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The classic concept of neurotransmitters is defined as endogenous chemical messengers which are synthesized by a neuron and released into a synapse, and can transmit signals to a target cell through binding to their receptors. Conventionally, neurotransmitters can be divided into three types . Amino acid and biogenic amines belong to two classic types of neurotransmitters. The former includes glutamate, glycine and Î³ aminobutyric acid (GABA). The latter consists of dopamine, norepinephrine, epinephrine and serotonin. A large number of neuroactive substances (termed neuropeptides) are categorized as the third type. The members include but not limited to substance P, neuropeptide Y, opioids, vasoactive intestinl polypeptide (VIP), bombasin, gastrin and neurotesin, etc. Many emerging peptide molecules are being identified as new neuropeptides due to exerting similar physiological effects to neurotransmitters.
In the past four decades, enormous advances have been shed light on about the understanding neurotransmitters and their receptors. Meanwhile, many notable discoveries also further expand the conventional roles of neuroscience as chemical messengers to adjust the physiological functions of all organs and tissues . Several studies have demonstrated that neurotransmitters exert a strong influence on the immune system and tumor cells . A tumor is not an entity independent from organism, and it strongly and extensively interplays with its environment and neuro-endocrine system . Tumor cells express the neurotransmitter receptors and might react with different neurotransmitters released by the autonomic nervous system from the brain, peripheral plexuses, ganglia and the adrenal medulla. On the other hand, tumor cells also can produce endogenous neurotransmitters through receipts of various stimulations from their environment or nervous system, and might be regulated by these endogenous neurotransmitters in an autocrine/paracrine manner. More and more evidences have suggested that neurotransmitters are playing an essential role in the development and progression (including migration, invasion and metastasis) of the most human cancers .
Tumor angiogenesis is considered as one of important hallmarks of cancer development. Recently, lymphangiogenesis is also supposed to be of equal importance with tumor angiogenesis for tumor metastasis . At the same time, the concept of "neoneurogenesis" is also put forward and attracting more and more interests . Clinical reports have implicated that innervations occur in the tumor tissues of esophageal and cardiac carcinoma as well as prostate cancer . It has been validated that tumor cells are able to release some substances such as the nerve growth factor (NGF) and the brain-derived nerve factor (BDNF) which are indispensible to cause innervations. In addition, some growth factors such as VEGF, a famous pro-angiogenesis factor, also promote neurogenesis under certain conditions . And NGF is also found to have potential pro-angiogenic effects on endothelial cells . Thus, it is possible that these three processes (neoangiogenesis, lymphangiogenesis and neoneurogenesis) occur in concert in the tumor tissue. Tumor innervations will cause the neurotransmitters directly to be released into neuro-neoplastic synapse and interact with tumor cells to influence the tumor development and progression . Therefore, it is evident that the interaction between tumor cells and nervous system is a complicate process as described herein.
For keeping clarity and focus in this review, and because of space limitation, the present review will be concentrated on the effect of the most common and well-characterized several transmitters and their receptors on tumor growth and therapy.
Catecholamines and tumor growth and therapy
Catecholamines are derived from the amino acid tyrosine and belong to sympathomimetic 'fight-or-flight' neurotransmitters as they are released in a stress reaction. Catecholamines are comprised of norepinephrine (noradrenaline, NE) , epinephrine (adrenaline, E) and dopamine in the human body.
