Special Issue "Targeted Intervention for Pancreatic Cancer Associated with Smoking, Alcohol Abuse and Psychological Stress"

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 April 2015)

Special Issue Editor

Guest Editor
Prof. Dr. Hildegard M. Schuller

Experimental Oncology Laboratory, Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA
Website | E-Mail
Phone: 865-974-8217
Interests: lung cancer; pancreatic cancer; neurotransmitters as regulators of cancer; effects of nicotine and tobacco-specific nitrosamines ion cancer; effects of psychological factors on cancer

Special Issue Information

Dear Colleagues,

Pancreatic cancer is the fourth leading cause of cancer deaths with a mortality near 100% within 2 years of diagnosis. Neither cancer prevention efforts nor advances in cancer therapy have improved the prognosis of this disease and the incidence of pancreatic cancer is even rising.

Smoking and alcoholism are established risk factors, while evidence for psychological stress as an additional risk factor has emerged more recently. Tobacco-specific carcinogenic nitrosamines cause activating point mutations in K-ras and inactivating mutations in the tumor suppressor gene p53, with both mutations frequently expressed in pancreatic cancer. In addition, these nitrosamines interfere with the autonomic regulation of cell and organ functions by the nervous system, thus compromising its important role in maintaining homeostasis. Both smoking and alcoholism can additionally cause pancreatitis, an independent additional risk factor for pancreatic cancer. A potential etiological link between pancreatic cancer and psychological stress has been suggested by  preclinical data generated by two independent laboratories: chronic social stress significantly promoted the growth of pancreatic cancer xenografts in mice via the stress neurotransmitter-induced activation of multiple cellular pathways downstream of beta-adrenergic receptors and chronic treatment of mice with the stress neurotransmitter epinephrine caused p53 suppression via beta-adrenergic receptor signaling.

For this Special Issue of Cancers, we invite contributions that focus on mechanisms: how smoking, alcoholism, and psychological stress may contribute to the development and progression of pancreatic cancer and how the targeting of such mechanisms can be exploited to improve pancreatic cancer prevention and therapy.

Prof. Dr. Hildegard M. Schuller
Guest Editor

Manuscript Submission Information

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Keywords

  • pancreatic cancer
  • smoking
  • alcoholism
  • nicotinic receptor signaling
  • G-protein-coupled receptor signaling
  • cancer prevention
  • cancer therapy
  • psychological stress

Published Papers (7 papers)

