World’s Tiniest Engine Created @ A team of researchers from Trinity College Dublin and the Universität Mainz has developed the world’s smallest engine. & What to do if my co-authors don’t contribute? @ Role of the nervous system in cancer metastasis & How the body’s nerves become accomplices in the spread of cancer @ Black holes stunt growth of dwarf galaxies @ Scientists Discover Biophotons In The Brain That Could Hint Our Consciousness is Directly Linked to Light! September 21, 2017 Role of the nervous system in cancer metastasis

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World’s Tiniest Engine Created

Aug 23, 2019 by News Staff / Source« PreviousNext »

A team of researchers from Trinity College Dublin and the Universität Mainz has developed the world’s smallest engine.

The nanoscale heat engine. Image credit: John Goold, Trinity College Dublin.

The nanoscale heat engine. Image credit: John Goold, Trinity College Dublin.

The nanoscale engine — a trapped 40Ca+ ion — is approximately 10 billion times smaller than a car engine.

It is electrically charged, which makes it easy to trap using electric fields.

The working substance of the engine is the ion’s ‘intrinsic spin’ (angular momentum). This spin is used to convert heat absorbed from laser beams into oscillations, or vibrations, of the trapped ion.

These vibrations act like a ‘flywheel,’ which captures the useful energy generated by the engine. This energy is stored in discrete units called ‘quanta,’ as predicted by quantum mechanics.

“The flywheel allows us to actually measure the power output of an atomic-scale motor, resolving single quanta of energy, for the first time,” said team member Dr. Mark Mitchison, a scientist at Trinity College Dublin.

The world’s smallest engine works due to its intrinsic spin, which converts heat absorbed from laser beams into oscillations of the trapped ion. Image credit: John Goold, Trinity College Dublin.

The world’s smallest engine works due to its intrinsic spin, which converts heat absorbed from laser beams into oscillations of the trapped ion. Image credit: John Goold, Trinity College Dublin.

Starting the flywheel from rest — or, more precisely, from its ‘ground state’ — the team observed the little engine forcing the flywheel to run faster and faster.

Crucially, the state of the 40Ca+ ion was accessible in the experiment, allowing the researchers to precisely assess the energy deposition process.

“This experiment and theory ushers in a new era for the investigation of the energetics of technologies based on quantum theory, which is a topic at the core of our research,” said Dr. John Goold, also from Trinity College Dublin.

“Heat management at the nanoscale is one of the fundamental bottlenecks for faster and more efficient computing.”

“Understanding how thermodynamics can be applied in such microscopic settings is of paramount importance for future technologies.”

The team’s work was published in today’s issue of the journal Physical Review Letters.


D. von Lindenfels et al. 2019. Spin Heat Engine Coupled to a Harmonic-Oscillator Flywheel. Phys. Rev. Lett 123 (8): 080602; doi: 10.1103/PhysRevLett.123.080602Published in

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BLOG23: What to do if my co-authors don’t contribute?

Lazy man on grass

23: What to do if my co-authors don’t contribute?

September 10, 2019 by Tress Academic

“Alright, let’s write a paper together! What a great idea!” The enthusiasm can be great at the beginning of writing a journal article, but when it comes to the task of actually putting words on paper, you can quickly discover you’re alone. So what do you do if you have one or more passive co-authors who don’t deliver their share of the writing? Let us give you some tips and advice on how to turn a passive author into a real contributor. Don’t forget to download our helpful “checklist of authorship roles” which you can print out and bring to your next author’s meeting!

We recently heard a story like this again on one of our How to publish in peer-reviewed journals” course.

A participant (let’s call him Peter) explained to us over lunch his frustration with writing a paper with some co-authors for his PhD study. Peter, who is in his third year of a doctoral study, collaborates on his project with a postdoc, his supervisor and two external colleagues. All were initially very excited about the research that came out of the project, and it was agreed they should write a paper and get it published in a decent journal as soon as possible. 

Yet, over the next few weeks nothing happened. None of the senior researchers took the initiative or the responsibility to get started. The postdoc was snowed in under a lot of his own publishing projects and Peter did not dare to push the others. But all the while time was ticking along and Peter needed the paper to complete his PhD, it was going to be his first ever paper. 

After a while, Peter decided to consult his supervisor and finally get the paper started. The co-authors had willingly agreed to contribute as well as they could. Enthusiastically, Peter drafted various sections and regularly approached his co-authors for their advice and help with things like finding out how to formulate the paper’s research aim, or picking the best findings for the result section. Unfortunately, Peter’s call for collaboration to his co-authors remained unanswered. Frustrated, he told us, “they literally haven’t done anything for the paper”. 

If you are an inexperienced author like Peter, you may think that this is just the way co-authorship works. Someone does all the work and all other ‘big names’ put their name on the paper anyway. 

