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 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 9  |  Issue : 7  |  Page : 123-128

The role of neural-related factors in the metastasis of the gastrointestinal cancer


1 Department of Oncology, Remin Hospital Wuhan University, Hubei 430060, China
2 Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, China

Date of Web Publication30-Nov-2013

Correspondence Address:
Heng Zeng
Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan 430030, PR
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.122505

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 > Abstract 

Neurotransmitters are identified to be endogenous chemicals and act on neurons to transmit signals to each other or to a target cell across synapse. They are involved in many brain functions including analgesia, reward, food intake, metabolism, reproduction, social behaviors, learning, and memory. Recently, sympathetic nerve fibers were detected in many solid tumors including gastrointestinal cancer, supporting the idea that neural system has effects on tumor progression. Neurotransmitters were secreted from the sympathetic nerve fibers and subsequently infiltrated into tumor tissues. Further studies disclosed the different mechanisms of various kinds of neurotransmitters in the progression of carcinogenesis, including tumor cell proliferation, angiogenesis, and tumor invasion and metastasis. Neurotransmitters are mainly subdivided into four types, amino acids, monoamines, peptides, and others, each of which contains multiple chemicals. For this reason, we cannot describe each in detail. In this review, we will focus on several important neurotransmitters including tachykinis, neuropeptide Y, and b-adrenergic receptors. How they function and their crosstalks with the immune system in the progression, especially the metastasis of gastrointestinal cancer, will be described. Finally, we will summarize the clinical implications in the treatment of gastrointestinal cancer.

Keywords: Gastrointestinal cancer, metastasis, neurotransmitters, neuropeptide Y, tachykinis, β-adrenergic receptors


How to cite this article:
Xu Xt, Xu B, Song Qb, Zeng H. The role of neural-related factors in the metastasis of the gastrointestinal cancer. J Can Res Ther 2013;9, Suppl S2:123-8

How to cite this URL:
Xu Xt, Xu B, Song Qb, Zeng H. The role of neural-related factors in the metastasis of the gastrointestinal cancer. J Can Res Ther [serial online] 2013 [cited 2019 Jun 18];9:123-8. Available from: http://www.cancerjournal.net/text.asp?2013/9/7/123/122505


 > Introduction Top


Gastrointestinal cancer is termed as a malignant condition of the gastrointestinal tract, including the esophagus, stomach, biliary system, pancreas, bowels, and anus. Malignancies affecting the gastrointestinal tract have always been thought as aggressive tumors with a poor prognosis mainly due to metastasis. Metastasis is identified as a complicated activity that consists of a multistep process in which malignant tumor cells invade locally, survive in the blood and lymphatic vessels, and finally colonize in the distant organ. The frequent target sites for metastasis of gastrointestinal cancer are the liver, lymph nodes, peritoneal, and lung, and it is the major cause of gastrointestinal cancer-related deaths. [1],[2],[3],[4],[5]

Functional activities of many organs are under the control of the neural system including central nervous system (CNS) and sympathetic nervous system (SNS). [6] The brain-gut axis, a bidirectional signaling pathway between the nervous system and the gastrointestinal tract, maintains the homeostasis of the gastrointestinal system. [7] Nerve fibers are detected in some kinds of solid tumors, including gastrointestinal tract stroma (GIST), [8] suggesting that the neural system may be involved in the progression of tumor. Further researches elucidate that the neural system plays a key role in tumor metastasis. [9],[10],[11] For example, electrical stimulation of the midbrain increased the metastatic potential of carcinosarcoma cells in rats. [12] Associations of pineal gland function and spatial disorientation with metastasis were elucidated in mice bearing Lewis lung carcinoma. [13] Transplantation of β-endorphin neurons into the hypothalamus inhibited the metastasis of mammary tumors in rats. [14] In an orthotopic syngeneic model of breast cancer, chronic immobilization stress significantly increased metastatic colonization to lung by tenfold and to lymph node by threefold from the primary tumors. [15] Pharmacologic activation of SNS signaling pathways with the β-adrenergic agonist isoproterenol also promoted mammary tumor metastasis. [15] Clinical and epidemiological studies indicate that negative psychological factors are significantly correlated with increased cancer recurrence, short survival, and poor prognosis in patients with breast, lung, head and neck, hepatobiliary, lymphoid, and hematopoietic cancers, implying that the actions of the CNS may impact on tumor development. [16]

