC12 cells, a model for sympathetic neuron-like cells, was promoted by co-culture with gastric cancer cells expressing high NGF levels whereas nerve elongation was suppressed by NGF knockdown. Furthermore, noradrenaline, a neurotransmitter released from sympathetic nerve endings, induced malignant transformation by promoting epithelial-mesenchymal transition, increasing invasiveness and enhancing the ability of gastric cancer cells to migrate. These findings suggest that gastric cancer with high NGF expression might promote sympathetic innervation within tumor tissue, fostering malignant transformation through noradrenaline signaling. Thus, suppressing sympathetic nerve elongation or activation in gastric cancer might be a target for new therapeutic interventions.
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Affiliation(s)
- Takefumi Itami
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Takaomi Hagi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Shinnosuke Nagano
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Rennosuke Nakamoto
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yu Kamakura
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takuro Saito
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kazuyoshi Yamamoto
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kota Momose
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kotaro Yamashita
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Koji Tanaka
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kiyokazu Nakajima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan
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3
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Vermeer PD, Restaino AC, Barr JL, Yaniv D, Amit M. Nerves at Play: The Peripheral Nervous System in Extracranial Malignancies. Cancer Discov 2025; 15:52-68. [PMID: 39801235 DOI: 10.1158/2159-8290.cd-23-0397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 04/22/2024] [Accepted: 07/26/2024] [Indexed: 04/06/2025]
Abstract
The exponential growth of the cancer neuroscience field has shown that the host's immune, vascular, and nervous systems communicate with and influence each other in the tumor microenvironment, dictating the cancer malignant phenotype. Unraveling the nervous system's contributions toward this phenotype brings us closer to cancer cures. In this review, we summarize the peripheral nervous system's contributions to cancer. We highlight the effects of nerve recruitment and tumor innervation, the neuro-immune axis, glial cell activity, and neural regulation on cancer development and progression. We also discuss harnessing the neural control of peripheral cancers as a potential therapeutic approach in oncology. Significance: The continued and growing interest in cancer neuroscience by the scientific and medical communities reflects the rapidly accumulating interdisciplinary understanding of the nervous system's modulation of immune, vascular, and cancer cells' functions in malignancies. Understanding these regulatory functions can identify targets for intervention that may already be clinically available for other indications. This potential brings great excitement and hope for patients with cancer worldwide.
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Affiliation(s)
- Paola D Vermeer
- Sanford Research, Cancer Biology and Immunotherapies Group, Sioux Falls, South Dakota
- Sanford School of Medicine, Health Sciences Center, University of South Dakota, Sioux Falls, South Dakota
| | - Anthony C Restaino
- Sanford Research, Cancer Biology and Immunotherapies Group, Sioux Falls, South Dakota
- Sanford School of Medicine, Health Sciences Center, University of South Dakota, Sioux Falls, South Dakota
| | - Jeffrey L Barr
- Sanford Research, Cancer Biology and Immunotherapies Group, Sioux Falls, South Dakota
| | - Dan Yaniv
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Moran Amit
- Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Trachtenberg E, Ruzal K, Sandbank E, Bigelman E, Ricon-Becker I, Cole SW, Ben-Eliyahu S, Ben-Ami Bartal I. Deleterious effects of social isolation on neuroendocrine-immune status, and cancer progression in rats. Brain Behav Immun 2025; 123:524-539. [PMID: 39378972 DOI: 10.1016/j.bbi.2024.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 09/20/2024] [Accepted: 10/05/2024] [Indexed: 10/10/2024] Open
Abstract
Accumulating evidence indicates that social isolation (SI) in humans and rodents is associated with increased cancer incidence and mortality, yet mediating mechanisms remain elusive. Here, we examine the neuroendocrine and immunological consequences of SI and its short- and long-term physiological impacts in naïve and cancer-bearing rats. Findings indicate that isolated animals experienced a significant decrease in weight compared to controls. Specifically, females showed a marked weight decrease during the first week of isolation. Isolated rats had significantly higher numbers of MADB106 experimental pulmonary metastases. Although mortality rates were higher in isolated tumor-bearing rats, unexpectedly, they exhibited a reduced growth rate of orthotopically implanted MADB106 tumors. Transcriptomic analyses of these excised tumors indicated a major downregulation in the expression of various genes, including those associated with pro-metastatic processes (e.g., EMT). In naïve rats (no cancer), levels of IL-6 increased, and total IgG levels decreased under SI conditions. A mixed effect was found for TNFα, which increased in females and decreased in males. In the central nervous system, isolated rats showed altered gene expression in key brain regions associated with stress responses and social behavior. The paraventricular nucleus of the thalamus emerged as a significantly affected region, along with the bed nucleus of the stria terminalis. Changes were observed in the expression of oxytocin, serotonin, and dopamine receptors. Isolated rats also exhibited greater alterations in hypothalamic-pituitary-adrenal (HPA) axis-related regulation and an increase in plasma CORT levels. Our study highlights the profound impact of SI on metastatic processes. Additionally, the potential detrimental effects of SI on thermoregulation were discussed, emphasizing the importance of social thermoregulation in maintaining physiological stability and highlighting the need to avoid single-caging practices in research. We report neuro-immune interactions and changes in brain gene expression, highlighting the need for further research into these underlying processes to improve outcomes in animal models and potential interventions for cancer patients through increased social support.
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Affiliation(s)
- Estherina Trachtenberg
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Keren Ruzal
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Elad Sandbank
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Einat Bigelman
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Itay Ricon-Becker
- Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA
| | - Steve W Cole
- Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California Los Angeles (UCLA), Los Angeles, CA, USA
| | - Shamgar Ben-Eliyahu
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Inbal Ben-Ami Bartal
- School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
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Dong ZK, Wang YF, Li WP, Jin WL. Neurobiology of cancer: Adrenergic signaling and drug repurposing. Pharmacol Ther 2024; 264:108750. [PMID: 39527999 DOI: 10.1016/j.pharmthera.2024.108750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 10/04/2024] [Accepted: 11/05/2024] [Indexed: 11/16/2024]
Abstract
Cancer neuroscience, as an emerging converging discipline, provides us with new perspectives on the interactions between the nervous system and cancer progression. As the sympathetic nervous system, in particular adrenergic signaling, plays an important role in the regulation of tumor activity at every hierarchical level of life, from the tumor cell to the tumor microenvironment, and to the tumor macroenvironment, it is highly desirable to dissect its effects. Considering the far-reaching implications of drug repurposing for antitumor drug development, such a large number of adrenergic receptor antagonists on the market has great potential as one of the means of antitumor therapy, either as primary or adjuvant therapy. Therefore, this review aims to summarize the impact of adrenergic signaling on cancer development and to assess the status and prospects of intervening in adrenergic signaling as a therapeutic tool against tumors.
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Affiliation(s)
- Zi-Kai Dong
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China; Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China
| | - Yong-Fei Wang
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China; Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China
| | - Wei-Ping Li
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China; Department of Urology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, PR China
| | - Wei-Lin Jin
- The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China; Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou 730000, PR China.
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6
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Trachtenberg E. The beneficial effects of social support and prosocial behavior on immunity and health: A psychoneuroimmunology perspective. Brain Behav Immun Health 2024; 37:100758. [PMID: 38524896 PMCID: PMC10960128 DOI: 10.1016/j.bbih.2024.100758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 02/16/2024] [Accepted: 03/17/2024] [Indexed: 03/26/2024] Open
Abstract
The COVID-19 pandemic emphasized the pivotal role of the social environment, prompting a surge in research on its impact on well-being and health. This article aims to examine the link between the social environment, the immune system, and health outcomes, with a particular focus on positive aspects like social support and prosocial behaviors that are under-explored. Different aspects of the social environment are examined: the negative effects of loneliness and adverse social conditions, contrasted with the benefits of social support and prosocial behaviors. While the mechanisms behind negative effects are partially studied, those driving the positive effects remain elusive. Understanding the mechanisms of lack of social connection and their effects will allow us to explore the benefits of social connections and whether they can reverse the adverse outcomes. Potential psychoneuroimmunology mechanisms are proposed, highlighting the promotion of a 'safe' state by the vagus nerve, oxytocin circuits, and the additional contribution of the reward pathways. This article reviews the need to bridge knowledge gaps, urging further research to study the causal effects of positive social interactions on immune response and health outcomes to raise clinical awareness and interventions. Such interventions may include integrating lonely individuals with prosocial activities, thereby improving their physical and mental health. There is growing potential to harness the power of social connections for the betterment of individual health and society as a whole.
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Affiliation(s)
- Estherina Trachtenberg
- Sagol School of Neuroscience, Tel Aviv University, Israel
- School of Psychological Sciences, Faculty of Social Sciences, Tel Aviv University, Israel
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7
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Shiralkar J, Anthony T, McCallum GA, Durand DM. Neural recordings can differentiate between spontaneously metastasizing melanomas and melanomas with low metastatic potential. PLoS One 2024; 19:e0297281. [PMID: 38359031 PMCID: PMC10868782 DOI: 10.1371/journal.pone.0297281] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/02/2024] [Indexed: 02/17/2024] Open
Abstract
Multiple studies report that melanomas are innervated tumors with sensory and sympathetic fibers where these neural fibers play crucial functional roles in tumor growth and metastasis with branch specificity. Yet there is no study which reports the direct neural recording and its pattern during in-vivo progression of the cancer. We performed daily neural recordings from male and female mice bearing orthotopic metastasizing- melanomas and melanomas with low metastatic poential, derived from B16-F10 and B16-F1 cells, respectively. Further, to explore the origins of neural activity, 6-Hydroxidopamine mediated chemical sympathectomy was performed followed by daily microneurographic recordings. We also performed the daily bioluminescent imaging to track in vivo growth of primary tumors and distant metastasis to the cranial area. Our results show that metastasizing tumors display high levels of neural activity while tumors with low metastatic potential lack it indicating that the presence of neural activity is linked to the metastasizing potential of the tumors. Moreover, the neural activity is not continuous over the tumor progression and has a sex-specific temporal patterns where males have two peaks of high neural activity while females show a single peak. The neural peak activity originated in peripheral sympathetic nerves as sympathectomy completely eliminated the peak activity in both sexes. Peak activities were highly correlated with the distant metastasis in both sexes. These results show that sympathetic neural activity is crucially involved in tumor metastasis and has sex-specific role in malignancy initiation.
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Affiliation(s)
- Jay Shiralkar
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Tiana Anthony
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Grant A. McCallum
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States of America
| | - Dominique M. Durand
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio, United States of America
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8
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Hathaway CA, Townsend MK, Conejo-Garcia JR, Fridley BL, Moran Segura C, Nguyen JV, Armaiz-Pena GN, Sasamoto N, Saeed-Vafa D, Terry KL, Kubzansky LD, Tworoger SS. The relationship of lifetime history of depression on the ovarian tumor immune microenvironment. Brain Behav Immun 2023; 114:52-60. [PMID: 37557966 PMCID: PMC10592154 DOI: 10.1016/j.bbi.2023.08.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Revised: 08/04/2023] [Accepted: 08/06/2023] [Indexed: 08/11/2023] Open
Abstract
BACKGROUND Depression is associated with a higher ovarian cancer risk. Prior work suggests that depression can lead to systemic immune suppression, which could potentially alter the anti-tumor immune response. METHODS We evaluated the association of pre-diagnosis depression with features of the anti-tumor immune response, including T and B cells and immunoglobulins, among women with ovarian tumor tissue collected in three studies, the Nurses' Health Study (NHS; n = 237), NHSII (n = 137) and New England Case-Control Study (NECC; n = 215). Women reporting depressive symptoms above a clinically relevant cut-point, antidepressant use, or physician diagnosis of depression at any time prior to diagnosis of ovarian cancer were considered to have pre-diagnosis depression. Multiplex immunofluorescence was performed on tumor tissue microarrays to measure immune cell infiltration. In pooled analyses, we estimated odds ratios (OR) and 95% confidence intervals (CI) for the positivity of tumor immune cells using a beta-binomial model comparing those with and without depression. We used Bonferroni corrections to adjust for multiple comparisons. RESULTS We observed no statistically significant association between depression status and any immune markers at the Bonferroni corrected p-value of 0.0045; however, several immune markers were significant at a nominal p-value of 0.05. Specifically, there were increased odds of having recently activated cytotoxic (CD3+CD8+CD69+) and exhausted-like T cells (CD3+Lag3+) in tumors of women with vs. without depression (OR = 1.36, 95 %CI = 1.09-1.69 and OR = 1.24, 95 %CI = 1.01-1.53, respectively). Associations were comparable when considering high grade serous tumors only (comparable ORs = 1.33, 95 %CI = 1.05-1.69 and OR = 1.25, 95 %CI = 0.99-1.58, respectively). There were decreased odds of having tumor infiltrating plasma cells (CD138+) in women with vs. without depression (OR = 0.54, 95 %CI = 0.33-0.90), which was similar among high grade serous carcinomas, although not statistically significant. Depression was also related to decreased odds of having naïve and memory B cells (CD20+: OR = 0.54, 95 %CI = 0.30-0.98) and increased odds of IgG (OR = 1.22, 95 %CI = 0.97-1.53) in high grade serous carcinomas. CONCLUSION Our results provide suggestive evidence that depression may influence ovarian cancer outcomes through changes in the tumor immune microenvironment, including increasing T cell activation and exhaustion and reducing antibody-producing B cells. Further studies with clinical measures of depression and larger samples are needed to confirm these results.