Norepinephrine/Epinephrine and Cancer growth/therapy
The circulation levels of NE and E are obviously increased during stress. NE and E exert their functions through Î± and Î² adrenoceptors on their respective target cells. Chronic stress related to psychosocial factors has been implicated in tumor progression as early as 1926 . Recently, Thaker PH and colleagues reported that chronic behavioral stress resulted in tumor growth and angiogenesis in a mouse model of ovarian carcinoma through catecholamine and adrenoceptor system. And Î² adrenoceptor 2 on the human cancer cells was identified as a critical component mediated the effects from stress which make tumor tissue highly express the VEGF, metalloproteases MMP2 and MMP9. All of these cytokines can enhance tumor vascularization and more aggressive growth and invasion of malignant cells; but the stress-inducing effect can be blocked by a Î² adrenoceptor antagonist, propranolol. Similarly, surgical stress also obviously promotes the ovarian cancer growth in mouse model and increase the expression of VEGF and microvessel density (MVD) in tumor tissue . But propranolol completely abrogated the effects of surgical stress on tumor growth, suggesting that Î² adrenoceptor plays a critical role in the effects of surgical stress on tumor growth . Additionally, we have previously demonstrated that epinephrine (E) can promote esophageal squamous-cell carcinoma cell proliferation via Î² adrenoceptor-dependent transactivation of extracellular signal-regulated kinase (ERK)/cyclooxygenase-2 pathway. Furthermore, epinephrine can enhance the expression of VEGF, VEGF receptor-1 and -2 in a Î²2 adrenoceptor-dependent manner . We even found that epidermal growth factor (EGF) induces esophageal cancer cell proliferation through increasing the cellular release of epinephrine and the expression of its synthesis enzyme tyrosine hydroxylase, and Î² adrenoceptor antagonists could attenuate the proliferative effect of cancer cells induced by EGF . These work provided the in vitro evidence that stress stimulation can induce proliferative potential of esophageal cancer cells and Î² adrenoceptor antagonists might be a promising therapeutic agent for prevention and treatment esophageal cancer .
Besides the anti-proliferation effect of catecholamine on cancer growth, studies from different groups have validated that NE or E can strongly induce the migration and invasion of various cancer cells in vitro and drive the metastasis development of primary tumors in vivo . Î² adrenoceptor blockers, especially Î²2 selective blocker could partly or completely abolish the migration, invasion or metastasis caused by stress-related stimulations(NE or E), indicating that Î² blockers might be a useful pharmacological tool for the treatment of metastatic cancer . Taken together with the anti-proliferative action of Î² blockers to tumor cells, it seems that Î² blockers might not only inhibit the primary cancer growth but also counteract the migration and metastasis of primary tumor. Some clinical studies that have indicated that the incidence of cancer (such as prostate cancer) is decreased among patients treated by Î² blockers are inclined to support this view .
Nicotine, Adrenoreceptors and Cancer growth/therapy
Cigarette smoking (CS) is estimated to involve at least eight different types of cancers (lung, mouth, pharynx, larynx, esophagus, pancreas, kidney, and bladder). Tobacco smoke is a complex mixture containing several thousand different chemical constituents, and nicotine is believed to be highly associated with cardiovascular disease and addiction related to smoking . The acetylcholine receptors (AChRs) are identified to mediate the effects of nicotine in the body. Acetylcholine receptors include the nicoÂtinic AChRs (nAChRs) and muscarinic AChRs (mAChRs) which are mainly responsible for transmitting the signal of the acetylcholine, a neurotransmitter of the parasympathicus . Nicotine induces its biological effects through binding to nAChRs expressing nervous tissues or non-neuronal mammalian cells. Nicotine, while not a carcinogen by itself, promotes proliferation and invasion of various cancer cells in vitro and tumor growth, even metastasis in vivo , which has been documented by a large number of research reports from different labs including our lab. In addition, tobacco-specific nitroÂsamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) formed from nicotine by nitrosamine also binds to nAChRs with higher affinity than their natural ligand aceÂtylcholine. Studies about NNK have indicated that it exhibits the extreme potential as a carcinogen promoting the development of various tumors such lung, pancreas, colorectum, stomach and breast etc through nAChRs .