Neurotransmitters, the executers released from the neural cells, which are stimulated under certain circumstances, bind to the corresponding receptors on the targeted cell to modulate the functions of cancer cells. There are four major categories of chemicals that act as neurotransmitter substances, which are small molecule neurotransmitter substances, amino acids, neuroactive peptides, and soluble gases. Each category consists of many members. Given the writing length limitation, we will focus on three neurotransmitters, which are tachykinis, neuropeptide Y (NPY), and norepinephrine (NE) as they are widely studied, and discuss their functions in tumor progression, while the others will be summarized briefly.

Neural-related factors establish a direct connection between the neural system and tumor cells. [6] For example, these factors modulate not only the process of metastasis, such as degradation of base membranes, cancer cell invasion, migration, extravasation, and colonization, [17 ],[18],[19],[20],[21],[22],[23],[24],[25] but also angiogenesis [26],[27],[28],[29],[30],[31],[32],[ 33] and immune functions [34],[35] to further influence metastasis. Peripheral nerve invasion (PNI) provides an alternative pathway for the spread of cancer cells when blood and lymphatic metastases are absent. [36],[37],[38] Moreover, stress and social isolation may increase distant metastasis through releasing hormones from the brain, the hypothalamic-pituitary-adrenal (HPA) axis, and autonomic nervous system (ANS).

Dopamine exhibits inhibitory effects on tumor proliferation, invasion, and angiogenesis. [39] Daily dopamine treatment reduces cyclic adenosine monophosphate (cAMP) level and inhibits vascular endothelial growth factor (VEGF)-induced Src kinase activation, [40] consequently leading to the inhibition of tumor growth and suppression of angiogenesis. In addition, dopamine enhances the efficacies of chemotherapy drugs in breast and colon cancer preclinical models. Angiotensin II, a potent vasoconstrictor peptide from rennin-angiotensin system in the kidney, functions not only as an important effector controlling blood pressure and volume in the cardiovascular system, but also as a major stress hormone whose expression is remarkably increased during acute or chronic stress. [41] In the context of cancer metastasis, angiotensin II is characterized as an enhancer to promote tumor metastasis by directly inducing tumor cell adhesion to endothelial cells, transendothelial migration, ultimately resulting in increasing the number and size of metastatic foci at the secondary sites. [42],[43],[44] Calcitonin gene-related peptide (CGRP), a neuropeptide, is widely expressed in the neural system and closely correlated with tumor growth. [45] In CGRP-knockout mice, tumor growth and tumor-associated angiogenesis were dramatically reduced, when compared with the wild-type mice. [46] The expression of VEGF in tumor stroma was down-regulated in CGRP-knockout mice. [47]


 > Tachykinis Top


Tachykinin peptides are a large family of neuropeptides that are characterized by a common sequence at the C-terminal, Phe-X-Gly-Leu-Met-NH2. Originally, tachykinin peptides were described to induce the contraction of gut tissue rapidly. [7] Further researches elucidated the functions of tachykinis, including exciting the neurons, evoking behavioral responses, and directly or indirectly contracting the smooth muscle. [7] There are two human tachykinin genes called TAC1 and TAC3, which are equivalent to Tac1 and Tac2 of the mouse, respectively. TAC1 encodes neurokinin A, neuropeptide K, neuropeptide gamma, and substance P (SP), whereas TAC3 encodes neurokinin B. Among these tachykinins, SP is the most notable.