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Review

Open AccessFeature PaperReview Diet and Pancreatic Cancer Prevention
Cancers 2015, 7(4), 2309-2317; https://doi.org/10.3390/cancers7040892
Received: 12 August 2015 / Revised: 6 November 2015 / Accepted: 10 November 2015 / Published: 23 November 2015
Cited by 9 | PDF Full-text (202 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer is without any doubt the malignancy with the poorest prognosis and the lowest survival rate. This highly aggressive disease is rarely diagnosed at an early stage and difficult to treat due to its resistance to radiotherapy and chemotherapy. Therefore, there is [...] Read more.
Pancreatic cancer is without any doubt the malignancy with the poorest prognosis and the lowest survival rate. This highly aggressive disease is rarely diagnosed at an early stage and difficult to treat due to its resistance to radiotherapy and chemotherapy. Therefore, there is an urgent need to clarify the causes responsible for pancreatic cancer and to identify preventive strategies to reduce its incidence in the population. Some circumstances, such as smoking habits, being overweight and diabetes, have been identified as potentially predisposing factors to pancreatic cancer, suggesting that diet might play a role. A diet low in fat and sugars, together with a healthy lifestyle, regular exercise, weight reduction and not smoking, may contribute to prevent pancreatic cancer and many other cancer types. In addition, increasing evidence suggests that some food may have chemo preventive properties. Indeed, a high dietary intake of fresh fruit and vegetables has been shown to reduce the risk of developing pancreatic cancer, and recent epidemiological studies have associated nut consumption with a protective effect against it. Therefore, diet could have an impact on the development of pancreatic cancer and further investigations are needed to assess the potential chemo preventive role of specific foods against this disease. This review summarizes the key evidence for the role of dietary habits and their effect on pancreatic cancer and focuses on possible mechanisms for the association between diet and risk of pancreatic cancer. Full article
Open AccessReview Molecular Targeted Intervention for Pancreatic Cancer
Cancers 2015, 7(3), 1499-1542; https://doi.org/10.3390/cancers7030850
Received: 14 May 2015 / Revised: 24 July 2015 / Accepted: 4 August 2015 / Published: 10 August 2015
Cited by 18 | PDF Full-text (771 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet [...] Read more.
Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies. Full article
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Open AccessReview The Role of nAChR and Calcium Signaling in Pancreatic Cancer Initiation and Progression
Cancers 2015, 7(3), 1447-1471; https://doi.org/10.3390/cancers7030845
Received: 16 June 2015 / Revised: 14 July 2015 / Accepted: 15 July 2015 / Published: 31 July 2015
Cited by 9 | PDF Full-text (987 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression [...] Read more.
Pancreatic cancer shows a strong correlation with smoking and the current therapeutic strategies have been relatively ineffective in improving the survival of patients. Efforts have been made over the past many years to understand the molecular events that drive the initiation and progression of pancreatic cancer, especially in the context of smoking. It has become clear that components of tobacco smoke not only initiate these cancers, especially pancreatic ductal adenocarcinomas (PDACs) through their mutagenic properties, but can also promote the growth and metastasis of these tumors by stimulating cell proliferation, angiogenesis, invasion and epithelial-mesenchymal transition. Studies in cell culture systems, animal models and human samples have shown that nicotinic acetylcholine receptor (nAChR) activation enhances these tumor-promoting events by channeling signaling through multiple pathways. In this context, signaling through calcium channels appear to facilitate pancreatic cancer growth by itself or downstream of nAChRs. This review article highlights the role of nAChR downstream signaling events and calcium signaling in the growth, metastasis as well as drug resistance of pancreatic cancer. Full article
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Open AccessReview Neural Regulation of Pancreatic Cancer: A Novel Target for Intervention
Cancers 2015, 7(3), 1292-1312; https://doi.org/10.3390/cancers7030838
Received: 5 June 2015 / Revised: 7 July 2015 / Accepted: 13 July 2015 / Published: 17 July 2015
Cited by 7 | PDF Full-text (516 KB) | HTML Full-text | XML Full-text
Abstract
The tumor microenvironment is known to play a pivotal role in driving cancer progression and governing response to therapy. This is of significance in pancreatic cancer where the unique pancreatic tumor microenvironment, characterized by its pronounced desmoplasia and fibrosis, drives early stages of [...] Read more.
The tumor microenvironment is known to play a pivotal role in driving cancer progression and governing response to therapy. This is of significance in pancreatic cancer where the unique pancreatic tumor microenvironment, characterized by its pronounced desmoplasia and fibrosis, drives early stages of tumor progression and dissemination, and contributes to its associated low survival rates. Several molecular factors that regulate interactions between pancreatic tumors and their surrounding stroma are beginning to be identified. Yet broader physiological factors that influence these interactions remain unclear. Here, we discuss a series of preclinical and mechanistic studies that highlight the important role chronic stress plays as a physiological regulator of neural-tumor interactions in driving the progression of pancreatic cancer. These studies propose several approaches to target stress signaling via the β-adrenergic signaling pathway in order to slow pancreatic tumor growth and metastasis. They also provide evidence to support the use of β-blockers as a novel therapeutic intervention to complement current clinical strategies to improve cancer outcome in patients with pancreatic cancer. Full article