Well, after hearing another story like this on our course, we advise the unfortunate author on the various duties and responsibilities researchers have if they want to be a co-author on a paper. There are plenty of guidelines about what makes one an author and co-author on a paper and what not. If you want a good example, you just need to look at the COPE guidelines for authorship and contributorship or the ICMJE’s definition of roles of authors and contributors. Consulting these or other similar resources should leave no doubt that being passive does not entitle you to be a co-author on a paper. 

Not only from an ethical perspective, but also from a purely practical one, authors who do not contribute to the work they are supposed to be co-authoring can be a pain. They load off the work onto other’s shoulders and can drain a lot of motivation from the active author. 

If you have ever been in such a situation, or fear you might end up dealing with passive co-authors, we know exactly how awful this feels. You feel alone, trying to steer the ship into the harbour yourself, realising how much energy this Herculean task entails. It feels unfair that you have to do a large amount – if not all – of the work yourself and others are contributing in name only. Let us be clear, it should not feel this way, and importantly, it doesn’t have to be this way. We want to give you some tips and advice you can have at hand for how to reactivate the less active co-authors around you. 

Man leaning towards blue wall and thinking about something

Tip 1: Agree on roles of authorship 

“What is my task on this paper writing project? What am I supposed to do?” These are the questions that different authors rarely agree on. Why? Because the team of authors has not sat down and clearly defined the potentially different roles of the group of authors. 

To avoid such a poorly orchestrated effort, begin by calling for a meeting with all potential co-authors, where you set out which role each individual author has. Who takes the lead in the paper? Who starts with writing? Ask explicitly what roles your (senior) colleagues will play, and for what kind of requests you can come to them for. Ask what kind of help in the paper writing process you can expect to receive. After the meeting, draft a short note on the agreement with the allocation of roles and circulate it in the group. 

We prepared a handy “checklist of authorship roles” for you that you can use specifically for this purpose. 

Tip 2: Prepare, share and discuss a paper outline

Too many cooks in the kitchen can spoil the soup. Unless you are a team of well-coordinated and smooth-operating co-authors (in which case you would not need to worry about this topic and can get back to work), it is not easy to create a collective draft of a paper. Everybody probably has different ideas and priorities and it is difficult to harmonise them in the early stage of paper writing. 

We suggest that you start by sitting down and preparing a first draft, most likely an outline of the paper elements (which question you address, which methods necessary to describe, which results to present and do so on). Once you are fine with this 1-2 pages paper outline, then send it to your co-authors and ask for feedback. 

Tip 3: Define order of authorship

“Who will be first author? Who will be co-authors? In which order?” This, sometimes, is the most difficult decision in the whole writing process. Clarify this before starting to write (and not later)! Everybody needs to know what’s in it for him or her. 

For example, if the paper is based on your own intellectual work for your PhD project, and if you will do most of the writing as well, then it is absolutely fine for you to be the first author! You should then discuss with your (senior) colleagues also the order of the remaining co-authors. In particular, discuss who will be the last author as this – in some fields – is a very popular author position as well. Once agreed, circulate the agreement in your group (see our “checklist of authorship roles”). 

Tip 4: Agree on a joint time plan

Agreeing on authorship roles and a paper outline are essential steps, but in order to get the paper finished, you should agree on a joint time plan. Sit down with your co-authors and estimate how long it will take you to do the different steps of the paper. Also, consider whether you still have to complete some research tasks before being able to write all the paper sections or if you’re done with that. 

Create a realistic plan, that translates to: don’t be too ambitious. If you do not have a great deal of writing experience, things may take a bit longer. Don’t forget to consider holiday or travel periods where someone from the author team might not be available. Set deadlines for drafting the individual major paper sections (introduction, methods, results, discussion), for content editing, for style and language editing and for feedback from co-authors. Circulate the plan in the group and monitor the progress (see our “checklist of authorship roles”). 

Tip 5: Act as a paper manager 

To write a journal paper with co-authors is a project. Projects work best if they are managed. You will then need a manager for your paper as well. Paper writing with co-authors can easily end up as a mess because nobody cares about giving directions. The senior co-authors might be too busy with other projects and sideline the paper, and you as a junior researcher, think you cannot direct them. Yes, you can!

If you are the lead author on the paper and do the majority of the work, we suggest you as the paper manager for the respective manuscript. Act according to your role and facilitate the process that leads to paper creation and submission. Make sure you communicate regularly with your co-authors and keep them informed about problems and progress equally. You will see, they will appreciate your leadership on this project as you take a  responsibility off their shoulders. 

Tip 6: Communicate regularly with co-authors

Often, co-authors have so many other projects and tasks, they might forget this particular project because, to them, it has lower priority. If you want to avoid your paper from getting lost on their desk, keep in contact with them regularly and exchange views on the paper. Talk to them when you realise that the paper isn’t progressing the way it was agreed. Consult with your co-authors, not only when you are in desperate need of help on something. Rather establish a regular flow of exchange on this paper. Then, they will see that you are committed to working on the paper, and when they hear about the progress they are more inclined to contribute their share as well. 