It is known that nAChRs is capable of regulate the synthesis and release of catecholamines (NE and E) from the adrenal medulla and sympathicus nerve endings. Thus, it is no surprise that nicotine or NNK stimulate the cancer tissues through the synergy among nAChRs, stress hormones and Î² adrenoceptors. The data from our lab have demonstrated that nicotine, NNK or cigarette extract can promote cell proliferation in a variety of human cancer cells from GI tract including colon, stomach and esophagi through nAChRs and/or Î² adrenoceptors, and nAChR antagonist and Î² adrenoceptor antagonist can partly or completely block cell proliferation and down-stream signal transduction . Meanwhile, we also found that nicotine can induce the epinephrine (E) production on colon cancer cells and in vivo tumor model, and Î² adrenoceptor antagonist can block the nicotine-stimulated tumor growth dose-dependently in vivo . And it is evident that dual stimulations of cigarette smoke and stress more obviously accelerate the tumor growth compared with any single stimulation . Similar findings are being reported in different types of cancer cells or model . Additionally, recent studies reported that nicotine can not only elevate the level of stress neurotransmitters (NE and E) but also simultaneously decrease the production of inhibitory neurotransmitter Î³-aminobutyric acid (GABA, discussed below) in the pancreatic ductal adenocarcinoma (PDAC), and administration of GABA can nearly abolish the tumor growth related to nicotine . Similarly, NNK have also been found to be able to cause an increase in stress neurotransmitters and suppress the production of GABA-synthesizing enzyme and GABA in NNK-induced adenocarcinoma of the lung s and pancreas .
Dopamine and Cancer growth/therapy
Actually, dopamine (DA) is not only an precursor in the synthesis of other two catecholamines (NE and E), but is also an important neurotransmitter in the brain. DA dose not translocate across the blood-brain barrier, but it can be detected in the urine, which implicates that there are its origins in the peripheral tissues. Up to now, at least three sources (sympathetic neurons, adrenal medulla and neuroendocrine cells) were identified to contribute to the production of peripheral DA . Stress stimulations also elevate the release of DA, but DA is involved in antagonizing the stress responses via two types of receptor (D1-like or D2-like families) rather than promoting the fight-or flight response as NE and E . Moreover, growing evidence is suggesting that DA or DA receptor agonists seem to exerts inhibitory effect on cancer growth, such as breast, colon, gastric cancer and sarcoma . Studies implicated that DA, DA agonist or DA in combination with anticancer drugs can obviously inhibit tumor growth and increase the life span, but DA itself does not affect the proliferation and survival of cancer cells. The main mechanism of anti cancer effect is associated with the inhibitory effect on proliferation and migration of tumor endothelial cells through restraining the phosphorylation of VEGF receptor-2 and preventing the activation of mitogen-activated protein kinase (MAPK), etc . And the effect of DA is mainly mediated by DR2 which expresses in the tumor endothelial cells.
In addition to the effect of DA on anti-angiogenesis through endothelial cells, recent data also indicated that DA treatment of tumor-bearing mice could inhibit the mobilization of endothelial progenitor cells (EPC) from bone marrow which contributes to the process of tumor neovessel formation that is indispensable for tumor growth and metastasis . The further study found that the inhibitory effect of DA on EPC mobilization is mediated through preventing the VEGFA-induced ERK1/ERK2 phosphorylation and MMP-9 synthesis . Taken together, these findings reveal that DA and DA receptor agonists extensively used in the clinics exhibit a novel therapeutic value in the cancer therapy.
GABA and Cancer growth/therapy
Î³-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system, but it is also found to widely distribute the peripheral endocrine organs such as the pituitary, pancreas, testes, gastrointestinal tract, ovaries, placenta, uterus and adrenal medulla. Three types of GABA receptors have been identified: the ionotropic receptors (GABAA and GABAC) and metabotropic receptor (GABAB). A complicated linkage between GABA/GABA receptors and cancer is being established in several cancer cell lines and models. GABA might result in the different effects on cancer growth/metastasis in cancer-type or GABA receptor-type dependent manner. Several reports indicated that GABA or GABAB agonist (baclofen) can reduce the incidence and number of gastric cancer in rats ; inhibit the migration and metastasis of colon cancer in mice ; and decrease the human hepatocellular carcinoma cell growth in vitro and in vivo. But an opposite effect of GABA or GABAB agonist was found in prostate and renal cancer cells: GABA or GABAB agonist baclofen can significantly promote the invasive ability of prostate and renal cancer cells through the production of MMPs . On the other hand, recent data might indicate that different GABA receptors mediate different effect on cancer growth. Akio Takehara and colleagues found that GABA can increase pancreatic cancer cell proliferation through stimulating of overexpressing GABAA receptor Ï€ subunit , but the results of Hildegard and colleagues demonstrated that Stimulation of the GABABR by GABA or baclofen can block a series of response induced by Isoproterenol in human pancreatic cancer cells including the DNA synthesis, ERK1/2 activity, the cAMP level and cell migration .