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Open AccessReview Targeting NK-1 Receptors to Prevent and Treat Pancreatic Cancer: a New Therapeutic Approach
Cancers 2015, 7(3), 1215-1232; https://doi.org/10.3390/cancers7030832
Received: 19 May 2015 / Revised: 27 June 2015 / Accepted: 30 June 2015 / Published: 6 July 2015
Cited by 7 | PDF Full-text (363 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatic cancer (PC) is the fourth leading cause of cancer related-deaths in both men and women, and the 1- and 5-year relative survival rates are 25% and 6%, respectively. It is known that smoking, alcoholism and psychological stress are risk factors that can [...] Read more.
Pancreatic cancer (PC) is the fourth leading cause of cancer related-deaths in both men and women, and the 1- and 5-year relative survival rates are 25% and 6%, respectively. It is known that smoking, alcoholism and psychological stress are risk factors that can promote PC and increase PC progression. To date, the prevention of PC is crucial because there is no curative treatment. After binding to the neurokinin-1 (NK-1) receptor (a receptor coupled to the stimulatory G-protein Gαs that activates adenylate cyclase), the peptide substance P (SP)—at high concentrations—is involved in many pathophysiological functions, such as depression, smoking, alcoholism, chronic inflammation and cancer. It is known that PC cells and samples express NK-1 receptors; that the NK-1 receptor is overexpressed in PC cells in comparison with non-tumor cells, and that nanomolar concentrations of SP induce PC cell proliferation. By contrast, NK-1 receptor antagonists exert antidepressive, anxiolytic and anti-inflammatory effects and anti-alcohol addiction. These antagonists also exert An antitumor action since in vitro they inhibit PC cell proliferation (PC cells death by apoptosis), and in a xenograft PC mouse model they exert both antitumor and anti-angiogenic actions. NK-1 receptor antagonists could be used for the treatment of PC and hence the NK-1 receptor could be a new promising therapeutic target in PC. Full article
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Open AccessReview Role of Parathyroid Hormone-Related Protein Signaling in Chronic Pancreatitis
Cancers 2015, 7(2), 1091-1108; https://doi.org/10.3390/cancers7020826
Received: 27 April 2015 / Revised: 5 June 2015 / Accepted: 9 June 2015 / Published: 18 June 2015
Cited by 6 | PDF Full-text (368 KB) | HTML Full-text | XML Full-text
Abstract
Chronic pancreatitis (CP), a progressive inflammatory disease where acini are destroyed and replaced by fibrous tissue, increases the risk for pancreatic cancer. Risk factors include alcohol, smoking, and obesity. The effects of these risk factors are exacerbated in patients with mutations in genes [...] Read more.
Chronic pancreatitis (CP), a progressive inflammatory disease where acini are destroyed and replaced by fibrous tissue, increases the risk for pancreatic cancer. Risk factors include alcohol, smoking, and obesity. The effects of these risk factors are exacerbated in patients with mutations in genes that predispose to CP. The different environmental and genetic factors produce the same clinical phenotype; once CP develops, disease course is the same regardless of etiology. Critical questions still need to be answered to understand what modifies predisposition to develop CP in persons exposed to risk factors. We postulate that risk factors modulate endogenous pathways, with parathyroid hormone-related protein (PTHrP) signaling being one such pathway. In support, PTHrP levels are elevated in mice treated with alcohol, and in mouse models of cerulein- and pancreatic duct ligation-induced CP. Disrupting the Pthrp gene in acinar cells exerts protective effects (decreased edema, histological damage, amylase and cytokine release, and fibrosis) in these CP models. PTHrP levels are elevated in human CP. Currently, CP care lacks specific pharmacological interventions. Targeting PTHrP signaling may present a novel therapeutic strategy that inhibits pancreatic inflammation and fibrosis, especially since the risk of developing pancreatic cancer is strongly associated with duration of chronic inflammation. Full article
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Open AccessReview Pathologic Cellular Events in Smoking-Related Pancreatitis
Cancers 2015, 7(2), 723-735; https://doi.org/10.3390/cancers7020723
Received: 7 April 2015 / Revised: 17 April 2015 / Accepted: 21 April 2015 / Published: 29 April 2015
Cited by 6 | PDF Full-text (537 KB) | HTML Full-text | XML Full-text
Abstract
Pancreatitis, a debilitating inflammatory disorder, results from pancreatic injury. Alcohol abuse is the foremost cause, although cigarette smoking has recently surfaced as a distinct risk factor. The mechanisms by which cigarette smoke and its toxins initiate pathological cellular events leading to pancreatitis, have [...] Read more.
Pancreatitis, a debilitating inflammatory disorder, results from pancreatic injury. Alcohol abuse is the foremost cause, although cigarette smoking has recently surfaced as a distinct risk factor. The mechanisms by which cigarette smoke and its toxins initiate pathological cellular events leading to pancreatitis, have not been clearly defined. Although cigarette smoke is composed of more than 4000 compounds, it is mainly nicotine and the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which have been extensively studied with respect to pancreatic diseases. This review summarizes these research findings and highlights cellular pathways which may be of relevance in initiation and progression of smoking-related pancreatitis. Full article
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