Tip 7: If you need help, make concrete requests

“I am not sure about the paper draft, could you please read it and tell me what you think?” This is a common request of lead authors to co-authors asking for some kind of feedback or response. But this request does not really lead to good feedback. In fact, you are causing more problems for your co-authors by sending such a vague request because they don’t know exactly what your problem is. 

We recommend that when you approach your co-authors with questions to make them as concrete as possible. Point out problems that you have with your share of paper writing and ask your co-authors whether they could advise you how to proceed. The more concrete your requests are, the better the answers you’ll get. This way, you can also make sure that your co-authors will look into the specific problem and think about it. 

Tip 8: Give co-authors clear but do-able tasks

As the paper manager and lead author, you will not only have to do a big share of the work on the paper yourself, but you will also delegate some work to your co-authors because it is their field of expertise. When you want a co-author to perform a specific step that you need in order to progress with the paper, be clear about what you want them to do, and make sure it is an achievable task. Thus, be specific and realistic with your requests. 

Tip 9: Set clear but realistic deadlines 

After you agreed on a joint time plan for the paper, it is important that you monitor the progress and keep track of how things develop. In our courses, participants always stress how much they appreciate people giving them concrete deadlines for when they have to deliver something. Make use of this for the paper writing! Always set a deadline for the individual steps of writing your paper that tells everyone the date something has to be completed. Do not just make the deadline for yourself, rather discuss together and define a deadline that works for everybody. 

It is also important is that you indicate how you will proceed after the deadline. For instance, if you ask co-authors for a last read of the paper before submission, tell them you would love to have their comments at date XYZ, but if you have not heard from them by then, you will proceed with submitting the paper. 

If you are one of those people who has trouble making and keeping deadlines, check out our blog post #8 Deadline disaster: Seven easy steps to avoid. 


 A co-authored paper can really be a good experience to go through if you have a team of authors all committed to doing their job. It can be less enjoyable if you have the feeling that some of your co-authors don’t do anything to justify having their name on the paper. Our experience shows that these passive authors often face a daily bombardment of work from other projects and give the paper a low priority. 

Thus, if you want to work with a team of active co-authors, you’ll need to manage them, show them that you are interested in their contributions, and need their help. So, there is a lot you can do to get more from your co-authors. Follow our tips and advice above and you will increase interaction with and the benefits of working with co-authors. Check out our “checklist of co-authorship roles” to make sure everyone is making their contribution!. Putting everyone’s roles in writing is discussing their responsibilities is the #1 way to avoid delays and infighting over who’s slacking. Good luck! 

Relevant resources:  

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#WritingPapers, #Authorship, #Co-authors, #PassiveAuthors, #JournalPapers 

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J Exp Clin Cancer Res. 2018; 37: 5.Published online 2018 Jan 15. doi: 10.1186/s13046-018-0674-xPMCID: PMC5769535PMID: 29334991

Role of the nervous system in cancer metastasis

Nyanbol Kuol,1Lily Stojanovska,1Vasso Apostolopoulos,#1 and Kulmira Nurgali#1,2Author informationArticle notesCopyright and License informationDisclaimerThis article has been cited by other articles in PMC.Go to:


Cancer remains as one of the leading cause of death worldwide. The development of cancer involves an intricate process, wherein many identified and unidentified factors play a role. Although most studies have focused on the genetic abnormalities which initiate and promote cancer, there is overwhelming evidence that tumors interact within their environment by direct cell-to-cell contact and with signaling molecules, suggesting that cancer cells can influence their microenvironment and bidirectionally communicate with other systems. However, only in recent years the role of the nervous system has been recognized as a major contributor to cancer development and metastasis. The nervous system governs functional activities of many organs, and, as tumors are not independent organs within an organism, this system is integrally involved in tumor growth and progression.Keywords: Neurotransmitters, Neuropeptides, Neuro-cancer interaction, Metastasis, CancerGo to:


Cancer is the leading cause of death worldwide due to the aging population and unhealthy lifestyle [1]. Although it is highly treatable when localized, metastatic or recurrent cancer has a poor prognosis. Metastasis involves a complex series of steps including proliferation, angiogenesis, embolization, dissemination, evasion of immune system surveillance and surviving in ectopic organs [25]. However, despite significant advances in understanding metastasis and its mechanisms, the prognosis remains poor. In the past decades, research has focused on identifying and characterising genes and gene products that manipulate the metastatic processes [69]. More recently, the impact of the tumor microenvironment on tumor cell invasion and metastasis has attracted extensive attention (see ref. [10] for detailed review) [21013]. Multiple cellular and extracellular components within the tumor microenvironment, such as immune cells, endothelial cells, mesenchymal stromal cells (fibroblasts and myofibroblasts), and their secretory products, exert active functions to modulate gene expression patterns of tumor cells and to alter biological behavior of tumor cells [1416]. Invariable crosstalk amongst these components within the tumor microenvironment triggers pro-survival, invasion, and metastatic pathways of tumor cells [1720]. Several studies, both clinical and in vitro, reinforce the concept of the nervous system involvement in cancer metastasis [52126]. Nerve fibers present in and around the tumor could release neurotransmitters and neuropeptides directly acting on receptors expressed by cancer cells. The findings, primarily in cancer cell lines and animal models, indicate that there is a bi-directional correlation between the neural factors released and cancer progression and metastasis. Understanding the complex neurotransmitter-cancer interaction is important for the development of new avenues for targeted therapeutic intervention. This review presents an overview of the role of the nervous system in cancer metastasis.Go to:

The role of the nervous system in metastatic cascade

Studies have demonstrated that the nervous system facilitates development of tumor metastasis by modulating metastatic cascades through the release of neural-related factors from nerve endings such as neurotrophins, neurotransmitters and neuropeptides [2729]. The process of metastasis formation involves tumor cells breaking away from the primary tumor and overcoming the obstacles of primary tissue inhibition (initiation and clonal expansion), anoikis inhibition (evasion from apoptosis), breakdown of base membranes (epithelial-mesenchymal transition (EMT) and invasion), extravasation and colonization, angiogenesis, evasion of immune response and establishment of tumor microenvironment.

Initiation and clonal expansion

Tumor metastasis initiation and clonal expansion is a complex process where contributing factors are not well understood. It is believed that metastasis process is initiated when genetically unstable tumor cells adjust to a secondary site microenvironment [11]. This process involves selecting traits that are beneficial to tumor cells and affiliated recruitment of traits in the tumor stroma that accommodate invasion by metastatic cells. Metastasis-initiating cells possess these traits and can hijack some of the normal stem cell pathways to increase cellular plasticity and stemness [30]. Proteolytic enzymes such as matrix metalloproteinases (MMPs) facilitate this process by degrading the surrounding normal tissues. MMPs are regulated by neural-related factors and neurotransmitters and are overexpressed in tumors [3135]. Hence, nervous system modulates the initiation and clonal expansion via the expression of MMPs and the stimulation of metastasis-initiating cells.

Evasion from apoptosis

Anoikis is a programmed cell death induced upon cell detachment from extracellular matrix, acting as a critical mechanism in preventing adherent-independent cell growth and attachment to unsuitable matrix, thus avoiding colonizing of distant organs [3637]. For tumor metastasis to progress, tumor cells must be resistant to anoikis. Tumor cell resistance to anoikis is attributed to alteration in integrins’ repertoire, overexpression of growth factor receptor, activation of oncogene, activation of pro-survival signals, or upregulation/mutation of key enzymes involved in integrin or growth factor receptor signaling [37]. Neurotransmitters and neurotrophins play a role in tumor evasion from anoikis. Increased expression of brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) induces anoikis inhibition in rat intestinal epithelial cells [27]. Similarly, TrkB overexpression induces anoikis inhibition protecting colorectal cancer cells [38]. Application of recombinant human BDNF to gastric cancer cells inhibited anoikis and stimulated cellular proliferation, invasion and migration [39]. Nicotine exposure promotes anchorage-independent growth of A549, MDA-MB-468 and MCF-7 cell lines by downregulation of anoikis [40]. Furthermore, tumor microenvironment contributes to anoikis resistance of cancer cells by producing pro-survival soluble factors, triggering EMT, enhancing oxidative stress, regulating matrix stiffness, as well as leading to metabolic deregulations of cancer cells [37]. These events assist tumor cells to prevent the apoptosis mechanism and sustain pro-survival signals after detachment, counteracting anoikis.

EMT and invasion

EMT is a fundamental process for tumor progression by increasing invasiveness and resistance to anoikis and significantly elevating the production of extracellular matrix constituents leading to metastasis [4143]. EMT development results in the degradation of basement membrane and formation of mesenchymal-like cells [42]. Studies have demonstrated that nervous system regulates EMT development via the release of neurotransmitters and neurotrophins [4044]. The overexpression of TrkB or activation by BDNF in human endometrial cancer cell lines results in altered expression of EMT molecular mediators [44]. Nicotine treatment induces changes in gene expression associated with EMT in lung and breast cancer cells [40].

Extravasation and colonization

Nervous system modulates the function of vascular system which is essential for tumor cell extravasation and colonization. It has been found that neuropeptides such as substance P (SP) and bradykinin enhance vascular permeability promoting tumor cell extravasation and colonization [2829]. In a mouse model bearing sarcoma 180 cells, bradykinin enhances tumor-associated vascular permeability [28]. SP regulates physiological functions of vascular system including smooth muscle contractility, and vascular permeability [29]. Cell extravasation and colonization are prerequisite for angiogenesis which is a crucial step in the development of cancer metastasis.