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Affiliation(s)
| | - Mary K Townsend
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA
| | | | - Brooke L Fridley
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, USA
| | - Carlos Moran Segura
- Advanced Analytical and Digital Laboratory, Moffitt Cancer Center, Tampa, FL, USA
| | - Jonathan V Nguyen
- Advanced Analytical and Digital Laboratory, Moffitt Cancer Center, Tampa, FL, USA
| | - Guillermo N Armaiz-Pena
- Department of Basic Sciences, Division of Pharmacology, School of Medicine, Ponce Health Sciences University, Ponce, PR, USA
| | - Naoko Sasamoto
- Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Daryoush Saeed-Vafa
- Advanced Analytical and Digital Laboratory, Moffitt Cancer Center, Tampa, FL, USA; Department of Anatomic Pathology, Moffitt Cancer Center, Tampa, FL, USA
| | - Kathryn L Terry
- Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Laura D Kubzansky
- Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Shelley S Tworoger
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
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9
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Lempesis IG, Georgakopoulou VE, Papalexis P, Chrousos GP, Spandidos DA. Role of stress in the pathogenesis of cancer (Review). Int J Oncol 2023; 63:124. [PMID: 37711028 PMCID: PMC10552722 DOI: 10.3892/ijo.2023.5572] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 09/01/2023] [Indexed: 09/16/2023] Open
Abstract
Stress is a state of disrupted homeostasis, triggered by intrinsic or extrinsic factors, the stressors, which are counteracted by various physiological and behavioural adaptive responses. Stress has been linked to cancer development and incidence for decades; however, epidemiological studies and clinical trials have yielded contradictory results. The present review discusses the effects of stress on cancer development and the various underlying mechanisms. Animal studies have revealed a clear link between stress and cancer progression, revealing molecular, cellular and endocrine processes that are implicated in these effects. Thus, stress hormones, their receptor systems and their intracellular molecular pathways mediate the effects of stress on cancer initiation, progression and the development of metastases. The mechanisms linking stress and cancer progression can either be indirect, mediated by changes in the cancer microenvironment or immune system dysregulation, or direct, through the binding of neuroendocrine stress‑related signalling molecules to cancer cell receptors. Stress affects numerous anti‑ and pro‑cancer immune system components, including host resistance to metastasis, tumour retention and/or immune suppression. Chronic psychological stress through the elevation of catecholamine levels may increase cancer cell death resistance. On the whole, stress is linked to cancer development and incidence, with psychological stressors playing a crucial role. Animal studies have revealed a better link than human ones, with stress‑related hormones influencing tumour development, migration, invasion and cell proliferation. Randomized controlled trials are required to further evaluate the long‑term cancer outcomes of stress and its management.
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Affiliation(s)
- Ioannis G. Lempesis
- Department of Infectious Diseases-COVID-19 Unit, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Department of Pathophysiology, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Vasiliki Epameinondas Georgakopoulou
- Department of Infectious Diseases-COVID-19 Unit, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Department of Pathophysiology, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Petros Papalexis
- Unit of Endocrinology, First Department of Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
- Department of Biomedical Sciences, University of West Attica, 12243 Athens, Greece
| | - Georgios P. Chrousos
- Clinical, Translational and Experimental Surgery Research Centre, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
- University Research Institute of Maternal and Child Health and Precision Medicine and UNESCO Chair on Adolescent Health Care, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, 11527 Athens, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, School of Medicine, University of Crete, 71003 Heraklion, Greece
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10
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Kanbay M, Tanriover C, Copur S, Peltek IB, Mutlu A, Mallamaci F, Zoccali C. Social isolation and loneliness: Undervalued risk factors for disease states and mortality. Eur J Clin Invest 2023; 53:e14032. [PMID: 37218451 DOI: 10.1111/eci.14032] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/07/2023] [Accepted: 05/12/2023] [Indexed: 05/24/2023]
Abstract
Social isolation and loneliness are two common but undervalued conditions associated with a poor quality of life, decreased overall health and mortality. In this review, we aim to discuss the health consequences of social isolation and loneliness. We first provide the potential causes of these two conditions. Then, we explain the pathophysiological processes underlying the effects of social isolation and loneliness in disease states. Afterwards, we explain the important associations between these conditions and different non-communicable diseases, as well as the impact of social isolation and loneliness on health-related behaviours. Finally, we discuss the current and novel potential management strategies for these conditions. Healthcare professionals who attend to socially isolated and/or lonely patients should be fully competent in these conditions and assess their patients thoroughly to detect and properly understand the effects of isolation and loneliness. Patients should be offered education and treatment alternatives through shared decision-making. Future studies are needed to understand the underlying mechanisms better and to improve the treatment strategies for both social isolation and loneliness.
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Affiliation(s)
- Mehmet Kanbay
- Department of Medicine, Division of Nephrology, Koc University School of Medicine, Istanbul, Turkey
| | - Cem Tanriover
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Ibrahim B Peltek
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Ali Mutlu
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Francesca Mallamaci
- Nephrology, Dialysis and Transplantation Unit Azienda Ospedaliera "Bianchi-Melacrino-Morelli" & CNR-IFC, Institute of Clinical Physiology, Research Unit of Clinical Epidemiology and Physiopathology of Renal Diseases and Hypertension of Reggio Calabria, Reggio Calabria, Italy
| | - Carmine Zoccali
- Renal Research Institute, New York City, New York, USA
- Institute of Molecular Biology and Genetics (Biogem), Ariano Irpino, Italy and Associazione Ipertensione Nefrologia Trapianto Renal (IPNET), c/o Nefrologia, Grande Ospedale Metropolitano, Reggio Calabria, Italy
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11
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Hilakivi-Clarke L, de Oliveira Andrade F. Social Isolation and Breast Cancer. Endocrinology 2023; 164:bqad126. [PMID: 37586098 DOI: 10.1210/endocr/bqad126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 08/10/2023] [Accepted: 08/11/2023] [Indexed: 08/18/2023]
Abstract
Although the role of life stressors in breast cancer remains unclear, social isolation is consistently associated with increased breast cancer risk and mortality. Social isolation can be defined as loneliness or an absence of perceived social connections. In female mice and rats, social isolation is mimicked by housing animals 1 per cage. Social isolation causes many biological changes, of which an increase in inflammatory markers and disruptions in mitochondrial and cellular metabolism are commonly reported. It is not clear how the 2 traditional stress-induced pathways, namely, the hypothalamic-pituitary-adrenocortical axis (HPA), resulting in a release of glucocorticoids from the adrenal cortex, and autonomic nervous system (ANS), resulting in a release of catecholamines from the adrenal medulla and postganglionic neurons, could explain the increased breast cancer risk in socially isolated individuals. For instance, glucocorticoid receptor activation in estrogen receptor positive breast cancer cells inhibits their proliferation, and activation of β-adrenergic receptor in immature immune cells promotes their differentiation toward antitumorigenic T cells. However, activation of HPA and ANS pathways may cause a disruption in the brain-gut-microbiome axis, resulting in gut dysbiosis. Gut dysbiosis, in turn, leads to an alteration in the production of bacterial metabolites, such as short chain fatty acids, causing a systemic low-grade inflammation and inducing dysfunction in mitochondrial and cellular metabolism. A possible causal link between social isolation-induced increased breast cancer risk and mortality and gut dysbiosis should be investigated, as it offers new tools to prevent breast cancer.
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Affiliation(s)
- Leena Hilakivi-Clarke
- Department of Food Science and Nutrition, The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
| | - Fabia de Oliveira Andrade
- Department of Food Science and Nutrition, The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
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12
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Roberts AL, Ratanatharathorn A, Chibnik L, Kubzansky LD, Tworoger SS. Multiple types of distress are prospectively associated with increased risk of ovarian cancer. Cancer Med 2023; 12:15404-15413. [PMID: 37326414 PMCID: PMC10417295 DOI: 10.1002/cam4.6125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/05/2023] [Accepted: 05/14/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND Few modifiable risk factors for epithelial ovarian cancer have been identified. We and other investigators have found that individual psychosocial factors related to distress are associated with higher risk of ovarian cancer. The present study examined whether co-occurring distress-related factors are associated with ovarian cancer risk. METHODS Five distress-related factors were measured repeatedly over 21 years of follow-up: depression, anxiety, social isolation, widowhood, and, in a subset or women, posttraumatic stress disorder (PTSD). Cox proportional hazards models estimate relative risks (RR) and 95% confidence intervals (CI) of ovarian cancer for a time-updated count of distress-related factors, in age-adjusted models, then further adjusted for ovarian cancer risk factors and behavior-related health risk factors. RESULTS Across 1,193,927 person-years of follow-up, 526 incident ovarian cancers occurred. Women with ≥3 versus no distress-related psychosocial factors demonstrated increased ovarian cancer risk (HRage-adjusted = 1.71; 95% CI = 1.16, 2.52). No significant difference in ovarian cancer risk was observed in women with one or two versus no distress-related psychosocial factors. In the subsample with PTSD assessed, ≥3 versus no distress-related psychosocial factors was associated with twofold greater ovarian cancer risk (HRage-adjusted = 2.08, 95% CI = 1.01, 4.29). Further analysis suggested that women at highest ovarian cancer risk had PTSD co-occurring with any other distress-related factor (HR = 2.19, 95% CI = 1.20, 4.01). Adjusting for cancer risk factors and health behaviors minimally impacted risk estimates. CONCLUSIONS Presence of multiple indicators of distress was associated with risk of ovarian cancer. When including PTSD as an indicator of distress, the association was strengthened.
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Affiliation(s)
- Andrea L. Roberts
- Department of Environmental HealthHarvard T. H. Chan School of Public HealthBostonMassachusettsUSA
| | - Andrew Ratanatharathorn
- Department of Environmental HealthHarvard T. H. Chan School of Public HealthBostonMassachusettsUSA
| | - Lori Chibnik
- Department of Environmental HealthHarvard T. H. Chan School of Public HealthBostonMassachusettsUSA
| | - Laura D. Kubzansky
- Department of Environmental HealthHarvard T. H. Chan School of Public HealthBostonMassachusettsUSA
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13
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Cheraghian H, Moradian K, Nouri T. Structural model of resilience based on parental support: the mediating role of hope and active coping. BMC Psychiatry 2023; 23:260. [PMID: 37069519 PMCID: PMC10111699 DOI: 10.1186/s12888-023-04678-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 03/13/2023] [Indexed: 04/19/2023] Open
Abstract
Resilience is an essential trait in the academic and non-academic lives of students that has been associated with positive psychological and non-psychological outcomes. Given the importance and role of resilience, the main goal of this study was to create a structural model of resilience based on parental support and emphasizing the mediating role of hope and coping. The research design was correlational in nature and used structural equation modeling (SEM). The population of this study included high school students in Tehran city in 2019-2020 school year, and the sample consisted of 560 students selected by cluster sampling method. By applying Spearman correlation analysis and structural equation modeling, a significant relationship between hope, coping, resilience, and parental support was found. Both the SEM measurement and structural models provided a good fit. The significant findings of the present study include the direct and significant effect of parental support on resilience. The indirect and significant effect of parental support on resilience through the mediating role of hope and coping was also confirmed. Overall, the results of this study show that the effect of parental support on resilience can be improved by promoting hope and coping styles.
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14
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Abstract
The recently uncovered key role of the peripheral and central nervous systems in controlling tumorigenesis and metastasis has opened a new area of research to identify innovative approaches against cancer. Although the 'neural addiction' of cancer is only partially understood, in this Perspective we discuss the current knowledge and perspectives on peripheral and central nerve circuitries and brain areas that can support tumorigenesis and metastasis and the possible reciprocal influence that the brain and peripheral tumours exert on one another. Tumours can build up local autonomic and sensory nerve networks and are able to develop a long-distance relationship with the brain through circulating adipokines, inflammatory cytokines, neurotrophic factors or afferent nerve inputs, to promote cancer initiation, growth and dissemination. In turn, the central nervous system can affect tumour development and metastasis through the activation or dysregulation of specific central neural areas or circuits, as well as neuroendocrine, neuroimmune or neurovascular systems. Studying neural circuitries in the brain and tumours, as well as understanding how the brain communicates with the tumour or how intratumour nerves interplay with the tumour microenvironment, can reveal unrecognized mechanisms that promote cancer development and progression and open up opportunities for the development of novel therapeutic strategies. Targeting the dysregulated peripheral and central nervous systems might represent a novel strategy for next-generation cancer treatment that could, in part, be achieved through the repurposing of neuropsychiatric drugs in oncology.