5-Hydroxytryptamine and Cancer growth/therapy
5-Hydroxytryptamine (5-HT), also termed serotonin, is a monoamine neurotransmitter synthesized in the serotonergic neurons in the brain, and in the enterochromaffin cells of the gut mucosa which contain about more than 90% of the body's 5-HT and are the main source of peripheral 5-HT . 5-HT regulates a wide range of behavioral, physiological, and cognitive functions such as memory, mood, emotions, wakefulness, sleep, appetite, and temperature regulation. It is also involved in the pathophysiology of several clinical entities such as irritable bowel syndrome (IBS), carcinoid diarrhoea, and chemotherapy induced emesis, etc . Meanwhile, 5-HT is also identified as a potent mitogen for many cell types of nontumoral cells (such as fibroblasts, smooth muscle cells, osteoblasts, mesangial cells, and endothelial cells, etc) and tumor cells (such as pancreas, lung, bladder, colon and prostate, etc) . The multifunctional roles of 5-HT are mediated by serotonin receptors distributed ubiquitously in the human body mediate. To date, seven major families of receptors (5-HT 1-7) have been identified in various physiological systems . The role of 5-HT in tumor biology is being explored and elucidated. It has been shown that 5-HT receptors (5-HT1A and 1B) are overexpressed in prostate cancer tissues, especially in high-grade tumor cells . And 5-HT stimulates the proliferation of prostate cancer cells. Moreover, antagonists of 5-HT1A and 1B inhibit the effect to different extents and induce cell apoptosis . in addition to prostate cancer, 5-HT also is found to promote the cell proliferation of bladder cancer, breast cancer, lung and small intestine neuroendocrine tumor via different 5-HT receptors. A recent report implicates that 5-HT regulates tumor angiogenesis in a colon cancer model through reducing the expression of MMP-12 in tumor-infiltrating macrophages, resulting in lower level of angiostatin, an endogenous inhibitors of angiogenesis . These current investigations appear to indicate that 5-HT receptor antagonists may represent a promising anti-cancer therapeutic strategy through blocking the 5-HT actions.
Substance P and Cancer growth/therapy
Neuropeptides are the third type of neurotransmitter besides amino acid and biogenic amines, and include a large number of neuroactive peptides. Substance P (SP) consisting of 11 amino acids (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2) is widely expressed in the central, peripheral and enteric nervous system of vertebrates . It belongs to the tachykinin family of peptides which share common carboxyl-terminal amino acid sequence (Phe-X-Gly-Leu-Met-NH2) essential for ligand-receptor interaction and activation. But different amino-terminal sequences determine the receptor specificity of different tachykinin members including SP, neurokinin A, neurokinin B, neuropeptide K and neuropeptide-Î³ . SP and its high-affinity receptor , the neurokinin-1 receptor (NK1R) have been demonstrated to be involved in a myriad of physiological and pathophysiological processes such as respiration, thermoregulation, cardiovascular control, pain transmission, immunomodulation, depression, inflammation and oncogenesis . In recent years, the relationship between SP/NK1R and cancer is paying great attention. The presence of SP/NK1R have been demonstrated in several dozens cancer cell lines and cancer tissues. Moreover, it has been reported that the expression of NK1R in tumor tissues is elevated and is positively correlated to the degree of malignancy . It has been indicated that SP induces mitogenesis in several normal cells (such as T cell and endothelial cell) and cancer cells (originated from a variety of tissues such as brain, lung, prostate, colon, pancreas, retina and laryngeal, and so on) through activating the MAPK signal pathway triggered by the NK1R in autocrine/paracrine manners . The antagonists of NK1R can block the mitogen effects of SP and produce the pro-apoptotic action in vitro and in vivo, implicating that NK1R could become a novel and valuable therapeutic target for cancer therapy and NK1R antagonists might be useful for cancer treatment . On the other hand, SP participates immunomodulation and inflammation response through interacting with immune cells such as T cells, macrophages and mast cells, resulting in the release of various cytokines and chemokines . These mediators regulated and affected by SP are validated to take part in anti-tumor immunity. Therefore, it has been suggested that SP could exert anti-tumor function in some tumors, which might be mediated by T cells and NK cells-inducing immune reactions .