Development of tumor angiogenesis is essential for tumor growth and progression. Vascular endothelial growth factor (VEGF) plays significant role in tumor angiogenesis, leading to metastasis [4547]. Studies have demonstrated the important role of neurotransmitters and neuropeptides in regulating angiogenesis. In the xenograft models of ovarian cancer, chronic stress mediates the vascularization of intraperitoneal metastasis and enhances tumor angiogenesis via increasing VEGF expression [4849]. In breast cancer cell lines, direct activation of β-adrenergic signaling can amplify expression of VEGF and cytokines, interleukin (IL)-6, and IL-8 that stimulate tumor angiogenesis [50]. In colon tumor tissues from HT-29 cell-bearing BALB/c mice, VEGF expression is elevated by nicotine which correlates with enhanced microvessel density [51]. Neuropeptide Y (NPY) enhances the expression of VEGF and its secretion promoting angiogenesis and breast cancer progression [52].

Evasion of immune response

The nervous system plays a fundamental role in regulating immune responses [53]. Inflammatory mediators can activate sensory nerves that send signals regarding inflammation to the central nervous system, which in turn leads to the release of neuromediators modulating local inflammation and influencing immune cells [54]. Since inflammatory signals are important for tumor progression in both the early and late stages, the anti-inflammatory role of the vagus nerve may play an important role in cancer metastasis [55]. β-adrenergic receptor agonist suppressed natural killer (NK) cell activity resulting in increased lung metastasis in murine metastatic mammary adenocarcinoma [56]. In addition, pharmacological or stress-associated β-adrenergic stimulation results in increased macrophage infiltration and cancer metastasis in breast cancer model [57].

Tumor microenvironment

Tumor microenvironment (mainly contain stromal cells and signal molecules) plays essential role in the formation of cancer metastasis. Stromal cells produce neural-related factors and express β-adrenergic receptor that facilitated tumor cell proliferation and survival in the primary site and secondary organ [1024]. Tumor-associated macrophages play a role in β-adrenergic signaling pathways, by accelerating angiogenesis, chemokine secretion to attract tumor cells, secretion of pro-inflammatory cytokines (IL-1, IL-6, IL-8, and tumor necrosis factor (TNF)-α) and escape of anti-tumor responses [5860]. Hence, tumor microenvironment creates a feedback loop with the nervous system enabling the growth of primary and secondary tumors. Overall, these studies have demonstrated that the nervous system modulates each step of cancer metastasis through the release of neural-related factors.Go to:

Role of perineural invasion in cancer metastasis

Perineural invasion (PNI) also known as neurotropic carcinomatous spread is a process mainly categorized by neoplastic invasion of the nerves. PNI is defined as the presence of cancer cells in the perineurium; it is believed to be a common route for cancer metastasis can cause cancer-related pain [6168]. The presence of PNI is mostly associated with poor prognosis and high recurrence in colorectal [69], gastric [64], oral tongue squamous cell carcinoma (OTSCC) [62], and pancreatic [61] cancers. In stage II and III colorectal cancer patients, the presence of PNI is associated with tumor grade, metastasis to lymph nodes and poor patient survival [63]. However, in invasive breast carcinoma the presence of PNI has been demonstrated to have no prognostic value [6770].

PNI is influenced by the interaction between the nerve microenvironment and neurotrophic molecules expressed by cancer cells such as nerve growth factor (NGF), BDNF, glial cell line-derived neurotrophic factor (GDNF) and their receptors [616871]. A number of studies demonstrated correlation between the presence of PNI with high expression of NGF and its receptor tropomyosin related kinase A (TrkA) [617273]. It is speculated that neurotrophins released by neural tissue act as chemotactic factors, and in cancer cells where Trks are overexpressed, they provide mechanism to invade the perineural space. High expression of NGF or TrkA and P75NTR receptors is associated with lymph node metastasis in a mouse model of breast cancer [74]. In OTSCC patients [73], the presence of PNI and NGF is associated with larger tumor size and lymph node metastasis, suggesting that its presence can be a valuable marker to predict the disease progression and prognosis [65]. Overexpression of TrkA associates with enhanced growth, invasion and migration of breast cancer cells in vitro as well as enhanced metastasis in xenografted immunodeficient mice via the PI3K-AKT and ERK/P38 MAP kinases [75]. Conversely, immuno-histochemical evaluation of tissues from patients with extrahepatic cholangiocarcinoma shows that intra-tumoral NGF expression does not correlate with PNI, absence of disease recurrence and overall patient survival [76]. GDNF has been demonstrated to induce cancer cells migration. In human pancreatic adenocarcinoma tissues and MiaPaCa-2 cell lines, binding of GDNF to its receptor GFRα1 stimulates PNI via GDNF-(Ret proto-oncogene) RET signaling pathway [71]. Activation of GDNF-GFRα1-RET signaling triggers the MAPK signaling pathway leading to pancreatic cancer cell migration toward nerves in both in vitro and animal models of PNI [77]. Cancer-nerve interaction studied in in vitro co-cultures of DRG and MiaPaCa-2 pancreatic cancer cells demonstrated that GFRα1 facilitates migration of cancer cells along neurites toward the center of the DRG [71]. Furthermore, decreased release of soluble GFRα1 from DRG inhibits migration of cancer cells towards nerves in vivo providing further evidence that GFRα1 expression is important in facilitating PNI [71]. In a metastatic breast cancer model, in vivo inhibition of Ret suppresses tumour outgrowth and metastatic potential [78].