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Affiliation(s)
- Claire Magnon
- Laboratory of Cancer and Microenvironment-National Institute of Health and Medical Research (INSERM), Institute of Biology François Jacob-Atomic Energy Commission (CEA), University of Paris Cité, University of Paris-Saclay, Paris, France.
| | - Hubert Hondermarck
- School of Biomedical Sciences and Pharmacy, Hunter Medical Research Institute, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
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15
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Yan J, Chen Y, Luo M, Hu X, Li H, Liu Q, Zou Z. Chronic stress in solid tumor development: from mechanisms to interventions. J Biomed Sci 2023; 30:8. [PMID: 36707854 PMCID: PMC9883141 DOI: 10.1186/s12929-023-00903-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 01/17/2023] [Indexed: 01/29/2023] Open
Abstract
Chronic stress results in disturbances of body hormones through the neuroendocrine system. Cancer patients often experience recurrent anxiety and restlessness during disease progression and treatment, which aggravates disease progression and hinders treatment effects. Recent studies have shown that chronic stress-regulated neuroendocrine systems secret hormones to activate many signaling pathways related to tumor development in tumor cells. The activated neuroendocrine system acts not only on tumor cells but also modulates the survival and metabolic changes of surrounding non-cancerous cells. Current clinical evidences also suggest that chronic stress affects the outcome of cancer treatment. However, in clinic, there is lack of effective treatment for chronic stress in cancer patients. In this review, we discuss the main mechanisms by which chronic stress regulates the tumor microenvironment, including functional regulation of tumor cells by stress hormones (stem cell-like properties, metastasis, angiogenesis, DNA damage accumulation, and apoptotic resistance), metabolic reprogramming and immune escape, and peritumor neuromodulation. Based on the current clinical treatment framework for cancer and chronic stress, we also summarize pharmacological and non-pharmacological therapeutic approaches to provide some directions for cancer therapy.
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Affiliation(s)
- Jiajing Yan
- grid.263785.d0000 0004 0368 7397MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631 China
| | - Yibing Chen
- grid.207374.50000 0001 2189 3846Department of Gynecology and Obstetrics, First Affiliated Hospital, Genetic and Prenatal Diagnosis Center, Zhengzhou University, Zhengzhou, 450001 China
| | - Minhua Luo
- grid.263785.d0000 0004 0368 7397MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631 China
| | - Xinyu Hu
- grid.263785.d0000 0004 0368 7397MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631 China
| | - Hongsheng Li
- grid.410737.60000 0000 8653 1072Department of Breast Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095 China
| | - Quentin Liu
- grid.488530.20000 0004 1803 6191State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, 510631 China ,grid.411971.b0000 0000 9558 1426Institute of Cancer Stem Cell, Dalian Medical University, Dalian, 116044 Liaoning China
| | - Zhengzhi Zou
- grid.263785.d0000 0004 0368 7397MOE Key Laboratory of Laser Life Science & Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631 China ,grid.263785.d0000 0004 0368 7397Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631 China
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16
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Lutgendorf SK, Thaker PH, Goodheart MJ, Arevalo JM, Chowdhury MA, Noble AE, Dahmoush L, Slavich GM, Penedo FJ, Sood AK, Cole SW. Biobehavioral factors predict an exosome biomarker of ovarian carcinoma disease progression. Cancer 2022; 128:4157-4165. [PMID: 36251340 PMCID: PMC9744596 DOI: 10.1002/cncr.34496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND Biobehavioral factors such as social isolation and depression have been associated with disease progression in ovarian and other cancers. Here, the authors developed a noninvasive, exosomal RNA profile for predicting ovarian cancer disease progression and subsequently tested whether it increased in association with biobehavioral risk factors. METHODS Exosomes were isolated from plasma samples from 100 women taken before primary surgical resection or neoadjuvant (NACT) treatment of ovarian carcinoma and 6 and 12 months later. Biobehavioral measures were sampled at all time points. Plasma from 76 patients was allocated to discovery analyses in which morning presurgical/NACT exosomal RNA profiles were analyzed by elastic net machine learning to identify a biomarker predicting rapid (≤6 months) versus more extended disease-free intervals following initial treatment. Samples from a second subgroup of 24 patients were analyzed by mixed-effects linear models to determine whether the progression-predictive biomarker varied longitudinally as a function of biobehavioral risk factors (social isolation and depressive symptoms). RESULTS An RNA-based molecular signature was identified that discriminated between individuals who had disease progression in ≤6 months versus >6 months, independent of clinical variables (age, disease stage, and grade). In a second group of patients analyzed longitudinally, social isolation and depressive symptoms were associated with upregulated expression of the disease progression propensity biomarker, adjusting for covariates. CONCLUSION These data identified a novel exosome-derived biomarker indicating propensity of ovarian cancer progression that is sensitive to biobehavioral variables. This derived biomarker may be potentially useful for risk assessment, intervention targeting, and treatment monitoring.
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Affiliation(s)
- Susan K. Lutgendorf
- Department of Psychological & Brain Sciences, University of Iowa, Iowa City, IA
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA
| | - Premal H. Thaker
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO
| | - Michael J. Goodheart
- Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA
| | - Jesusa M.G. Arevalo
- Division of Hematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA
| | - Mamur A. Chowdhury
- Departments of Gynecologic Oncology, Cancer Biology and Center for RNA Interference and Noncoding RNA, University of Texas M.D. Anderson Cancer Center, Houston TX
| | - Alyssa E. Noble
- Department of Psychological & Brain Sciences, University of Iowa, Iowa City, IA
| | - Laila Dahmoush
- Department of Pathology, University of Iowa, Iowa City, IA
| | - George M. Slavich
- Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, CA
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA
| | - Frank J. Penedo
- Department of Psychology and Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL
| | - Anil K. Sood
- Departments of Gynecologic Oncology, Cancer Biology and Center for RNA Interference and Noncoding RNA, University of Texas M.D. Anderson Cancer Center, Houston TX
| | - Steven W. Cole
- Division of Hematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA
- Cousins Center for Psychoneuroimmunology, University of California, Los Angeles, CA
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA
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17
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Li G, Qian Y, Chen Y, Cao M, Yang X, Kong D, Wang G, An H, Yang N, Huang W, Liu Y. Wip1 contributes to the adaptation of HepG2 human liver cancer cells to stress hormone-induced DNA damage. Oncol Lett 2022; 25:31. [PMID: 36589663 PMCID: PMC9773319 DOI: 10.3892/ol.2022.13617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 10/19/2022] [Indexed: 12/03/2022] Open
Abstract
Numerous studies have shown that the release of stress hormones resulting from repeated exposure to chronic psychological stress increases DNA damage and promotes tumorigenesis. However, the mechanisms that enable cancerous cells adapt to stress hormone-induced DNA damage and survive remain unclear. The present study aimed to investigate the impact of stress hormones on the survival of liver cancer cells and the underlying mechanism. HepG2 human liver cancer cells were treated with dexamethasone (DEX), epinephrine (EPI) and norepinephrine (NE) and subjected to the testing of DNA damage, cell survival and cell apoptosis by alkaline comet assay, CCK-8 viability assay and flow cytometry, respectively. The protein expression levels of DNA damage response factors were determined by western blotting analysis. The results revealed that treatment of HepG2 cells with DEX, EPI and NE induced DNA damage without affecting cell survival or inducing apoptosis. The protein levels of wild-type p53-induced phosphatase 1 (Wip1), a type 2C family serine/threonine phosphatase, were increased, and the dephosphorylation of DNA damage response factors, including phosphorylated (p-)ataxia-telangiectasia mutated and p-checkpoint kinase 2, occurred following treatment with DEX, EPI and NE. In addition, a cycloheximide chase assay was performed to explore the protein stability under treatment with stress hormones. Compared with vehicle-treated cells, Wip1 exhibited increased protein stability in stress hormone-treated HepG2 cells. Eventually, the depletion of Wip1 using small interfering RNA verified the role of Wip1 in the modulation of stress hormone-induced DNA damage. These findings suggest that cancerous cells likely adapt to stress hormone-induced DNA damage via Wip1 upregulation. The present study provides an insight into the underlying mechanism that links chronic psychological stress with tumor growth and progression.
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Affiliation(s)
- Gaoxiang Li
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China,Medical College, Tibet University, Lhasa, Tibet Autonomous Region 850000, P.R. China
| | - Yazhi Qian
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China
| | - Yuzhu Chen
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China
| | - Mingyue Cao
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China
| | - Xiaozhou Yang
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China
| | - Dexin Kong
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China
| | - Guiping Wang
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China,Medical College, Tibet University, Lhasa, Tibet Autonomous Region 850000, P.R. China
| | - Haiyan An
- Department of Anesthesiology, Peking University People's Hospital, Beijing 100044, P.R. China
| | - Nan Yang
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China
| | - Wei Huang
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China,Correspondence to: Dr Yanyong Liu or Dr Wei Huang, Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Dong-Cheng, Beijing 100005, P.R. China, E-mail: , E-mail:
| | - Yanyong Liu
- Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China,Medical College, Tibet University, Lhasa, Tibet Autonomous Region 850000, P.R. China,Correspondence to: Dr Yanyong Liu or Dr Wei Huang, Department of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, 5 Dong Dan San Tiao, Dong-Cheng, Beijing 100005, P.R. China, E-mail: , E-mail:
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18
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Profiling the Adrenergic System in Breast Cancer and the Development of Metastasis. Cancers (Basel) 2022; 14:cancers14225518. [PMID: 36428611 PMCID: PMC9688855 DOI: 10.3390/cancers14225518] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/04/2022] [Accepted: 11/07/2022] [Indexed: 11/12/2022] Open
Abstract
Epidemiological studies and preclinical models suggest that chronic stress might accelerate breast cancer (BC) growth and the development of metastasis via sympathetic neural mechanisms. Nevertheless, the role of each adrenergic pathway (α1, α2, and β) in human samples remains poorly depicted. Herein, we propose to characterize the profile of the sympathetic system (e.g., release of catecholamines, expression of catecholamine metabolic enzymes and adrenoreceptors) in BC patients, and ascertain its relevance in the development of distant metastasis. Our results demonstrated that BC patients exhibited increased plasma levels of catecholamines when compared with healthy donors, and this increase was more evident in BC patients with distant metastasis. Our analysis using the BC-TCGA database revealed that the genes coding the most expressed adrenoreceptors in breast tissues (ADRA2A, ADRA2C, and ADRB2, by order of expression) as well as the catecholamine synthesizing (PNMT) and degrading enzyme (MAO-A and MAO-B) genes were downregulated in BC tissues. Importantly, the expression of ADRA2A, ADRA2C, and ADRB2 was correlated with metastatic BC and BC subtypes, and thus the prognosis of the disease. Overall, we gathered evidence that under stressful conditions, both the α2- and β2-signaling pathways might work on a synergetic matter, thus paving the way for the development of new therapeutic approaches.
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19
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Fraile-Martinez O, Alvarez-Mon MA, Garcia-Montero C, Pekarek L, Guijarro LG, Lahera G, Saez MA, Monserrat J, Motogo D, Quintero J, Alvarez-Mon M, Ortega MA. Understanding the basis of major depressive disorder in oncological patients: Biological links, clinical management, challenges, and lifestyle medicine. Front Oncol 2022; 12:956923. [PMID: 36185233 PMCID: PMC9524231 DOI: 10.3389/fonc.2022.956923] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 08/23/2022] [Indexed: 12/03/2022] Open
Abstract
In recent years, the incidence of different types of cancer and patient survival have been rising, as well as their prevalence. The increase in survival in recent years exposes the patients to a set of stressful factors such as more rigorous follow-up and more aggressive therapeutic regimens that, added to the diagnosis of the disease itself, cause an increase in the incidence of depressive disorders. These alterations have important consequences for the patients, reducing their average survival and quality of life, and for these reasons, special emphasis has been placed on developing numerous screening tests and early recognition of depressive symptoms. Despite that cancer and major depressive disorder are complex and heterogeneous entities, they also share many critical pathophysiological mechanisms, aiding to explain this complex relationship from a biological perspective. Moreover, a growing body of evidence is supporting the relevant role of lifestyle habits in the prevention and management of both depression and cancer. Therefore, the present study aims to perform a thorough review of the intricate relationship between depression and cancer, with a special focus on its biological links, clinical management, challenges, and the central role of lifestyle medicine as adjunctive and preventive approaches to improve the quality of life of these patients.