Neuropeptide Y and Cancer growth/therapy
Neuropeptide Y (NPY) is also another important neurotransmitter consisting of 36 amino-acid peptide characterized by a number of tyrosine residues . It belongs to the highly conserved NPY family which includes three members: NPY, peptide YY (PYY), and pancreatic polypeptide (PP). NPY is extensively distributed in the CNS, peripheral nervous system and many other organs such as liver, heart, spleen, endothelial cells of vasculature and adrenal medulla . NPY plays an important role in the modulation of many physiological functions and processes, including stress response, food intake, reproduction, circadian rhythms, anxiety and depression, pain processing and neuroendocrine. NYP exerts potent biological functions via at least six receptors (Y1R-Y6R); but studies have indicated that Y1R, Y2R and Y5R are the three major receptors mediated the biological action of NYP . Recently, it has been reported that NPY and its receptors are involved in the regulation of tumor development and progression such as cell proliferation, invasion, metastasis and neoangiogenesis . NPY and NPYR have been found to be expressed into the cells and vasculature from a variety of tumors including renal carcinomas, neuroblastomas, ovarian tumor, breast tumor and prostate cancer, suggesting that NPY system might produce effects on tumors . NPY can exhibit growth-sitmulatory or inhibitory effects on tumors, depending on the tumor cell lines used, the NPY receptor subtype on the cell surface, even experimental conditions . But it is accepted that NPY is a multifunctional angiogenic factor, which strongly induces the endothelial cell proliferation, differentiation and migration, and promotes the vascularization . The effects were also observed in the neural crest-derived tumors in nude mice . Actually, the role and function of NPY receptors attract more interests in the tumor-related studies compared with NPY itself. Because NPY receptors were found to be overexpressed in a large variety of human cancers and that the expression of receptor subtype is associated with different aspects of tumor development , which make them be potential targets for image diagnosis and therapy. Some receptor-selective NPY analogues have been designed for tumor-targeted imaging and chemotherapy .
Conclusions and Perspectives
The growing evidences have been shown that neurotransmitter/receptor system is involved in the regulation of tumor growth, development and progression. The elucidation of their roles in the tumor biology would greatly expand our understanding to oncogensis and open new prospects for cancer diagnosis and treatment. Chances are that the blockage of some neurotransmitter functions exacerbating tumor development may be a potent strategy for cancer therapy. Meanwhile, some classic drugs related to neurotransmitters such as Î² blockers, dopamine or dopamine receptor agonist might make fresh contribution to treat cancerous diseases. On the other hand, although neurotransmitter/receptor system produces various effects on tumors, they are indispensable to maintain normal physiological functions in human body. Hence, the interference of neurotransmitter functions for cancer therapy should take into consideration the influence on physiological functions (side effects). Therefore, targeted delivery of relevant pharmacological agents to tumor site represents a promising direction for cancer research and has vital clinical applications in cancer diagnosis and treatment, which increases the efficacy of anti-cancer action and decreases the undesired systemic side effects in other tissues . Combined with targeted delivery of pharmacological agents, we reason that it might be a potentially promising therapeutic strategy for cancerous disease to intervene neurotransmitter/receptor system associated with tumor development.