BDNF facilitates cancer metastasis via binding to its receptors, TrkB/ TrkC and/or p75NTR as demonstrated in breast [79], colorectal [8081], clear cell renal cell carcinoma [82] and non-small cell lung cancer (NSCLC) [83]. The expression of TrkB associates with nodal metastasis and peritoneal metastasis; whereas, TrkC expression associates with liver metastasis in colorectal cancer patients [81]. BDNF-TrkB signaling pathway mediates metastatic effect through modulation of cancer-associated fibroblasts (CAFs) as demonstrated in mouse model co-injected with OSC19-Luc transfected cell line and CAFs [84]. In melanoma, neurotrophin (NT)-3, NT-4, and NGF induce cell migration, with a stronger effect on metastatic cell lines via binding to p75NTR coreceptor sortilin [85]. In breast cancer, NT-3 enhances breast cancer metastasis in the brain via promoting the mesenchymal–epithelial transition of breast cancer cells to a more epithelial-like phenotype and via increasing the ability of these cells to proliferate in the brain [86].

Collectively, these studies demonstrate that neurotrophins and their receptors play crucial role in PNI. These studies also suggest that the presence of PNI could be an effective predictor of metastatic potential and patient survival.Go to:

Tumor innervation influencing cancer metastasis

Tumor innervation

Cancer-related neurogenesis (tumor innervation) is attributed to the ability of cancer cells to attract normal nerve fibers via the secretion of signalling molecules and neurotrophic factor. However, recent study has demonstrated that cancer stem cells are capable of directly initiating tumor neurogenesis [87]. Cancer stem cells derived from human gastric and colorectal cancer patients generate neurons including sympathetic and parasympathetic neurons which promote tumor progression [87]. Knocking down their neural cell generating abilities inhibit tumor growth in human xenograft mouse model. Neurogenesis and its putative regulatory mechanisms have been reported in prostate [88], gastric [89], colorectal [90] and breast [91] cancers. There is a correlation between the expression of a pan-neuronal marker protein gene product 9.5 with clinicopathological characteristics of breast cancer [91]. In fact, neurogenesis is associated with aggressive features including tumor grade, poor survival as well as angiogenesis, especially in estrogen receptor-negative and node-negative breast cancer subtypes [9192]. In prostate cancer, infiltration of the tumor microenvironment by nerve fibers associates with poor clinical outcomes [93] and is driven by the expression of granulocyte colony-stimulating factor (G-CSF) [94] and proNGF [95]. Similarly, in orthotopic PC3-luc xenografts model of prostate cancer, neurogenesis and axonogenesis correlate with aggressive features including metastatic spread which is attributed to the neo-cholinergic parasympathetic nerve fiber [94]. These findings indicate that neurogenesis, like angiogenesis, is also a trait of cancer invasion and can alter tumor behaviour.

Tumor denervation

On the other hand, disruption of tissue innervation might cause accelerated tumor growth and metastasis [5696101]. For instance, in humans, decreased vagal nerve activity correlates with advanced stages of cancer [9698]. Similarly, modulation of vagal nerve activity enhances metastasis of breast cancer in mice [99100]. In addition, capsaicin-induced inactivation of sensory neurons enhances metastasis of breast cancer cells [56101]. On contrary, pharmacological or surgical denervation supresses the tumor progression as noted in three independent mice models of gastric cancer [89]. Thus, these findings suggest that there might be differences in the effects of local tumor innervation and extrinsic innervation on cancer progression.Go to:

Neurotransmitters influencing cancer metastasis

Tumor innervation influences metastasis as the ingrown nerve endings release neurotransmitters (such as norepinephrine, dopamine and substance P), which enhance metastatic spread [102]. To date, several neurotransmitters and neuropeptides involved in tumor metastasis have been identified (Table 1 and Fig. 1). In fact, several cancer cells express receptors for a number of neuropeptides and neurotransmitters, like norepinephrine, epinephrine, dopamine, GABA, acetylcholine, SP and NPY which have stimulatory effects on migration of cancer cells [103112].