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Affiliation(s)
- Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | - Miguel A. Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Department of Psychiatry and Mental Health, Hospital Universitario Infanta Leonor, Madrid, Spain
- *Correspondence: Miguel A. Alvarez-Mon, ;
| | - Cielo Garcia-Montero
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | - Leonel Pekarek
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Oncology Service, Guadalajara University Hospital, Guadalajara, Spain
| | - Luis G. Guijarro
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Unit of Biochemistry and Molecular Biology, Department of System Biology, Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas (CIBEREHD), University of Alcalá, Alcala de Henares, Spain
| | - Guillermo Lahera
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Psychiatry Service, Center for Biomedical Research in the Mental Health Network, University Hospital Príncipe de Asturias Centro de Investigación Biomédica en Red en el Área temática de Salud Mental (CIBERSAM), Alcalá de Henares, Spain
| | - Miguel A. Saez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Pathological Anatomy Service, Central University Hospital of Defence-UAH Madrid, Alcala de Henares, Spain
| | - Jorge Monserrat
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
| | - Domitila Motogo
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
| | - Javier Quintero
- Department of Psychiatry and Mental Health, Hospital Universitario Infanta Leonor, Madrid, Spain
- Department of Legal Medicine and Psychiatry, Complutense University, Madrid, Spain
| | - Melchor Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Immune System Diseases-Rheumatology, Oncology Service an Internal Medicine, Centro de Investigación Biomédica en Red en el Área temática de Enfermedades Hepáticas (CIBEREHD), University Hospital Príncipe de Asturias, Alcala de Henares, Spain
| | - Miguel A. Ortega
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), Madrid, Spain
- Cancer Registry and Pathology Department, Principe de Asturias University Hospital, Alcala de Henares, Spain
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Obesity and cancer-extracellular matrix, angiogenesis, and adrenergic signaling as unusual suspects linking the two diseases. Cancer Metastasis Rev 2022; 41:517-547. [PMID: 36074318 PMCID: PMC9470659 DOI: 10.1007/s10555-022-10058-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 07/29/2022] [Indexed: 12/24/2022]
Abstract
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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21
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Gong C, Hu B, Chen H, Zhu J, Nie J, Hua L, Chen L, Fang Y, Hang C, Lu Y. β2-adrenergic receptor drives the metastasis and invasion of pancreatic ductal adenocarcinoma through activating Cdc42 signaling pathway. J Mol Histol 2022; 53:645-655. [PMID: 35717490 DOI: 10.1007/s10735-022-10076-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 05/23/2022] [Indexed: 10/18/2022]
Abstract
Recent investigations indicate that β2-adrenergic receptor (β2-AR) signaling may facilitate the progression of various tumors, whose underlying mechanisms remain largely elusive. In the present study, we showed that β2-AR recruited Cdc42 in response to isoproterenol (ISO, a β-AR selective agonist) exposure in pancreatic ductal adenocarcinoma (PDAC) cells. The association of β2-AR and Cdc42 promoted the activation of Cdc42, as revealed by increased levels of Cdc42-GTP, and co-incubation with β2-AR antagonist abrogated ISO-induced activation of Cdc42. β2-AR-mediated Cdc42 activation further led to the phosphorylation of downstream PAK1, LIMK1 and Merlin. Furthermore, we showed that the activation of β2-AR/Cdc42 signaling facilitated the migration and invasion of PDAC cells. In addition, β2-AR and Cdc42 were overexpressed in PDAC specimens, compared with adjacent non-tumor tissues. High expression of β2-AR and Cdc42 were correlated with lymph node metastasis and TNM stage in PDAC patients. Finally, we showed that overexpression of β2-AR and Cdc42 were indicative of unfavorable prognosis in PDAC patients. Taken together, our findings suggested that β2-AR might facilitate Cdc42 signaling to drive the migration and invasion of PDAC cells, consequently resulting in the metastasis and dismal prognosis of PDAC. These studies highlight targeting β2-AR/Cdc42 signaling as a therapeutic strategy against PDAC.
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Affiliation(s)
- Chen Gong
- Department of Gastroenterology, Taicang Affiliated Hospital of Soochow University, The First People's Hospital of Taicang, Taicang, 215400, Jiangsu Province, China
| | - Baoying Hu
- Department of Immunology, Nantong University School of Medicine, Nantong, 226001, Jiangsu Province, China
| | - Haifeng Chen
- Department of Gastroenterology, Taicang Affiliated Hospital of Soochow University, The First People's Hospital of Taicang, Taicang, 215400, Jiangsu Province, China
| | - Jianxin Zhu
- Department of Gastroenterology, Taicang Affiliated Hospital of Soochow University, The First People's Hospital of Taicang, Taicang, 215400, Jiangsu Province, China
| | - Jinshan Nie
- Department of Gastroenterology, Taicang Affiliated Hospital of Soochow University, The First People's Hospital of Taicang, Taicang, 215400, Jiangsu Province, China
| | - Lu Hua
- Department of Oncology, Taizhou People's Hospital, Taizhou, 225300, Jiangsu Province, China
| | - Long Chen
- Department of Gastroenterology, Taicang Affiliated Hospital of Soochow University, The First People's Hospital of Taicang, Taicang, 215400, Jiangsu Province, China
| | - Yanfei Fang
- Department of Gastroenterology, Taicang Affiliated Hospital of Soochow University, The First People's Hospital of Taicang, Taicang, 215400, Jiangsu Province, China
| | - Cheng Hang
- Department of Gastroenterology, Taicang Affiliated Hospital of Soochow University, The First People's Hospital of Taicang, Taicang, 215400, Jiangsu Province, China.
| | - Ye Lu
- Department of Hematology and Oncology, Taicang Affiliated Hospital of Soochow University, The First People's Hospital of Taicang, Taicang, 215400, Jiangsu Province, China.
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22
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Hamilton A, Rizzo R, Brod S, Ono M, Perretti M, Cooper D, D'Acquisto F. The immunomodulatory effects of social isolation in mice are linked to temperature control. Brain Behav Immun 2022; 102:179-194. [PMID: 35217174 DOI: 10.1016/j.bbi.2022.02.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 01/17/2022] [Accepted: 02/18/2022] [Indexed: 12/25/2022] Open
Abstract
Living in isolation is considered an emerging societal problem that negatively affects the physical wellbeing of its sufferers in ways that we are just starting to appreciate. This study investigates the immunomodulatory effects of social isolation in mice, utilising a two-week program of sole cage occupancy followed by the testing of immune-inflammatory resilience to bacterial sepsis. Our results revealed that mice housed in social isolation showed an increased ability to clear bacterial infection compared to control socially housed animals. These effects were associated with specific changes in whole blood gene expression profile and an increased production of classical pro-inflammatory cytokines. Interestingly, equipping socially isolated mice with artificial nests as a substitute for their natural huddling behaviour reversed the increased resistance to bacterial sepsis. Together these results suggest that the control of body temperature through social housing and huddling behaviour are important factors in the regulation of the host immune response to infection in mice and might provide another example of the many ways by which living conditions influence immunity.
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Affiliation(s)
- Alice Hamilton
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Raffaella Rizzo
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Samuel Brod
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Masahiro Ono
- University of London Imperial College Science Technology & Medicine, Department of Life Science, Faculty of Natural Science, London SW7 2AZ, England
| | - Mauro Perretti
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Dianne Cooper
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Fulvio D'Acquisto
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; School of Life and Health Science, University of Roehampton, London SW15, 4JD, UK.
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23
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Lourenço C, Conceição F, Jerónimo C, Lamghari M, Sousa DM. Stress in Metastatic Breast Cancer: To the Bone and Beyond. Cancers (Basel) 2022; 14:1881. [PMID: 35454788 PMCID: PMC9028241 DOI: 10.3390/cancers14081881] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/30/2022] [Accepted: 04/06/2022] [Indexed: 12/24/2022] Open
Abstract
Breast cancer (BRCA) remains as one the most prevalent cancers diagnosed in industrialised countries. Although the overall survival rate is high, the dissemination of BRCA cells to distant organs correlates with a significantly poor prognosis. This is due to the fact that there are no efficient therapeutic strategies designed to overcome the progression of the metastasis. Over the past decade, critical associations between stress and the prevalence of BRCA metastases were uncovered. Chronic stress and the concomitant sympathetic hyperactivation have been shown to accelerate the progression of the disease and the metastases incidence, specifically to the bone. In this review, we provide a summary of the sympathetic profile on BRCA. Additionally, the current knowledge regarding the sympathetic hyperactivity, and the underlying adrenergic signalling pathways, involved on the development of BRCA metastasis to distant organs (i.e., bone, lung, liver and brain) will be revealed. Since bone is a preferential target site for BRCA metastases, greater emphasis will be given to the contribution of α2- and β-adrenergic signalling in BRCA bone tropism and the occurrence of osteolytic lesions.
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Affiliation(s)
- Catarina Lourenço
- Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal; (C.L.); (F.C.); (M.L.)
- INEB—Instituto Nacional de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal;
| | - Francisco Conceição
- Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal; (C.L.); (F.C.); (M.L.)
- INEB—Instituto Nacional de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
- ICBAS-UP—School of Medicine & Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal
| | - Carmen Jerónimo
- Cancer Biology and Epigenetics Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), 4200-072 Porto, Portugal;
- Department of Pathology and Molecular Immunology—ICBAS-UP, 4050-313 Porto, Portugal
| | - Meriem Lamghari
- Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal; (C.L.); (F.C.); (M.L.)
- INEB—Instituto Nacional de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
- ICBAS-UP—School of Medicine & Biomedical Sciences, University of Porto, 4050-313 Porto, Portugal
| | - Daniela M. Sousa
- Instituto de Investigação e Inovação em Saúde (I3S), Universidade do Porto, 4200-135 Porto, Portugal; (C.L.); (F.C.); (M.L.)
- INEB—Instituto Nacional de Engenharia Biomédica, Universidade do Porto, 4200-135 Porto, Portugal
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24
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Restaino AC, Vermeer PD. Neural regulations of the tumor microenvironment. FASEB Bioadv 2022; 4:29-42. [PMID: 35024571 PMCID: PMC8728107 DOI: 10.1096/fba.2021-00066] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/18/2021] [Accepted: 08/25/2021] [Indexed: 12/16/2022] Open
Abstract
The identification of nerves in the tumor microenvironment has ushered in a new area of research in cancer biology. Numerous studies demonstrate the presence of various types of peripheral nerves (sympathetic, parasympathetic, sensory) within the tumor microenvironment; moreover, an increased density of nerves in the tumor microenvironment correlates with worse prognosis. In this review, we address the current understanding of nerve-mediated alterations of the tumor microenvironment and how they impact disease through a variety of processes, including direct nerve-cancer cell communication, alteration of the infiltrative immune population, and alteration of stromal components.
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Affiliation(s)
- Anthony C. Restaino
- Sanford ResearchCancer Biology and Immunotherapies GroupSioux FallsSouth DakotaUSA
- University of South Dakota Sanford School of MedicineVermillionSouth DakotaUSA
| | - Paola D. Vermeer
- Sanford ResearchCancer Biology and Immunotherapies GroupSioux FallsSouth DakotaUSA
- University of South Dakota Sanford School of MedicineVermillionSouth DakotaUSA
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25
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Filippi L, Pini A, Cammalleri M, Bagnoli P, Dal Monte M. β3-Adrenoceptor, a novel player in the round-trip from neonatal diseases to cancer: Suggestive clues from embryo. Med Res Rev 2021; 42:1179-1201. [PMID: 34967048 PMCID: PMC9303287 DOI: 10.1002/med.21874] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 09/29/2021] [Accepted: 12/15/2021] [Indexed: 01/19/2023]
Abstract
The role of the β-adrenoceptors (β-ARs) in hypoxia-driven diseases has gained visibility after the demonstration that propranolol promotes the regression of infantile hemangiomas and ameliorates the signs of retinopathy of prematurity (ROP). Besides the role of β2-ARs, preclinical studies in ROP have also revealed that β3-ARs are upregulated by hypoxia and that they are possibly involved in retinal angiogenesis. In a sort of figurative round trip, peculiarities typical of ROP, where hypoxia drives retinal neovascularization, have been then translated to cancer, a disease equally characterized by hypoxia-driven angiogenesis. In this step, investigating the role of β3-ARs has taken advantage of the assumption that cancer growth uses a set of strategies in common with embryo development. The possibility that hypoxic induction of β3-ARs may represent one of the mechanisms through which primarily embryo (and then cancer, as an astute imitator) adapts to grow in an otherwise hostile environment, has grown evidence. In both cancer and embryo, β3-ARs exert similar functions by exploiting a metabolic shift known as the Warburg effect, by acquiring resistance against xenobiotics, and by inducing a local immune tolerance. An additional potential role of β3-AR as a marker of stemness has been suggested by the finding that its antagonism induces cancer cell differentiation evoking that β3-ARs may help cancer to grow in a nonhospital environment, a strategy also exploited by embryos. From cancer, the round trip goes back to neonatal diseases for which new possible interpretative keys and potential pharmacological perspectives have been suggested.
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Affiliation(s)
- Luca Filippi
- Department of Clinical and Experimental Medicine, Neonatology and Neonatal Intensive Care UnitUniversity of PisaPisaItaly
| | - Alessandro Pini
- Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | - Maurizio Cammalleri
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
| | - Paola Bagnoli
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
| | - Massimo Dal Monte
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
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26
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Eckerling A, Ricon-Becker I, Sorski L, Sandbank E, Ben-Eliyahu S. Stress and cancer: mechanisms, significance and future directions. Nat Rev Cancer 2021; 21:767-785. [PMID: 34508247 DOI: 10.1038/s41568-021-00395-5] [Citation(s) in RCA: 145] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/23/2021] [Indexed: 02/08/2023]
Abstract
The notion that stress and cancer are interlinked has dominated lay discourse for decades. More recent animal studies indicate that stress can substantially facilitate cancer progression through modulating most hallmarks of cancer, and molecular and systemic mechanisms mediating these effects have been elucidated. However, available clinical evidence for such deleterious effects is inconsistent, as epidemiological and stress-reducing clinical interventions have yielded mixed effects on cancer mortality. In this Review, we describe and discuss specific mediating mechanisms identified by preclinical research, and parallel clinical findings. We explain the discrepancy between preclinical and clinical outcomes, through pointing to experimental strengths leveraged by animal studies and through discussing methodological and conceptual obstacles that prevent clinical studies from reflecting the impacts of stress. We suggest approaches to circumvent such obstacles, based on targeting critical phases of cancer progression that are more likely to be stress-sensitive; pharmacologically limiting adrenergic-inflammatory responses triggered by medical procedures; and focusing on more vulnerable populations, employing personalized pharmacological and psychosocial approaches. Recent clinical trials support our hypothesis that psychological and/or pharmacological inhibition of excess adrenergic and/or inflammatory stress signalling, especially alongside cancer treatments, could save lives.