SP is produced in the neuronal and glial cells of human central and peripheral nervous systems and is mainly responsible for regulating the emotional responses. [48] Stress is often associated with the elevation of SP level in animals and humans. Moreover, SP-knockout mice exhibited decreased and depression-related behaviors and anxiety level. Recently, it has been reported that SP and its specific receptor, neurokinin-1 receptor (NK-1R), play a role in tumor proliferation, invasion, metastasis, and angiogenesis. [49] Furthermore, ligation of NK-1R by SP triggers the activation of multiple signaling pathways involved in the malignant progression of cancer, including mitogen-activated protein kinases (MAPK), protein kinase A (PKA), protein kinase B (PKB), protein kinase C (PKC), and Rho/Rock. [2] In addition, SP functions as a proinflammatory mediator in acute pancreatitis by increasing microvascular permeability and promoting plasma extravasation from the intravascular to the extravascular space. [48]

Netrin, another important neurotransmitter, is a laminin-related secreted protein, conserved from nematode worms to humans. Netrin functions as a chemotropic molecule, highly expressed in the brain and peripheral tissues, which is involved in axon guidance and cell migration orientation in the developing nervous system. Long-term studies found that netrin also has functions outside the CNS, especially in controlling acute inflammation. Several groups have reported the anti-inflammatory potential of netrin and its capability to reduce local inflammatory tissue injury in various inflammation-based diseases, including kidney ischemia reperfusion injury, hypoxia-induced inflammation, acute lung injury, peritonitis, inflammatory bowel disease, and acute pancreatitis. [3],[25],[39],[40],[42]

Netrin acts through binding to immunoglobulin-like transmembrane receptors, which are deleted in colon cancer (DCC)/neogenin and UNC5A-D, as well as the G-protein-coupled adenosine A2B-receptor (A2B-R), consequently leading to axon outgrowth, controlling the morphogenesis of endothelial cells and vascular smooth muscle cells and resulting in epithelial cell adhesion and migration in lungs, mammary glands, and pancreas. [41],[43],[44] The combination of netrin with its receptors recruits a variety of signaling pathways such as Cdc42 small GTPases, MAPK, and src, [45],[50] which also play key roles in promoting tumor progression, suggesting that netrin and DCC/UNC5A-D might participate in the regulation of cancer cell invasion and metastasis. [51]
"Frequently, loss of dependence receptors or gain of functional netrin are the main mechanisms of tumor progression". including neuroblastoma, [52] breast cancer, [53] pancreatic ductal adenocarcinoma, [54] and colon cancer. [55],[56]

Inflammation (inflammatory bowel disease)-induced nuclear factor-kappa B (NF-kB) activation up-regulates the level of netrin-1, which is reported to be not only involved in colorectal tumor promotion and progression but also associated with worse outcome in poorly differentiated pancreatic adenocarcinoma. [57],[58],[59] Surprisingly, netrin-1 also plays a key role in improving pancreatic and pulmonary injury and possesses anti-inflammatory capability by inhibiting leukocyte infiltration in mice with severe acute pancreatitis, which may provide important clues for identifying novel treatment targets for pancreatitis and even pancreatic cancer. [54]

Enkephalins, the pentapeptides, are termed as endogenous ligands, whose internal receptor is opioid receptors. Three well-characterized families of opioid peptides produced by the body have been identified, which are enkephalins, endorphins, and dynorphins. Opioid receptors are a group of G-protein-coupled receptors. Immunostaining for enkephalins showed that they were widely expressed in the digestive system in the bulbus oris, esophagus, crop, stomach, gastric cecum, intestine, and posterior salivary glands. [56]


 > Neuropeptidey Top


NPY family is composed of three members, NPY, peptide YY (PYY), and pancreatic polypeptide (PP), and is expressed by cell systems at distinct levels of the gut-brain axis, which refers to the bidirectional communication between the gut and the brain. NPY members share the PP fold (hairpin fold) tertiary structural motif and consist of 36 amino acids. [60] In this context, we will mainly introduce the functions of NPY, especially in cancer progression.

