Current Cancer Therapy Reviews - Volume 8, Issue 2, 2012

Sympathetic neurotransmitters are known for their multiple and pleiotropic functions. Recently, regulation of tumor angiogenesis emerged as one of them. Norepinepherine and epinephrine have been shown to stimulate tumor vascularization via two independent mechanisms – induction of growth factor release from tumor and stromal cells, and a direct effect on endothelial cell (EC) proliferation. In contrast, their precursor, dopamine, interferes with vascular endothelial growth factor (VEGF) signaling in ECs and inhibits angiogenesis. Tumor vascularization can be also regulated by peptidergic neurotransmitters, such as neuropeptide Y (NPY), which acts as a potent angiogenic factor due to its direct stimulatory effect on EC proliferation, migration and capillary formation. The angiogenic activity of these neuronal factors is particularly apparent under the conditions of increased sympathetic activity during stress, or in tumors of sympathetic origin. However, there is also evidence indicating that basal sympathetic activity is essential for sustained growth of nonneuronal tumors. Importantly, sympathetic activity increases in hypoxia, which is a crucial factor inducing neovascularization. Moreover, in tumor cells, adrenergic stimulation up-regulates hypoxia-inducible factor 1α (HIF-1α) independently on oxygen levels, which mimics hypoxic conditions and increases the release of angiogenic factors. The pro- and antiangiogenic effects of sympathetic neurotransmitters are potent enough to alter rates of tumor growth and metastases, confirming their potential value as therapeutic targets. However, such therapy may be complicated by other activities of these neuronal factors, such as immunomodulation and direct effects on tumor cell functions, which are tumor specific and may both facilitate and inhibit tumor growth.

Breast cancer is the most frequent malignancy in women in the majority of western countries. Both acute and chronic stress cause the release of epinephrine and norepinephrine. These natural cateholamines bind to nine different adrenoceptors. Breast cancer epithelial cells express α2 and β2-adrenoceptors. Catecholamine binding to α2-adrenoceptors in cancer cells is associated with increased cell proliferation. On the contrary, catecholamine binding to β2-adrenoceptors result in diminished cell proliferation. Therefore, the relative concentration of these receptors in the tumor cell will enhance or diminish proliferation. Also in vivo, following stimulation with natural catecholamines, the tumor will experience enhanced or diminished growth depending on the relative concentration of α2 and β2-adrenoceptors. The administration of synthetic α2-adrenergic agonists enhances tumor growth whereas the administration of the α2-adrenergic antagonist rauwolscine diminishes tumor growth below control levels, behaving as an inverse agonist. The administration of β- adrenergic agonists could also be useful to lower tumor growth. The use of β-blockers in patients have been described by several groups as very promising specially in the case of the HER2 positive and triple negative tumors. Thus different therapeutic compounds targeting adrenergic receptors could become very important drugs for the treatment of selected cancer patients. Currently, adrenergic agonists/antagonists are used for the treatment of different diseases and have minimal side effects when compared with chemotherapy. The possibility of using them for treatment of breast cancer is an encouraging concept especially for the patients with resistance to the usual anti-cancer therapy.

A growing body of epidemiologic and clinical evidence points to a significant role of biobehavioral and associated neuroendocrine factors on cancer growth and progression. This review provides an overview of the emerging relationships between neuroendocrine pathways and ovarian cancer progression. The primary focus of this review is on the contributions of neuroendocrine influences on cancer cell biology and tumor microenvironment in ovarian cancer. This mechanistic understanding will inform new opportunities for pharmacological and behavioral interventions for improving the outcome of ovarian cancer patients.

It has been demonstrated by clinical and animal studies that stress stimulation plays a pivotal role in the tumor development and progression. Adrenergic system activation mediates most of the effects resulting from stress stimulation. Various cigarette components have been indicated for inducing the secretion of stress hormones such as noradrenaline and adrenaline which activate the adrenoceptors expressed on tumor cells and initiate different biological effects. Gastrointestinal (GI) cancers, a common malignancy in the body are also influenced by stress stimulation to a great extent. Combined stress stimulation with cigarette smoking can further accelerate tumor progression, and even develop chemoresistance in cancer cells. Therefore the involvement of adrenoceptors in these biological processes and habitual behaviours are becoming interesting therapeutic targets. Indeed various adrenoceptor blockers are implicated as promising therapeutic agents to prevent and treat relevant cancers including those in the GI tract. In this review, we sum up the possible relationship between the adrenergic system and GI cancers and provide a mechanistic understanding on this relationship. Meanwhile, we also further discuss the roles of cigarette smoke and its active ingredient nicotine which is highly associated with the adrenergic system in the development of GI cancers.