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Affiliation(s)
- Anabel Eckerling
- Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Itay Ricon-Becker
- Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Liat Sorski
- Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Elad Sandbank
- Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Shamgar Ben-Eliyahu
- Sagol School of Neuroscience and School of Psychological Sciences, Tel Aviv University, Tel Aviv, Israel.
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27
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The Adrenergic Nerve Network in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1329:271-294. [PMID: 34664245 DOI: 10.1007/978-3-030-73119-9_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/16/2023]
Abstract
The central and autonomic nervous systems interact and converge to build up an adrenergic nerve network capable of promoting cancer. While a local adrenergic sympathetic innervation in peripheral solid tumors influences cancer and stromal cell behavior, the brain can participate to the development of cancer through an intermixed dysregulation of the sympathoadrenal system, adrenergic neurons, and the hypothalamo-pituitary-adrenal axis. A deeper understanding of the adrenergic nerve circuitry within the brain and tumors and its interactions with the microenvironment should enable elucidation of original mechanisms of cancer and novel therapeutic strategies.
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28
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Nakajima M, Haji A, Sero A, Taha S, Habte H, Jama S, Hodges J, Mohamud S, Ahmed O, Hassan O, al'Absi M. Psychosocial Correlates of Experience and Intention to Receive Colorectal Cancer Screening: A Cross-Sectional Study Among East African Men in the U.S. J Prim Prev 2021; 42:603-623. [PMID: 34654996 DOI: 10.1007/s10935-021-00648-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/21/2021] [Indexed: 12/16/2022]
Abstract
Cancer screening is an important approach to reducing disease burden. The rate of colorectal cancer (CRC) screening among immigrants in the U.S. is very low. Our study's aim was to examine correlates of experience with, and intention to, receive CRC screening among East African men who were up-to-date (UTD) with CRC screening (n = 64, mean age 65) and those who had never been screened or were overdue for one (NOD; n = 47, mean age 60), compared on demographic characteristics, attitudes toward cancer, psychosocial stress, and health behaviors. UTD men had significantly less emotional concerns about cancer screening and experienced significantly greater distress and lower resiliency than NOD men. However, these results were attenuated after controlling for demographic confounders. Perceived risk, trust in the medical system, and PTSD symptoms were significantly associated with an intention to undertake CRC screening in the next 12 months. These results should be used to guide efforts toward increasing CRC screening rates among immigrant communities.
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Affiliation(s)
- Motohiro Nakajima
- Department of Family Medicine and Biobehavioral Health, University of Minnesota Medical School, Duluth, USA.
| | | | - Abdul Sero
- University of Minnesota Medical School, Duluth, USA
| | - Sartu Taha
- University of Minnesota Medical School, Duluth, USA
| | | | - Shamso Jama
- University of Minnesota Medical School, Duluth, USA
| | - James Hodges
- School of Public Health, Division of Biostatistics, University of Minnesota, Minneapolis, USA
| | | | | | - Obsa Hassan
- Mercy Hospital, Allina Health, Coon Rapids, USA
| | - Mustafa al'Absi
- Department of Family Medicine and Biobehavioral Health, University of Minnesota Medical School, Duluth, USA
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29
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Bandala C, Ávila-Luna A, Gómez-López M, Estrada-Villaseñor E, Montes S, Alfaro-Rodríguez A, Miliar-García Á, Cortés-Altamirano JL, Peralta R, Ibáñez-Cervantes G, Gómez-Manzo S, Cárdenas-Rodríguez N, Lara-Padilla E. Catecholamine levels and gene expression of their receptors in tissues of adults with osteosarcoma. Arch Physiol Biochem 2021; 127:337-343. [PMID: 31291139 DOI: 10.1080/13813455.2019.1638942] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
AIM The purpose of this work was to identify and measure catecholamines, their metabolites, and the gene expression of catecholamine receptors in osteosarcoma tissue. MATERIALS AND METHODS The levels of 3,4-dihydroxyphenylacetic acid, norepinephrine, serotonin, and 5-hydroxyindoleacetic acid in cancer tissue and in adjacent and non-oncological bone tissue were analysed by high-performance liquid chromatography, and the gene expression of catecholamine receptors and of dopamine β-hydroxylase, monoaminoxidase, ki67, and Runx2 in the osteosarcoma tissue, tissue adjacent to the tumour, non-oncological bone, and human brain tissue was analysed by RT-PCR. RESULTS We found significantly higher levels of 3,4-dihydroxyphenylacetic acid and norepinephrine in the cancer sample than in adjacent and non-oncological bone. We found that β-adrenergic receptors and dopaminergic receptors, dopamine β-hydroxylase, ki67, Runx2, and serotonergic receptor gene expression were significantly higher in tumour tissue than in adjacent and non-oncological bone. CONCLUSION Catecholamines and their receptors could be potential molecular markers for osteosarcoma progression.
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Affiliation(s)
- Cindy Bandala
- Division of Neurosciences, National Institute of Rehabilitation, Mexico City, Mexico
- Superior School of Medicine, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Alberto Ávila-Luna
- Division of Neurosciences, National Institute of Rehabilitation, Mexico City, Mexico
| | - Modesto Gómez-López
- Superior School of Medicine, Instituto Politécnico Nacional, Mexico City, Mexico
| | | | - Sergio Montes
- Department of Neurochemistry, National Institute of Neurology and Neurosurgery MVS, Mexico City, Mexico
| | | | - Ángel Miliar-García
- Superior School of Medicine, Instituto Politécnico Nacional, Mexico City, Mexico
| | - José L Cortés-Altamirano
- Division of Neurosciences, National Institute of Rehabilitation, Mexico City, Mexico
- Superior School of Medicine, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Raúl Peralta
- Center for Research in Cell Dynamics, Autonomous University of the State of Morelos, Cuernavaca, Mexico
| | | | - Saúl Gómez-Manzo
- Laboratory of Genetic Biochemistry, National Institute of Pediatrics, Mexico City, Mexico
| | | | - Eleazar Lara-Padilla
- Superior School of Medicine, Instituto Politécnico Nacional, Mexico City, Mexico
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30
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Chen G, Qiu L, Gao J, Wang J, Dang J, Li L, Jin Z, Liu X. Stress Hormones: Emerging Targets in Gynecological Cancers. Front Cell Dev Biol 2021; 9:699487. [PMID: 34307378 PMCID: PMC8299464 DOI: 10.3389/fcell.2021.699487] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 06/09/2021] [Indexed: 01/06/2023] Open
Abstract
In the past decade, several discoveries have documented the existence of innervation in ovarian cancer and cervical cancer. Notably, various neurotransmitters released by the activation of the sympathetic nervous system can promote the proliferation and metastasis of tumor cells and regulate immune cells in the tumor microenvironment. Therefore, a better understanding of the mechanisms involving neurotransmitters in the occurrence and development of gynecological cancers will be beneficial for exploring the feasibility of using inexpensive β-blockers and dopamine agonists in the clinical treatment of gynecological cancers. Additionally, this article provides some new insights into targeting tumor innervation and neurotransmitters in the tumor microenvironment.
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Affiliation(s)
- Guoqiang Chen
- Department of Obstetrics and Gynecology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Lei Qiu
- School of Pharmacy, Naval Medical University, Shanghai, China
| | - Jinghai Gao
- Department of Obstetrics and Gynecology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Jing Wang
- Department of Obstetrics and Gynecology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Jianhong Dang
- Department of Obstetrics and Gynecology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Lingling Li
- Department of Obstetrics and Gynecology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Zhijun Jin
- Department of Obstetrics and Gynecology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Xiaojun Liu
- Department of Obstetrics and Gynecology, Changzheng Hospital, Naval Medical University, Shanghai, China
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31
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Christie AJ, Powers-James C, Narayanan S, Chen M, Eddy C, Gomez T, Crawford K, Cohen L, Lopez G. Multidisciplinary lifestyle modification program (IM-FIT) for cancer survivors: implementation of a reimbursable model in a cancer hospital. Support Care Cancer 2021; 29:7365-7375. [PMID: 34050398 DOI: 10.1007/s00520-021-06305-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 05/17/2021] [Indexed: 11/25/2022]
Abstract
PURPOSE We examined the initial effects of a real-world application of a multimodal, reimbursable program to improve lifestyle and promote healthy weight loss in cancer survivors as part of their care. METHODS The lifestyle program (Integrative Medicine Fitness Program; IM-FIT) focusing on increasing physical activity and strength training, improving nutrition, and facilitating stress management and behavior change was delivered in a group format over 12 weeks. Patients met weekly with a physical therapist, dietitian, and psychologist. Body composition and behavioral data were collected at the start and end of 12 weeks, as well as fitness, nutrition, and psychological data. The first cohort started in September 2017, and the last cohort ended in August 2019. RESULTS Twenty-six patients (92% female; mean age = 62.7, SD = 9) completed the program, which was pre-approved and covered as in-network by their health insurance. Patients lost an average of 3.9% of their body weight (SD = - 2.2). There was a significant reduction in white bread and desserts and increase in legumes and non-dairy milk. Time spent in vigorous exercise (p < .001), strength training (p < .001), and total exercise (p < .001) significantly increased. Patients reported reduction in depression (7.76 to 4.29; p = .01), anxiety (6.14 to 3.29; p < .01), and overall distress (4.70 to 3.40; p < .01). CONCLUSION We demonstrated that a multi-disciplinary weight loss program can be tailored to cancer survivors leading to weight reduction and improvements in lifestyle factors and mental health. This program showed successful real-world implementation with insurance reimbursement.
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Affiliation(s)
- Aimee J Christie
- Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
| | - Catherine Powers-James
- Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Santhosshi Narayanan
- Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Minxing Chen
- Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Carol Eddy
- Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Telma Gomez
- Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Karla Crawford
- Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Lorenzo Cohen
- Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
| | - Gabriel Lopez
- Department of Palliative, Rehabilitation, and Integrative Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA
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Dlamini Z, Mathabe K, Padayachy L, Marima R, Evangelou G, Syrigos KN, Bianchi A, Lolas G, Hull R. Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination. Cancers (Basel) 2021; 13:cancers13092138. [PMID: 33946706 PMCID: PMC8125307 DOI: 10.3390/cancers13092138] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 04/16/2021] [Accepted: 04/24/2021] [Indexed: 12/27/2022] Open
Abstract
Simple Summary Significant progress has recently been made in understanding the role of the neuronal system in cancer biology, in many solid tumors such as prostate, breast, pancreatic, gastric and brain cancers. Solid tumors and the nervous system appear to influence each other’s development both directly and indirectly. A recurring element in such interactions is constituted by nerve-related substances such as neurotransmitters and neurotrophins, to which the first part of the current review is devoted. The second part of the review focuses on the potential role played by alternative splicing in cancer progression associated with neural signaling. Alternative splicing is the process where pre-mRNA is cut and re-ligated in different ways to give rise to multiple protein isoforms whose expression profile is often cancer specific. Alternative splicing is known to take place in the mRNA of genes that code for proteins involved in neuronal development and the creation of new nerve fibers. The change in alternative splicing patterns that occur as tumors develop and progress may make these splice variants potential targets for the development of drug treatments. They may also serve as diagnostic or prognostic biomarkers. Abstract During development, as tissues expand and grow, they require circulatory, lymphatic, and nervous system expansion for proper function and support. Similarly, as tumors arise and develop, they also require the expansion of these systems to support them. While the contribution of blood and lymphatic systems to the development and progression of cancer is well known and is targeted with anticancer drugs, the contribution of the nervous system is less well studied and understood. Recent studies have shown that the interaction between neurons and a tumor are bilateral and promote metastasis on one hand, and the formation of new nerve structures (neoneurogenesis) on the other. Substances such as neurotransmitters and neurotrophins being the main actors in such interplay, it seems reasonable to expect that alternative splicing and the different populations of protein isoforms can affect tumor-derived neurogenesis. Here, we report the different, documented ways in which neurons contribute to the development and progression of cancer and investigate what is currently known regarding cancer-neuronal interaction in several specific cancer types. Furthermore, we discuss the incidence of alternative splicing that have been identified as playing a role in tumor-induced neoneurogenesis, cancer development and progression. Several examples of changes in alternative splicing that give rise to different isoforms in nerve tissue that support cancer progression, growth and development have also been investigated. Finally, we discuss the potential of our knowledge in alternative splicing to improve tumor diagnosis and treatment.
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Affiliation(s)
- Zodwa Dlamini
- SAMRC Precision Prevention and Novel Drug Targets for HIV-Associated Cancers (PPNDTHAC) Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa; (K.M.); (L.P.); (R.M.); (G.L.); (R.H.)
- Correspondence:
| | - Kgomotso Mathabe
- SAMRC Precision Prevention and Novel Drug Targets for HIV-Associated Cancers (PPNDTHAC) Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa; (K.M.); (L.P.); (R.M.); (G.L.); (R.H.)
- Department of Urology, University of Pretoria, Pretoria 0084, South Africa
| | - Llewellyn Padayachy
- SAMRC Precision Prevention and Novel Drug Targets for HIV-Associated Cancers (PPNDTHAC) Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa; (K.M.); (L.P.); (R.M.); (G.L.); (R.H.)