NPY is mainly produced by the neurons of the SNS, and acts as a vasoconstrictor and causes the growth of fat tissue. [61] In addition, NPY can also be produced in the brain in various locations such as the hypothalamus and vascular endothelial cells, [62] and is involved in several activities including increasing food intake and storage of energy as fat, reducing anxiety and stress, reducing pain perception, affecting the circadian rhythm, reducing voluntary alcohol intake, lowering blood pressure, and controlling epileptic seizures. NPY has been demonstrated to modulate the affective behaviors and associated disorders, and the role of NPY has been determined in animal models by both genetic and pharmacological manipulations. The activity of NPY is mainly through its binding to its specific receptor, G-protein-coupled receptor, in the rhodopsin-like seven-transmembrane G protein coupled receptor (GPCR) family. [63] Till now, five subtypes of the NPY receptor have been identified in mammals, four of which have been demonstrated to be functional in humans. NPY receptors including Y1, Y2, and Y5 are expressed in various types of cancers, such as pancreatic, breast, ovarian cancers, and neuroblastoma. [64],[65],[66],[67] The actions of NPY/NPY receptors in cancer progression are dependent on cancer type or receptor type. Y1 receptor is predominantly expressed in human breast cancer, while Y2 receptor is preferentially expressed in normal human breast cells. [68] Besides its physiological functions, NPY also functions as a growth and angiogenic factor controlling the inflammatory and immunologic tumoral response. [26] By immunohistochemistry staining, NPY was found to be closely correlated with the progression of cutaneous melanoma, whose expression is significantly higher in the clinical melanoma specimens, especially the nodular type, and is associated with invasiveness independent of proliferative markers such as thickness, ulceration, and mitotic index. [55]


 > Norepinephrine Top


NE functions not only as a neurotransmitter when it is released from noradrenergic neurons in the locus coeruleus, but also as a hormone when released from the adrenal medulla into the blood. NE is synthesized from dopamine by dopamine ββ-hydroxylase in the secretory granules of the medullary chromaffin cells. When NE is released from the SNS, it increases the rate of contractions in the heart. In addition, NE influences some parts of the brain, such as the amygdala where attention and responses are controlled. NE directly increases the heart rate, triggers the release of glucose from energy stores, and increases blood flow to the skeletal muscle. Moreover, NE can suppress neuroinflammation when released diffusely in the brain from the locus coeruleus.

The actions of NE are accomplished via the binding to adrenergic receptors. The adrenergic receptors, a class of G-protein-coupled receptors, are widely expressed in many cells. The binding of NE to the receptors generally stimulates the SNS, which further initiates the fight-or-flight response, including widening the pupils of the eye, mobilizing energy, and diverting blood flow from the non-essential organs to the skeletal muscle. The adrenergic receptors can be divided into two groups, α and β, each of which contains several subtypes.

Tumor cell adhesion to extracellular matrix (ECM) is a critical event for cancer cell migration and invasion. Several studies have revealed that β2-adrenergic receptor involved signaling pathway has effects on tumor cell adhesion. NE promoted the invasiveness in pancreatic cancer cell lines by increasing the expression of matrix metalloproteinase (MMP)-2/-9 and VEGF, which were inhibited after the cells were treated with the blocker, propranolol. [69] Similar phenomenon is detected in melanoma both in vitro and in vivo. [70] These studies provide evidences supporting the idea that physiological factors play a role in the progression of several cancers via cellular immune function, angiogenesis, and metastasis. NE, the neurotransmitter or the stress-induced hormone, has been shown to increase the expression of various cancer progressive factors, including VEGF, MMPs, and interleukins.