Small airway epithelial cells from, which most pulmonary adenocarcinomas (PACs) derive, and pancreatic duct epithelia, from which pancreatic ductal adenocarcinomas (PDACs) originate, share the ability to synthesize and release bicarbonate. This activity is stimulated in both cell types by the α7nicotinic acetylcholine receptor (α7nAChR)-mediated release of noradrenaline and adrenaline, which in turn activate β-adrenergic receptor (β-AR) signaling, leading to the cAMP-dependent release of bicarbonate. The same signaling pathway also stimulates a complex network of intracellular signaling cascades which regulate the proliferation, migration, angiogenesis and apoptosis of PAC and PDAC cells. The amino acid neurotransmitter γ-aminobutyric acid (GABA) serves as the physiological inhibitor of this cancer stimulating network by blocking the activation of adenylyl cyclase. This review summarizes experimental, epidemiological and clinical data that have identified risk factors for PAC and PDAC such as smoking, alcoholism, chronic non neoplastic diseases and their treatments as well as psychological stress and analyzes how these factors increase the cancer-stimulating effects of this regulatory cascade in PAC and PDAC. This analysis identifies the careful maintenance of balanced levels in stimulatory stress neurotransmitters and inhibitory GABA as a key factor for the prevention of PDAC and suggests the marker-guided use of beta-blockers, GABA or GABA-B receptor agonists as well as psychotherapeutic or pharmacological stress reduction as important tools that may render currently ineffective cancer intervention of PAC and PDAC more successful.

Limitations in successfully treating metastasis development remain an obstacle in preventing disease progression in aggressive forms of cancer. Despite an improved understanding about the mechanistic biological pathways of metastasis formation, the ability to translate laboratory findings into therapies for significant patient benefit have been disappointingly slow. In this perspective, we briefly summarise the principal concepts of metastasis development, and the strengths and weaknesses associated with the current clinical approach to its treatment. Moreover, the recent clinical evidence for a new antimetastatic treatment is reviewed concerning the use of adrenergic receptor antagonists (betablockers). The principal aim of this Special Edition is to illustrate that a high science methodology approach has been used in testing the hypothesis that stress can drive disease progression in cancer. Stimulation of adrenergic receptors resulting from stress hormones and mediators released from the sympathetic nervous system have been shown to enhance disease progression in several cancer types. Current levels of understanding based on in vitro studies suggest that this is achieved through direct effects on cancer cells involving pro-migratory stimulation. But more recent in vivo investigations suggest increased complexity involving interaction between the primary tumour and inflammatory cells in its immediate microenvironment. Further studies are needed to better understand the relationship between the sympathetic and inflammatory disease pathways in cancer disease progression. But ahead of this, increasing clinical evidence from epidemiology studies demonstrate that blocking adrenergic receptors in patients with some forms of cancer translates into significant gains in survival, achieved through a reduction in metastasis formation.

Apoptosis is an induced and ordered process in which the cell actively participates in bringing about its own death. Dysregulation in either of the apoptotic pathways leads to various diseases including cancer, neurodegenerative disorders and autoimmunity. Bcl-2 (B cell lymphoma 2) proteins such as pro-and anti-apoptotic play a vital role in the mitochondrial pathway of apoptosis which results in cellular commitment to death or cell survival. So, therefore many small molecule antagonists that targets Bcl-2 anti-apoptotic proteins that lead to cellular survival are in their pre-clinical and clinical stages. In this review we focus on the apoptotic players of Bcl-2 group of proteins and their anti-apoptotic inhibitors.

Children diagnosed with cancer are commonly treated with anthracyclines, which have increased the number of survivors to more than 325,000 in the United States. However, anthracyclines are limited by their cardiotoxicity, which increases the risk of treatment-related complications. Survivors are more likely than their healthy siblings to experience heart failure, coronary artery disease, and stroke within the first 30 years after diagnosis. The mechanisms of anthracycline cardiotoxicity are not well understood. Cardiotoxicity can develop any time, from the start of chemotherapy to decades after its completion, and can manifest sub-clinically (e.g., echocardiographic abnormalities) or clinically (e.g., heart failure). However, not all survivors are affected equally, despite receiving similar doses of anthracyclines. Factors such as age at diagnosis, female sex, and cumulative anthracycline dose are risk factors for cardiotoxicity. Possible genetic risk factors that may explain the variability among survivors need to be explored. Identifying the highest-risk patients may help inform the frequency of monitoring during and after treatment and identify those who would benefit most from other treatment and prevention options, such as limiting the cumulative dose of anthracyclines, replacing them with liposomal anthracyclines, and using dexrazoxane as a cardioprotectant. The ultimate goal is to maximize the oncologic efficacy of anthracyclines and to minimize their late cardiotoxic effects in the vulnerable and less-studied population of childhood cancer survivors.

During the course of cancer metastasis development, invasive tumor cells circulate through the blood stream and disseminate to other tissues. Circulating and disseminated tumor cells (CTCs and DTCs, respectively) may be the source of local and distant metastases and are a promising target for anticancer therapy. Multiple studies have shown that the detection of DTCs or CTCs correlates with increased risk of disease recurrence, suggesting that reducing the prevalence and persistence of these cells is clinically relevant. The development of metastases is a multistep process that involves complex biologic processes and a multitude of growth factors. The bone marrow provides a portion of these growth factors and a nutrient-rich microenvironment in which dormant cancer cells can survive and transition to metastasis- initiating cells. The molecular interactions between DTCs and the bone marrow microenvironment enable DTCs to evade cytotoxic chemotherapy, allowing them to lie dormant for extended periods of time before becoming active and metastasizing to secondary sites. Alteration of the bone marrow microenvironment with antiresorptive agents, such as bisphosphonates, may render the bone marrow less suitable for cancer cell growth, possibly interfering with the metastatic cascade. Clinical studies have shown that the nitrogen-containing bisphosphonate zoledronic acid can reduce the persistence and prevalence of DTCs in patients with breast cancer, suggesting that zoledronic acid may improve clinical outcomes. Targeting the metastatic niche by altering the microenvironment in the bone marrow may be an effective anticancer strategy.