- Department of Neurosurgery, University of Pretoria, Pretoria 0084, South Africa
| | - Rahaba Marima
- SAMRC Precision Prevention and Novel Drug Targets for HIV-Associated Cancers (PPNDTHAC) Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa; (K.M.); (L.P.); (R.M.); (G.L.); (R.H.)
| | - George Evangelou
- 3rd Department of Medicine, National & Kapodistrian University of Athens, 11527 Athens, Greece; (G.E.); (K.N.S.)
| | - Konstantinos N. Syrigos
- 3rd Department of Medicine, National & Kapodistrian University of Athens, 11527 Athens, Greece; (G.E.); (K.N.S.)
| | | | - Georgios Lolas
- SAMRC Precision Prevention and Novel Drug Targets for HIV-Associated Cancers (PPNDTHAC) Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa; (K.M.); (L.P.); (R.M.); (G.L.); (R.H.)
- 3rd Department of Medicine, National & Kapodistrian University of Athens, 11527 Athens, Greece; (G.E.); (K.N.S.)
| | - Rodney Hull
- SAMRC Precision Prevention and Novel Drug Targets for HIV-Associated Cancers (PPNDTHAC) Unit, Pan African Cancer Research Institute (PACRI), University of Pretoria, Hatfield 0028, South Africa; (K.M.); (L.P.); (R.M.); (G.L.); (R.H.)
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Anti-Angiogenic Therapy: Current Challenges and Future Perspectives. Int J Mol Sci 2021; 22:ijms22073765. [PMID: 33916438 PMCID: PMC8038573 DOI: 10.3390/ijms22073765] [Citation(s) in RCA: 216] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 02/07/2023] Open
Abstract
Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.
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Carey P, Low E, Harper E, Stack MS. Metalloproteinases in Ovarian Cancer. Int J Mol Sci 2021; 22:3403. [PMID: 33810259 PMCID: PMC8036623 DOI: 10.3390/ijms22073403] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/21/2021] [Accepted: 03/25/2021] [Indexed: 01/25/2023] Open
Abstract
Proteases play a crucial role in the progression and metastasis of ovarian cancer. Pericellular protein degradation and fragmentation along with remodeling of the extracellular matrix (ECM) is accomplished by numerous proteases that are present in the ovarian tumor microenvironment. Several proteolytic processes have been linked to cancer progression, particularly those facilitated by the matrix metalloproteinase (MMP) family. These proteases have been linked to enhanced migratory ability, extracellular matrix breakdown, and development of support systems for tumors. Several studies have reported the direct involvement of MMPs with ovarian cancer, as well as their mechanisms of action in the tumor microenvironment. MMPs play a key role in upregulating transcription factors, as well as the breakdown of structural proteins like collagen. Proteolytic mechanisms have been shown to enhance the ability of ovarian cancer cells to migrate and adhere to secondary sites allowing for efficient metastasis. Furthermore, angiogenesis for tumor growth and development of metastatic implants is influenced by upregulation of certain proteases, including MMPs. While proteases are produced normally in vivo, they can be upregulated by cancer-associated mutations, tumor-microenvironment interaction, stress-induced catecholamine production, and age-related pathologies. This review outlines the important role of proteases throughout ovarian cancer progression and metastasis.
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Affiliation(s)
- Preston Carey
- Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; (P.C.); (E.L.); (E.H.)
- Department of Preprofessional Studies, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Ethan Low
- Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; (P.C.); (E.L.); (E.H.)
- Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Elizabeth Harper
- Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; (P.C.); (E.L.); (E.H.)
- Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
- Integrated Biomedical Sciences Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA
| | - M. Sharon Stack
- Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; (P.C.); (E.L.); (E.H.)
- Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
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Qiao G, Chen M, Mohammadpour H, MacDonald CR, Bucsek MJ, Hylander BL, Barbi JJ, Repasky EA. Chronic Adrenergic Stress Contributes to Metabolic Dysfunction and an Exhausted Phenotype in T Cells in the Tumor Microenvironment. Cancer Immunol Res 2021; 9:651-664. [PMID: 33762351 DOI: 10.1158/2326-6066.cir-20-0445] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 12/10/2020] [Accepted: 03/22/2021] [Indexed: 11/16/2022]
Abstract
Metabolic dysfunction and exhaustion in tumor-infiltrating T cells have been linked to ineffectual antitumor immunity and the failure of immune checkpoint inhibitor therapy. We report here that chronic stress plays a previously unrecognized role in regulating the state of T cells in the tumor microenvironment (TME). Using two mouse tumor models, we found that blocking chronic adrenergic stress signaling using the pan β-blocker propranolol or by using mice lacking the β2-adrenergic receptor (β2-AR) results in reduced tumor growth rates with significantly fewer tumor-infiltrating T cells that express markers of exhaustion, with a concomitant increase in progenitor exhausted T cells. We also report that blocking β-AR signaling in mice increases glycolysis and oxidative phosphorylation in tumor-infiltrating lymphocytes (TIL), which associated with increased expression of the costimulatory molecule CD28 and increased antitumor effector functions, including increased cytokine production. Using T cells from Nur77-GFP reporter mice to monitor T-cell activation, we observed that stress-induced β-AR signaling suppresses T-cell receptor (TCR) signaling. Together, these data suggest that chronic stress-induced adrenergic receptor signaling serves as a "checkpoint" of immune responses and contributes to immunosuppression in the TME by promoting T-cell metabolic dysfunction and exhaustion. These results also support the possibility that chronic stress, which unfortunately is increased in many patients with cancer following their diagnoses, could be exerting a major negative influence on the outcome of therapies that depend upon the status of TILs and support the use of strategies to reduce stress or β-AR signaling in combination with immunotherapy.
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Affiliation(s)
- Guanxi Qiao
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Minhui Chen
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Hemn Mohammadpour
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Cameron R MacDonald
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Mark J Bucsek
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Bonnie L Hylander
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Joseph J Barbi
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Elizabeth A Repasky
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
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Cui B, Peng F, Lu J, He B, Su Q, Luo H, Deng Z, Jiang T, Su K, Huang Y, Ud Din Z, Lam EWF, Kelley KW, Liu Q. Cancer and stress: NextGen strategies. Brain Behav Immun 2021; 93:368-383. [PMID: 33160090 DOI: 10.1016/j.bbi.2020.11.005] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 10/17/2020] [Accepted: 11/01/2020] [Indexed: 12/12/2022] Open
Abstract
Chronic stress is well-known to cause physiological distress that leads to body balance perturbations by altering signaling pathways in the neuroendocrine and sympathetic nervous systems. This increases allostatic load, which is the cost of physiological fluctuations that are required to cope with psychological challenges as well as changes in the physical environment. Recent studies have enriched our knowledge about the role of chronic stress in disease development, especially carcinogenesis. Stress stimulates the hypothalamic-pituitaryadrenal (HPA) axis and the sympathetic nervous system (SNS), resulting in an abnormal release of hormones. These activate signaling pathways that elevate expression of downstream oncogenes. This occurs by activation of specific receptors that promote numerous cancer biological processes, including proliferation, genomic instability, angiogenesis, metastasis, immune evasion and metabolic disorders. Moreover, accumulating evidence has revealed that β-adrenergic receptor (ADRB) antagonists and downstream target inhibitors exhibit remarkable anti-tumor effects. Psychosomatic behavioral interventions (PBI) and traditional Chinese medicine (TCM) also effectively relieve the impact of stress in cancer patients. In this review, we discuss recent advances in the underlying mechanisms that are responsible for stress in promoting malignancies. Collectively, these data provide approaches for NextGen pharmacological therapies, PBI and TCM to reduce the burden of tumorigenesis.
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Affiliation(s)
- Bai Cui
- Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, Liaoning Province 116044, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, 651 Dongfeng East Road, Guangzhou, Guangdong Province 510060, China
| | - Fei Peng
- Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, Liaoning Province 116044, China
| | - Jinxin Lu
- Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, Liaoning Province 116044, China
| | - Bin He
- Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, Liaoning Province 116044, China
| | - Qitong Su
- Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, Liaoning Province 116044, China
| | - Huandong Luo
- Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, Liaoning Province 116044, China
| | - Ziqian Deng
- Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, Liaoning Province 116044, China
| | - Tonghui Jiang
- Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, Liaoning Province 116044, China
| | - Keyu Su
- Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, Liaoning Province 116044, China
| | - Yanping Huang
- Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, Liaoning Province 116044, China
| | - Zaheer Ud Din
- Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, Liaoning Province 116044, China
| | - Eric W-F Lam
- Department of Surgery and Cancer, Imperial College London, London W12 0NN, UK
| | - Keith W Kelley
- Department of Pathology, College of Medicine and Department of Animal Sciences, College of ACES, University of Illinois at Urbana-Champaign, 212 Edward R. Madigan Laboratory, 1201 West Gregory Drive, Urbana, Il 61801, USA.
| | - Quentin Liu
- Institute of Cancer Stem Cell, Dalian Medical University, 9 West Section, Lvshun South Road, Dalian, Liaoning Province 116044, China; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, 651 Dongfeng East Road, Guangzhou, Guangdong Province 510060, China.
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Modzelewska B, Jóźwik M, Kleszczewski T, Sulkowski S, Jóźwik M. Myometrial Responses to Beta-Adrenoceptor Antagonists in Gynecological Malignancies. Gynecol Obstet Invest 2021; 86:162-169. [PMID: 33640886 DOI: 10.1159/000513718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 12/11/2020] [Indexed: 11/19/2022]
Abstract
OBJECTIVE The aim of the study was to determine the influence of beta-adrenoceptor (ADRB) antagonists on contractile activity of the nonpregnant human uterus in patients affected by gynecological malignancies. DESIGN This was a controlled and prospective ex vivo study. SETTING The work was conducted as a collaboration between 4 academic departments. MATERIALS AND METHODS Myometrial specimens were obtained from women undergoing hysterectomy for benign gynecological disorders (reference group; N = 15), and ovarian (N = 15), endometrial (N = 15), synchronous ovarian-endometrial (N = 3), and cervical cancer (N = 10). Contractions of myometrial strips in an organ bath before and after applications of ADRB antagonists (propranolol, bupranolol, SR 59230A, and butoxamine) were studied under isometric conditions. RESULTS Propranolol and bupranolol attenuated contractions in the endometrial and cervical cancer groups similar to that in the reference group (all p < 0.05), whereas opposite effects were observed in the ovarian and synchronous ovarian-endometrial cancer groups. SR 59230A and butoxamine significantly increased contractions in the ovarian cancer group (both p < 0.001). LIMITATIONS These results require now to be placed into a firm clinical context. CONCLUSIONS Our study indicates that ovarian cancer considerably alters contractile activity of the nonpregnant human uterus in response to ADRB antagonists. This suggests a pathogenetic role of beta-adrenergic pathways in this malignancy. Furthermore, propranolol and bupranolol substantially influence spontaneous uterine contractility.
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Affiliation(s)
- Beata Modzelewska
- Department of Biophysics, Medical University of Białystok, Białystok, Poland
| | - Marcin Jóźwik
- Department of Gynecology and Obstetrics, Faculty of Medicine, Collegium Medicum, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
| | - Tomasz Kleszczewski
- Department of Biophysics, Medical University of Białystok, Białystok, Poland
| | - Stanisław Sulkowski
- Department of General Pathomorphology, Medical University of Białystok, Białystok, Poland
| | - Maciej Jóźwik
- Department of Gynecology and Gynecologic Oncology, Medical University of Białystok, Białystok, Poland,
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Minas TZ, Kiely M, Ajao A, Ambs S. An overview of cancer health disparities: new approaches and insights and why they matter. Carcinogenesis 2021; 42:2-13. [PMID: 33185680 PMCID: PMC7717137 DOI: 10.1093/carcin/bgaa121] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 11/01/2020] [Accepted: 11/06/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer health disparities remain stubbornly entrenched in the US health care system. The Affordable Care Act was legislation to target these disparities in health outcomes. Expanded access to health care, reduction in tobacco use, uptake of other preventive measures and cancer screening, and improved cancer therapies greatly reduced cancer mortality among women and men and underserved communities in this country. Yet, disparities in cancer outcomes remain. Underserved populations continue to experience an excessive cancer burden. This burden is largely explained by health care disparities, lifestyle factors, cultural barriers, and disparate exposures to carcinogens and pathogens, as exemplified by the COVID-19 epidemic. However, research also shows that comorbidities, social stress, ancestral and immunobiological factors, and the microbiome, may contribute to health disparities in cancer risk and survival. Recent studies revealed that comorbid conditions can induce an adverse tumor biology, leading to a more aggressive disease and decreased patient survival. In this review, we will discuss unanswered questions and new opportunities in cancer health disparity research related to comorbid chronic diseases, stress signaling, the immune response, and the microbiome, and what contribution these factors may have as causes of cancer health disparities.