Table 1

Neurotransmitters influencing tumor metastasis

NeurotransmittersReceptorType of cancerModelMechanism/pathwayRef.
NEβ2-ARPancreatic cancerCFPAC1, MiaPaCa2 Panc1, and IMIM-PC2 cellsNE treatment reduces migratory activity of pancreatic cancer cells. NE mediates inhibitory effect via imbalanced activation of PKC/PLC signaling pathway → to activation of anti-migratory cAMP/PKA signalling.[155]
Prostate cancerSubcutaneous injection of PC-3 cells in BALB/c nude mice↑ NE leads to lumbar lymph node metastasis in an animal model.[156157]
DADR1 & DR5HCCTumor and non-tumor adjacent tissues from patients; LM3, Huh7 and SNU449 cells;
subcutaneous injection of LM3 cells in BALB/c nude mice
DR5 is upregulated in tumor tissue and DR1 is upregulated in non-tumor human tissues.
Dopamine ↑ cell proliferation in SNU449 cells.
Administration of DR antagonist (thioridazine) inhibits cell proliferation in vitro and in and cell migration through EMT → ↓ tumor metastasis
GABAGABAAHCCHuman primary and adjacent non-tumor tissues, and Orthotopic inoculation of SMMC-7721 cells into the liver of BALB/c nude miceGABAAreceptor subunit ε1 expression is lower in human HCC tissues than in non-tumor liver tissues.
GABA inhibits invasion and migration of human liver cancer cells in vitro.
In mice, inoculation of SMMC-7721 cells pretreated with GABA ↓ tumor metastasis.
GABABPLC/PRF/5 and Huh cellsAdministration of GABAB agonist (baclofen) ↓ cell migration associated with ↓ in intracellular cAMP levels.[132]
Breast cancerHuman tissues, 4 T1 and MCF-7 cellsAdministration of GABAB agonist (baclofen) promotes invasion and migration of breast cancer cells in vitro and metastasis in vivo via ERK1/2 and MMP-2signaling pathway.[107]
Prostate cancerHuman prostate and lymph node tissues, C4–2 cells↑ Expression of GABA → cell invasion in vitro and lymph node metastasis in patients mediated by activation of MMPs signalling.[158]
HCCHuman primary and adjacent non-tumor tissuesThe mRNA levels of GABAB R1.2 and GABAB R1.4 are higher in HCC tissues than in non-tumor liver tissues[128]
AChARHCCSNU-449 cellsACh activates AR receptors → ↑ invasion and migration of SNU-449 cells via activation of AKT and STAT3 signaling pathways.[133]
α7-nAChRPancreatic cancerCD18/HPAF, Capan1, FG/Colo357 cells in vitro and orthotopically implanted CD18/HPAF cells in immunodeficient miceNicotine treatment stimulates the expression of α7-nAChR and MUC4 in vitro. In the in vivo model, exposure to low and high cigarette smoking increases the tumor metastasis and MUC4 expression compared to sham controls.
Nicotine induces tumor metastasis by upregulating MUC4 via α7-nAChR-mediated JAK2/STAT3 signaling in collaboration with Ras/Raf/MEK/ERK1/2 signalling pathway.
Lung cancerLine 1 cells in vitro, and subcutaneous injection of Line 1 cells in BALB/c miceIntraperitoneal injection of nicotine ↑ tumor growth and metastasis through change in gene expression via nAChR signalling pathway.[159]
nAChR β2Lung cancerB16 cells intravenous injection in C57BL/6 mice↑ Nicotine exposure → activation of nAChR β2 on NK cells mediates metastasis[160]
α9-nAChRBreast cancerMDA-MB-231 and MCF-7 cellsNicotine treatment enhances the migratory abilities of both cells by activating α9-nAChR through elevated expression of EMT markers[134]
mAChRColon cancerHh508 and SNU-C4 cellsAdministration of muscarinic inhibitor (atropine) → ↓ cell invasion and migration.
ACh binding to M3R mediates cell migration via the activation of post-ERBB1, ERK and PI3K-dependent RhoA pathway.
NSCLCHuman tissues, micA549, PC9, SPC-A1, GLC82, L78 and HLF cellsM3R expression correlates with clinical stage and poor survival in patients.
M3R stimulation by ACh enhances in vitro cell invasion and migration via PI3K/AKt pathway.
Prostate cancerHuman tissues,
Hi-Myc transgenic mice-bearing PC-3
Presences of cholinergic nerve fibers associate with poor clinical outcome in human patients.
Pharmacological blockade or genetic disruption of the M1R inhibit metastasis leading to improved survival of the mice
SPNK-1RPancreatic cancerMiaPaCa-2, BxPC-3, CFPAC-1, HAPC, Panc-1, and SW1990 cellsBinding of SP to NK-1R promotes cell invasion and migratory potential which is mediated by expression of MMP-2. SP also increases cell migration and neurite outgrowth toward DRG demonstrating important role in metastasis and PNI.[146161]
NPYEwing sarcomaHuman serum,
SCID/beige mice bearing SK-ES1 cells
Enhanced level of systemic NPY associate with metastatic tumors.
In the xenograft model, NPY expression associate with bone metastases.
Y5Breast cancer4 T1 cell lineNPY mediates metastatic effect via the activation of Y5 receptor.[148]
NeurotensinNTSR1Breast cancerHuman tissuesThe expression of NTSR1 associates with lymph node metastasis.[151]