β-adrenergic receptors (β-AR) located on hematopoietic stem cells (HSCs), osteoblasts, and mesenchymal stem/progenitor cells participate in the circadian regulation of bone formation and HSC traffic in bone and bone marrow (BM). After being secreted rhythmically from the nerve terminals, NE activated β3-AR and down-regulated stromal-derived factor-1 (also called CXCL12), which subsequently induced the release of circadian HSCs. [71]

Granulocyte colony-stimulating factor (G-CSF) is capable of mediating hematopoietic stem and progenitor cell (HSPC) mobilization. However, the mechanism remains complex. NE is reported to be an important regulator of homeostasis. β-AR is also found on the immature human CD34+ cells, and treatment with the myeloid cytokines, G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF), further increases the β-AR expression on the immature human CD34+ cells. Moreover, NE treatment enhanced the proliferation, colony formation, and motility of human progenitor cells, along with increased polarity and expression of the MMPs. In animal models, NE treatment enhanced human CD34+ cell engraftment of Nonobese Diabetic/Severe Combined Immunodeficiency (NOD/SCID) mice and increased the cells' mobilization and BM Sca-1+/c-Kit+/Lin- cell numbers, which was mediated through Wnt signaling, suggesting that the combination of NE and myeloid cytokines influences human and mouse progenitor cell migration and development. [72] Another study showed that NE reuptake was reduced significantly when peripheral sympathetic nerve neurons were stimulated with G-CSF, suggesting that G-CSF potentiates the sympathetic tone by increasing NE availability. After treatment with desipramine, the NE reuptake inhibitor, the HSPCs' mobilization triggered by G-CSF was increased dramatically. Moreover, desipramine rescued the mobilization in a model mimicking "poor mobilizers." These data indicated that inhibition of NE reuptake might be a novel therapeutic method to enhance stem cell yield in patients. [73]

Besides, osteocytes are reported to be involved in the regulation of mobility of HSPC out of the BM niche and into the circulation. G-CSF is able to stimulate morphology changes and gene expression of the osteocytic network, which is under the control of the SNS. Although the number of HSPCs showed no change in the mice with targeted ablation of osetocytes or a disrupted osteocyte network, the mobility of HSPCs induced by G-CSF was abolished. These results demonstrated that skeletal tissues play an important physiological role in hematopoietic functions. [74]


 > Clinical Implications Top


From the above findings, we can conclude that neural system has a great impact on cancer progression, especially metastasis. Neural-related factors stimulated after stress or other psychological problems have been identified to be closely correlated with cancer metastasis. Due to these reasons, development of targeting neural-related factors will be an effective method to inhibit cancer progression. [49]

NK-1R, specifically binding to SP, is a well-studied example. The NK-1 antagonist shows efficient anti-tumor effect by inducing apoptosis after binding to the NK-1R, indicating that the NK-1 antagonist may be a promising therapeutic strategy for the treatment of human cancer. [75]

Given that β-AR signaling has been characterized to modulate tumor progression via multiple downstream molecular pathways, the antagonist of β-AR, β-antagonist, exhibits great potential in the clinical treatment of the primary tumor, its surrounding microenvironment, and metastatic target sites, for it has been approved to be safe, inexpensive, and with minimal side effects. Nonselective β-antagonists such as propranolol and nadolol have been demonstrated to have effects in the preclinical models of ovarian, breast, and prostate cancers in which the SNS effects are mediated predominantly by β2- or β3-adrenergic receptors. [76]


 > Conclusion Top


From the above discussion, we have observed that the nervous systems play an important role in tumor progression mediated by the neural-related factors. After being stimulated and released, these neurotransmitters initiate the cancer metastasis by influencing departure from primary cancer, invasion, extravasion, migration, and colonization. Also, neurotransmitters further stimulate metastasis by coordinating with immunity, inflammation, or BM. Furthermore, neural-related factors are also involved in apoptosis and angiogenesis. All these data demonstrate that neural-related factors are important chemicals for linking the nervous system and cancer, providing not only an alternative route to explore the complicated process of tumor progression but also a promising target to dezvelop the clinical strategies for the treatment of human cancers.

Future studies should be carried out with an aim to disclose the underlying molecular mechanisms in which the neural-related factors participate. How neural-related factors influence the immunity, inflammation, or BM to further modulate cancer metastasis is another important project. All these studies will help to shed new light on the development of therapeutic treatments.

 
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