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Affiliation(s)
- Tsion Zewdu Minas
- Laboratory of Human Carcinogenesis, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Maeve Kiely
- Laboratory of Human Carcinogenesis, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Anuoluwapo Ajao
- Laboratory of Human Carcinogenesis, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Stefan Ambs
- Laboratory of Human Carcinogenesis, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Iftikhar A, Islam M, Shepherd S, Jones S, Ellis I. Cancer and Stress: Does It Make a Difference to the Patient When These Two Challenges Collide? Cancers (Basel) 2021; 13:cancers13020163. [PMID: 33418900 PMCID: PMC7825104 DOI: 10.3390/cancers13020163] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/23/2020] [Accepted: 12/28/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Head and neck cancers are the sixth most common cancer in the world. The burden of the disease has remained challenging over recent years despite the advances in treatments of other malignancies. The very use of the word malignancy brings about a stress response in almost all adult patients. Being told you have a tumour is not a word anyone wants to hear. We have embarked on a study which will investigate the effect of stress pathways on head and neck cancer patients and which signalling pathways may be involved. In the future, this will allow clinicians to better manage patients with head and neck cancer and reduce the patients’ stress so that this does not add to their tumour burden. Abstract A single head and neck Cancer (HNC) is a globally growing challenge associated with significant morbidity and mortality. The diagnosis itself can affect the patients profoundly let alone the complex and disfiguring treatment. The highly important functions of structures of the head and neck such as mastication, speech, aesthetics, identity and social interactions make a cancer diagnosis in this region even more psychologically traumatic. The emotional distress engendered as a result of functional and social disruption is certain to negatively affect health-related quality of life (HRQoL). The key biological responses to stressful events are moderated through the combined action of two systems, the hypothalamus–pituitary–adrenal axis (HPA) which releases glucocorticoids and the sympathetic nervous system (SNS) which releases catecholamines. In acute stress, these hormones help the body to regain homeostasis; however, in chronic stress their increased levels and activation of their receptors may aid in the progression of cancer. Despite ample evidence on the existence of stress in patients diagnosed with HNC, studies looking at the effect of stress on the progression of disease are scarce, compared to other cancers. This review summarises the challenges associated with HNC that make it stressful and describes how stress signalling aids in the progression of cancer. Growing evidence on the relationship between stress and HNC makes it paramount to focus future research towards a better understanding of stress and its effect on head and neck cancer.
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Priyanka HP, Nair RS, Kumaraguru S, Saravanaraj K, Ramasamy V. Insights on neuroendocrine regulation of immune mediators in female reproductive aging and cancer. AIMS MOLECULAR SCIENCE 2021. [DOI: 10.3934/molsci.2021010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Gardner AB, Sanders BE, Mann AK, Liao CI, Eskander RN, Kapp DS, Chan JK. Relationship status and other demographic influences on survival in patients with ovarian cancer. Int J Gynecol Cancer 2020; 30:1922-1927. [PMID: 32920535 DOI: 10.1136/ijgc-2020-001512] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 07/18/2020] [Accepted: 07/21/2020] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVE To evaluate the influence of marital status and other demographic factors on survival of patients with ovarian cancer. STUDY DESIGN Data were obtained from the Surveillance, Epidemiology, and End Results database from 2010 to 2015. Analyses were performed using Kaplan-Meier and multivariate Cox proportional hazard methods. RESULTS Of 19 643 patients with ovarian cancer (median age 60 years, range 18-99), 16 278 (83%), 1381 (7%), 1856 (9%), and 128 (1%) were White, Black, Asian, and Native American, respectively. The majority of patients (10 769, 55%) were married while 4155 (21%) were single, 2278 (12%) were divorced, and 2441 (12%) were widowed. Patients were more likely to be married if they were Asian (65%) or White (56%) than if they were Black (31%) or Native American (39%) (p<0.001). Most married patients were insured (n=9760 (91%), non-Medicaid) compared with 3002 (72%) of single, 1777 (78%) divorced, and 2102 (86%) of widowed patients (p<0.001). Married patients were more likely to receive chemotherapy than single, divorced, and widowed patients (8515 (79%) vs 3000 (72%), 1747 (77%), and 1650 (68%), respectively; p<0.001). The 5-year disease-specific survival of the overall group was 58%. Married patients had improved survival of 60% compared with divorced (52%) and widowed (44%) patients (p<0.001). On multivariate analysis, older age (HR 1.02, 95% CI 1.016 to 1.021, p<0.001), Black race (HR 1.24, 95% CI 1.11 to 1.38, p<0.001), and Medicaid (HR 1.19, 95% CI 1.09 to 1.30, p<0.001) or uninsured status (HR 1.23, 95% CI 1.05 to 1.44, p<0.01) carried a worse prognosis. Single (HR 1.17, 95% CI 1.08 to 1.26, p<0.001), divorced (HR 1.14, 95% CI 1.04 to 1.25, p<0.01), and widowed (HR 1.16, 95% CI 1.06 to 1.26, p<0.001) patients had decreased survival. CONCLUSION Married patients with ovarian cancer were more likely to undergo chemotherapy with better survival rates. Black, uninsured, or patients with Medicaid insurance had poorer outcomes.
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Affiliation(s)
- Austin B Gardner
- Obstetrics and Gynecology, University of California Irvine School of Medicine, Irvine, California, USA
- Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Brooke E Sanders
- Obstetrics and Gynecology, University of California San Diego School of Medicine, La Jolla, California, USA
| | | | - Cheng-I Liao
- Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Ramez Nassef Eskander
- Obstetrics and Gynecology, University of California San Diego School of Medicine, La Jolla, California, USA
| | - Daniel S Kapp
- Stanford University School of Medicine, Stanford, California, USA
| | - John K Chan
- California Pacific Medical Center, San Francisco, California, USA
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Momeni-Varposhti Z, Kazemi MH, Talebi M, Chegeni R, Roshandel E, Hajifathali A, Movassaghpour AA. Plasma levels of norepinephrine and expression levels of ß2-adrenergic receptor gene correlate with the incidence of acute graft-versus-host disease. Med J Islam Repub Iran 2020; 34:151. [PMID: 33437747 PMCID: PMC7787040 DOI: 10.34171/mjiri.34.151] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Indexed: 11/05/2022] Open
Abstract
Background: Acute graft-versus-host disease is a major complication in allogeneic hematopoietic stem-cell transplantation. Epinephrine and norepinephrine are stress hormones which affect many cells, including immune cells through interaction with adrenergic receptors, mainly β2-adrenergic receptor. The immunomodulatory effects of epinephrine, norepinephrine, and signaling of the adrenergic receptor have been shown to decrease the probability of the acute graft-versus-host disease in animal models. The aim of our study was to investigate the possible correlations between the serum levels of epinephrine and norepinephrine and also leukocytic expression levels of β2-adrenergic receptor with the incidence of acute graft-versus-host disease in patients undergoing allogeneic hematopoietic stem-cell transplantation. Methods: In this study, the plasma levels of epinephrine and norepinephrine and the leukocytic expression of β2-adrenergic receptor gene were measured and compared in allogeneic hematopoietic stem-cell transplantation patients with and without acute graft-versus-host disease. Data were analyzed and illustrated using SPSS 19 and GraphPad Prism 6. The student T-test, Pearson, and Spearman's tests were performed and p<0.05 was considered as significant. Results: We showed that the plasma levels of norepinephrine and the relative amount of the mRNA of β2-adrenergic receptor at 7 and 21 days after allogeneic hematopoietic stem-cell transplantation were significantly lower in patients with acute graft-versus-host disease than recipients without acute graft-versus-host disease. There were also negative correlations between the plasma levels of norepinephrine, leukocytic levels of the mRNA of β2-adrenergic receptor, and the incidence of acute graft-versus-host disease. Conclusion: Our results suggest that stress hormones and their receptor might have a role in preventing acute graft-versus-host disease and could be promising factors in controlling the outcome of allogeneic hematopoietic stem-cell transplantation.
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Affiliation(s)
- Zahra Momeni-Varposhti
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Kazemi
- Student Research Committee, Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Talebi
- Department of Applied Cell Sciences, School of Advance Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Rouzbeh Chegeni
- The Michener Institute of Education, University Health Network, Toronto, Canada
| | - Elham Roshandel
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Hajifathali
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Movassaghpour
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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Gandhi S, Pandey MR, Attwood K, Ji W, Witkiewicz AK, Knudsen ES, Allen C, Tario JD, Wallace PK, Cedeno CD, Levis M, Stack S, Funchain P, Drabick JJ, Bucsek MJ, Puzanov I, Mohammadpour H, Repasky EA, Ernstoff MS. Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity. Clin Cancer Res 2020; 27:87-95. [PMID: 33127652 DOI: 10.1158/1078-0432.ccr-20-2381] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 09/09/2020] [Accepted: 10/21/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective β-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma. PATIENTS AND METHODS A 3 + 3 dose escalation study for propranolol twice a day with pembrolizumab (200 mg every 3 weeks) was completed. The primary objective was to determine the recommended phase II dose (RP2D). Additional objectives included safety, antitumor activity, and biomarker analyses. Responders were defined as patients with complete or partial response per immune-modified RECIST at 6 months. RESULTS Nine patients with metastatic melanoma received increasing doses of propranolol in cohorts of 10, 20, and 30 mg twice a day. No dose-limiting toxicities were observed. Most common treatment-related adverse events (TRAEs) were rash, fatigue, and vitiligo, observed in 44% patients. One patient developed two grade ≥3 TRAEs. Objective response rate was 78%. While no significant changes in treatment-associated biomarkers were observed, an increase in IFNγ and a decrease in IL6 was noted in responders. CONCLUSIONS Combination of propranolol with pembrolizumab in treatment-naïve metastatic melanoma is safe and shows very promising activity. Propranolol 30 mg twice a day was selected as RP2D in addition to pembrolizumab based on safety, tolerability, and preliminary antitumor activity.
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Affiliation(s)
- Shipra Gandhi
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
| | - Manu R Pandey
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Kristopher Attwood
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Wenyan Ji
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Agnieszka K Witkiewicz
- Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Erik S Knudsen
- Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Cheryl Allen
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Joseph D Tario
- Department of Flow Cytometry, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Paul K Wallace
- Department of Flow Cytometry, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Carlos D Cedeno
- Department of Flow Cytometry, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Maria Levis
- Clinical Research Service, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Suzanne Stack
- Clinical Research Service, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Pauline Funchain
- Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, Ohio
| | - Joseph J Drabick
- Division of Hematology and Oncology, Penn State Cancer Institute, Hershey, Pennsylvania
| | - Mark J Bucsek
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Igor Puzanov
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Hemn Mohammadpour
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Elizabeth A Repasky
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | - Marc S Ernstoff
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.,Division of Cancer Treatment and Diagnosis/Developmental Therapy Program-ImmunoOncology Branch, NIH/NCI, Bethesda, Maryland
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44
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Mravec B, Horvathova L, Hunakova L. Neurobiology of Cancer: the Role of β-Adrenergic Receptor Signaling in Various Tumor Environments. Int J Mol Sci 2020; 21:ijms21217958. [PMID: 33114769 PMCID: PMC7662752 DOI: 10.3390/ijms21217958] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/21/2020] [Accepted: 10/26/2020] [Indexed: 12/13/2022] Open
Abstract
The development and progression of cancer depends on both tumor micro- and macroenvironments. In addition, psychosocial and spiritual “environments” might also affect cancer. It has been found that the nervous system, via neural and humoral pathways, significantly modulates processes related to cancer at the level of the tumor micro- and macroenvironments. The nervous system also mediates the effects of psychosocial and noetic factors on cancer. Importantly, data accumulated in the last two decades have clearly shown that effects of the nervous system on cancer initiation, progression, and the development of metastases are mediated by the sympathoadrenal system mainly via β-adrenergic receptor signaling. Here, we provide a new complex view of the role of β-adrenergic receptor signaling within the tumor micro- and macroenvironments as well as in mediating the effects of the psychosocial and spiritual environments. In addition, we describe potential preventive and therapeutic implications.
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Affiliation(s)
- Boris Mravec
- Institute of Physiology, Faculty of Medicine, Comenius University, 813 72 Bratislava, Slovakia
- Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, 814 39 Bratislava, Slovakia;
- Correspondence: ; Tel.: +421-(2)-59357527; Fax: +421-(2)-59357601
| | - Lubica Horvathova
- Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, 814 39 Bratislava, Slovakia;
| | - Luba Hunakova
- Institute of Microbiology, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
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Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, Madhur MS, Tomaszewski M, Maffia P, D’Acquisto F, Nicklin SA, Marian AJ, Nosalski R, Murray EC, Guzik B, Berry C, Touyz RM, Kreutz R, Wang DW, Bhella D, Sagliocco O, Crea F, Thomson EC, McInnes IB. COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options. Cardiovasc Res 2020; 116:1666-1687. [PMID: 32352535 PMCID: PMC7197627 DOI: 10.1093/cvr/cvaa106] [Citation(s) in RCA: 920] [Impact Index Per Article: 184.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 04/11/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023] Open
Abstract
The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC). Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19. Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.
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Affiliation(s)
- Tomasz J Guzik
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- Department of Internal Medicine, Jagiellonian University, Collegium Medicum, Kraków, Poland
| | - Saidi A Mohiddin
- Barts Heart Center, St Bartholomew’s NHS Trust, London, UK
- William Harvey Institute Queen Mary University of London, London, UK
| | | | - Vimal Patel
- Barts Heart Center, St Bartholomew’s NHS Trust, London, UK
| | | | | | - Meena S Madhur
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Maciej Tomaszewski
- Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, UK
| | - Pasquale Maffia
- Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Stuart A Nicklin
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Ali J Marian
- Department of Medicine, Center for Cardiovascular Genetics, Institute of Molecular Medicine, University of Texas Health Sciences Center at Houston, Houston, TX, USA
| | - Ryszard Nosalski
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- Department of Internal Medicine, Jagiellonian University, Collegium Medicum, Kraków, Poland
| | - Eleanor C Murray
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Bartlomiej Guzik
- Jagiellonian University Medical College, Institute of Cardiology, Department of Interventional Cardiology; John Paul II Hospital, Krakow, Poland
| | - Colin Berry
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Rhian M Touyz
- Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Reinhold Kreutz
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institut für Klinische Pharmakologie und Toxikologie, Germany
| | - Dao Wen Wang
- Division of Cardiology and Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - David Bhella
- MRC-University of Glasgow Centre for Virus Research, University of Glasgow, UK
| | - Orlando Sagliocco
- Emergency Department, Intensive Care Unit; ASST Bergamo Est Bolognini Hospital Bergamo, Italy
| | - Filippo Crea
- Department of Cardiovascular and Thoracic Sciences, Catholic University of the Sacred Heart, Largo A. Gemelli, 8, 00168 Rome, Italy
| | - Emma C Thomson
- Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
- MRC-University of Glasgow Centre for Virus Research, University of Glasgow, UK
- Department of Infectious Diseases, Queen Elizabeth University Hospital, Glasgow, UK
| | - Iain B McInnes
- Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
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Lutgendorf SK, Penedo F, Goodheart MJ, Dahmoush L, Arevalo JMG, Thaker PH, Slavich GM, Sood AK, Cole SW. Epithelial-mesenchymal transition polarization in ovarian carcinomas from patients with high social isolation. Cancer 2020; 126:4407-4413. [PMID: 32691853 DOI: 10.1002/cncr.33060] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 05/27/2020] [Accepted: 05/30/2020] [Indexed: 11/12/2022]
Abstract
BACKGROUND Social isolation has shown robust associations with clinical outcomes in the general population and in patients with cancer. In patients with ovarian cancer, social isolation has been found to be related to decreased survival and multiple biomarkers supporting tumor progression. However, to the authors' knowledge, little is known regarding the relationship between social isolation and the molecular characteristics of ovarian tumors. Herein, the authors have used genome-wide transcriptional profiling to quantify associations between social isolation and epithelial-mesenchymal transition (EMT) polarization in ovarian tumors and transcriptome-driven, promoter-based bioinformatics analyses to identify gene regulatory pathways that may potentially underlie these changes. METHODS Tumor was sampled during primary surgical resection and immediately frozen in liquid nitrogen. After RNA extraction, microarray analysis of the transcriptome was performed and samples were analyzed to assess associations between EMT-related gene transcripts and social isolation (as indicated by a Social Provisions Scale Attachment subscale score <15). Convergent validation was provided by a promoter-based bioinformatic analysis of transcription factor activity. RESULTS Primary analyses of 99 women demonstrated a lower average expression of gene transcripts previously associated with epithelial differentiation in women with high social isolation (-0.143 ± 0.048 log2 mRNA abundance; P = .004), but no difference in mesenchymal differentiation as a function of social isolation (+0.007 ± 0.0064 log2 mRNA abundance; P = .900). Upregulated activity was shown for 3 of the 4 targeted EMT-related transcription factors, including GATA4 (P = .014); SMAD2, SMAD3, and/or SMAD4 (P < .001); and TWIST1 (P < .001). Analyses of SNAIL2/SLUG activity indicated a directional trend toward increased activity that did not reach statistical significance (P = .123). CONCLUSIONS The findings of the current study demonstrated differential EMT polarization and EMT-related transcription factor activity according to social isolation, a known socioenvironmental risk factor. LAY SUMMARY Social isolation has shown robust associations with clinical outcomes in the general population and in patients with cancer. Herein, the authors examined the relationship between social isolation and the molecular characteristics of ovarian tumors. The authors investigated the epithelial-mesenchymal transition (EMT), a process whereby tumor cells lose epithelial characteristics and become more embryonic (mesenchymal), thereby enhancing invasiveness. Primary analyses demonstrated lower expression of genes previously associated with epithelial differentiation and increased activity of specific EMT-related transcription factors in individuals with high social isolation, indicating increased EMT polarization in these patients. These findings extend the understanding of how socioenvironmental factors may modulate tumor growth.
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Affiliation(s)
- Susan K Lutgendorf
- Department of Psychological and Brain Sciences, University of Iowa, Iowa City, Iowa.,Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa.,Department of Urology, University of Iowa, Iowa City, Iowa.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
| | - Frank Penedo
- Department of Psychology, University of Miami, Miami, Florida.,Sylvester Cancer Center, University of Miami, Miami, Florida
| | - Michael J Goodheart
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Iowa, Iowa City, Iowa.,Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
| | - Laila Dahmoush
- Department of Pathology, University of Iowa, Iowa City, Iowa
| | - Jesusa M G Arevalo
- Division of Hematology/Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.,Cousins Center for Psychoneuroimmunology, University of California at Los Angeles, Los Angeles, California
| | - Premal H Thaker
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, Missouri
| | - George M Slavich
- Cousins Center for Psychoneuroimmunology, University of California at Los Angeles, Los Angeles, California.,Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, California
| | - Anil K Sood
- Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Center for RNA Interference and Noncoding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Steve W Cole
- Division of Hematology/Oncology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California.,Cousins Center for Psychoneuroimmunology, University of California at Los Angeles, Los Angeles, California.,Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, California
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Li H, Xia N. The role of oxidative stress in cardiovascular disease caused by social isolation and loneliness. Redox Biol 2020; 37:101585. [PMID: 32709420 PMCID: PMC7767744 DOI: 10.1016/j.redox.2020.101585] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/11/2020] [Accepted: 05/14/2020] [Indexed: 02/06/2023] Open
Abstract
Loneliness and social isolation are common sources of chronic stress in modern society. Epidemiological studies have demonstrated that loneliness and social isolation increase mortality risk as much as smoking or alcohol consumption and more than physical inactivity or obesity. Loneliness in human is associated with higher blood pressure whereas enhanced atherosclerosis is observed in animal models of social isolation. Loneliness and social isolation lead to activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, enhanced sympathetic nerve activity, impaired parasympathetic function and a proinflammatory immune response. These mechanisms have been implicated in the development of cardiovascular disease conferred by social isolation although a causal relationship has not been established so far. There is evidence that oxidative stress is likely to be a key molecular mechanism linking chronic psychosocial stress to cardiovascular disease. NADPH oxidase-mediated oxidative stress in the hypothalamus has been shown to be required for social isolation-induced HPA axis activation in socially isolated rats. Oxidative stress in the rostral ventrolateral medulla is also a key regulator of sympathetic nerve activity. In the vasculature, oxidative stress increases vascular tone and promote atherogenesis through multiple mechanisms. Thus, preventing oxidative stress may represent a therapeutic strategy to reduce the detrimental effects of social stress on health.
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Affiliation(s)
- Huige Li
- Department of Pharmacology, Johannes Gutenberg University Medical Center, 55131, Mainz, Germany.
| | - Ning Xia
- Department of Pharmacology, Johannes Gutenberg University Medical Center, 55131, Mainz, Germany.
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48
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Mravec B, Tibensky M, Horvathova L. Stress and cancer. Part II: Therapeutic implications for oncology. J Neuroimmunol 2020; 346:577312. [PMID: 32652364 DOI: 10.1016/j.jneuroim.2020.577312] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 06/26/2020] [Indexed: 02/06/2023]
Abstract
Accumulated evidence has confirmed the ability of stress to promote the induction and progression of cancer (for review see Stress and cancer. Part I: Mechanisms mediating the effect of stressors on cancer). In support of this, data from clinical trials utilizing approaches that reduce stress-related signaling have shown prolonged survival of cancer patients. Therefore, the question has arisen as to how we can utilize this knowledge in the daily treatment of cancer patients. The main aim of this review is to critically analyze data from studies utilizing psychotherapy or treatment by β-blockers on the survival of cancer patients. Because these approaches, especially treatment by β-blockers, have been routinely used in clinical practice for decades in the treatment of non-cancer patients, their wider introduction into oncology might be realized in the near future.
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Affiliation(s)
- Boris Mravec
- Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, Slovakia; Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia.
| | - Miroslav Tibensky
- Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, Slovakia
| | - Lubica Horvathova
- Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia
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Filippi L, Bruno G, Domazetovic V, Favre C, Calvani M. Current Therapies and New Targets to Fight Melanoma: A Promising Role for the β3-Adrenoreceptor. Cancers (Basel) 2020; 12:cancers12061415. [PMID: 32486190 PMCID: PMC7352170 DOI: 10.3390/cancers12061415] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/15/2020] [Accepted: 05/25/2020] [Indexed: 02/07/2023] Open
Abstract
Melanoma is one of the most aggressive types of cancer and the most deadly skin cancer. According to World Health Organization, about 132,000 melanoma skin cancers occur globally each year. Thanks to the efficacy of new therapies, life expectation has been improved over the last years. However, some malignant melanomas still remain unresponsive to these therapies. The β-adrenergic system, among its many physiological roles, has been recognized as the main mediator of stress-related tumorigenic events. In particular, catecholamine activation of β-adrenergic receptors (β-ARs) affects several processes that sustain cancer progression. Among the β-AR subtypes, the β3-AR is emerging as an important regulator of tumorigenesis. In this review, we summarize data of different experimental studies focused on β3-AR involvement in tumor development in various types of cancer and, particularly, in melanoma. Taken together, the preclinical evidences reported in this review demonstrate the crucial role of β3-AR in regulating the complex signaling network driving melanoma progression. Therefore, a need exists to further disseminate this new concept and to investigate more deeply the role of β3-AR as a possible therapeutic target for counteracting melanoma progression at clinical level.
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Affiliation(s)
- Luca Filippi
- Neonatal Intensive Care Unit, Medical Surgical Feto-Neonatal Department, A. Meyer University Children’s Hospital, 50139 Florence, Italy
- Correspondence: (L.F.); (G.B.)
| | - Gennaro Bruno
- Department of Health Science, University of Florence, 50139 Florence, Italy;
- Department of Paediatric Haematology-Oncology, A. Meyer University Children’s Hospital, 50139 Florence, Italy; (C.F.); (M.C.)
- Correspondence: (L.F.); (G.B.)
| | - Vladana Domazetovic
- Department of Health Science, University of Florence, 50139 Florence, Italy;
- Department of Paediatric Haematology-Oncology, A. Meyer University Children’s Hospital, 50139 Florence, Italy; (C.F.); (M.C.)
| | - Claudio Favre
- Department of Paediatric Haematology-Oncology, A. Meyer University Children’s Hospital, 50139 Florence, Italy; (C.F.); (M.C.)
| | - Maura Calvani
- Department of Paediatric Haematology-Oncology, A. Meyer University Children’s Hospital, 50139 Florence, Italy; (C.F.); (M.C.)
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50
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Lamboy-Caraballo R, Ortiz-Sanchez C, Acevedo-Santiago A, Matta J, N.A. Monteiro A, N. Armaiz-Pena G. Norepinephrine-Induced DNA Damage in Ovarian Cancer Cells. Int J Mol Sci 2020; 21:ijms21062250. [PMID: 32213975 PMCID: PMC7139728 DOI: 10.3390/ijms21062250] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/18/2020] [Accepted: 03/20/2020] [Indexed: 12/17/2022] Open
Abstract
Multiple studies have shown that psychological distress in epithelial ovarian cancer (EOC) patients is associated with worse quality of life and poor treatment adherence. This may influence chemotherapy response and prognosis. Moreover, although stress hormones can reduce cisplatin efficacy in EOC treatment, their effect on the integrity of DNA remains poorly understood. In this study, we investigated whether norepinephrine and epinephrine can induce DNA damage and modulate cisplatin-induced DNA damage in three EOC cell lines. Our data show that norepinephrine and epinephrine exposure led to increased nuclear γ-H2AX foci formation in EOC cells, a marker of double-strand DNA breaks. We further characterized norepinephrine-induced DNA damage by subjecting EOC cells to alkaline and neutral comet assays. Norepinephrine exposure caused DNA double-strand breaks, but not single-strand breaks. Interestingly, pre-treatment with propranolol abrogated norepinephrine-induced DNA damage indicating that its effects may be mediated by β-adrenergic receptors. Lastly, we determined the effects of norepinephrine on cisplatin-induced DNA damage. Our data suggest that norepinephrine reduced cisplatin-induced DNA damage in EOC cells and that this effect may be mediated independently of β-adrenergic receptors. Taken together, these results suggest that stress hormones can affect DNA integrity and modulate cisplatin resistance in EOC cells.
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Affiliation(s)
- Rocio Lamboy-Caraballo
- Department of Basic Sciences, Division of Pharmacology, School of Medicine, Ponce Health Sciences University, Ponce, PR 00716, USA; (R.L.-C.); (J.M.)
| | | | | | - Jaime Matta
- Department of Basic Sciences, Division of Pharmacology, School of Medicine, Ponce Health Sciences University, Ponce, PR 00716, USA; (R.L.-C.); (J.M.)
- Division of Cancer Biology, Ponce Research Institute, Ponce, PR 00716, USA;
| | - Alvaro N.A. Monteiro
- Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA;
| | - Guillermo N. Armaiz-Pena
- Department of Basic Sciences, Division of Pharmacology, School of Medicine, Ponce Health Sciences University, Ponce, PR 00716, USA; (R.L.-C.); (J.M.)
- Division of Cancer Biology, Ponce Research Institute, Ponce, PR 00716, USA;
- Division of Women’s Health, Ponce Research Institute, Ponce, PR 00716, USA
- Correspondence:
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