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Ach acetylcholine, AR androgen receptor, β2-AR β2-adrenergic receptor, cAMP cyclic adenosine monophosphate, DA dopamine, DR dopamine receptor, DRG dorsal root ganglia, ERBB1 epidermal growth factor receptor 1, EMT epithelial–mesenchymal transition, ERK1/2 extracellular signal-regulated kinase, GABA gamma-aminobutyric acid, GABA A&B gamma-aminobutyric acid receptor A&BHCC, hepatocellular carcinoma, JAK2 janus kinase 2, MEK MAPK/ERK kinase, MMP matrix metallopeptidase, RAF mitogen activated protein kinase, RAS mitogen activated protein kinase, MUC4 mucin 4, mAChRs muscarinic acetylcholine receptors, M3R muscarinic receptors 3, NK natural killer cells, NK-1R neurokinin-1 receptor, nAChR nicotinic acetylcholine receptor, NSCLC non-small cell lung cancer, NE norepinephrine, PNI perineural invasion, PLC phospholipase C, PI3K phosphoinositide 3-kinase, PKA protein kinase A, PKC protein kinase C, RhoA Ras homolog gene family member A, AKT serine/threonine kinase or protein kinase B, STAT3 signal transducer and activator of transcription 3, SP substance PFig. 1

Neurotransmitters signalling pathways in cancer. Cancer neuro-immune communication is through the release of neurotransmitters using different signalling kinases which promote cancer progression via metastasis. Perineural invasion mediate cancer metastasis through the release of the NGF and GDNF via the activation of different signaling pathway. Ach, acetylcholine; β2-AR, β2-adrenergic receptor;cAMP, cyclic adenosine monophosphate; DA, dopamine; DR, dopamine receptor; EGFR, epidermal growth factor receptor;EMT,epithelial–mesenchymal transition; ERK1/2, extracellular signal-regulated kinase;FAK, focal adhesion kinase; GABA, gamma-aminobutyric acid; GABAB,gamma-aminobutyric acid receptorB;GDNF, glial cell line-derived neurotrophic factor; GFRα, glial cell line-derived neurotrophic factor receptor 1;ICAM-1, intercellular adhesion molecule-1; JAK2,janus kinase 2;MEK, MAPK/ERK kinase;mTOR, mammalian/mechanistic target of rapamycin;MMP, matrix metallopeptidase;MAPK,mitogen-activated protein kinases;RAF, mitogen activated protein kinase;RAS, mitogen activated protein kinase;mAChRs, muscarinic acetylcholine receptors;NK-1R, neurokinin-1 receptor; NGF, nerve growth factor;nAChR, nicotinic acetylcholine receptor;NE, norepinephrine;NF-kB, nuclear factor-kappa B;PLC, phospholipase C; PI3K, phosphoinositide 3-kinase;PKA, protein kinase A;PKC, protein kinase C;RET, proto-oncogene;AKT, serine/threonine kinase or protein kinase B;STAT3,signal transducer and activator of transcription 3; SP,substance P;TrkA,tropomyosin related kinase A


The increased expression of β-adrenergic receptor for catecholamines is associated with poor prognosis in breast cancer [113]. Stress stimulation leads to macrophage infiltration to the tumor site which activates β-adrenergic signaling pathways leading to increased metastasis in an orthotopic breast cancer model in BALB/c mice [57]. In this model, administration of β-adrenergic antagonist, propranolol, decreases breast cancer metastasis [57]. Similarly, the use of β-blockers in breast cancer patients inhibits metastasis and disease recurrence as well as improving survival of patients [113114]. In ovarian cancer patients, the grade and stage of tumors correlate with higher tumor norepinephrine levels associated with stress [115]. In an orthotopic mouse model of ovarian cancer, chronic stress elevates tumor noradrenaline levels and increases the aggressiveness of tumor growth [49]. In prostate cancer C42 xenografts in nude mice and Hi-Myc mice with prostate cancer, plasma adrenaline promotes carcinogenesis via β2 adrenergic receptor/protein kinase A/BCL2-associated death protein anti-apoptotic signaling pathway [116]. Hence, stimulation of catecholamines plays a major role in activation of signals for breast cancer metastasis. Therefore, inhibition of the sympathetic nervous system signaling pathways with β-blockers holds great promise in preventing metastasis of various tumors including breast cancer. On the other hand, involvement of α-adrenergic receptors in cancer metastasis is not well understood. In the murine model of metastatic mammary adenocarcinoma induced by 4 T1 cells in BALB/c mice, activation of α2-adrenergic receptors increases tumor growth rate and the number of metastasis [117]. In contrast, blockade of α-adrenergic receptors in the absence of stress increases distant metastasis in the orthotopic model of mammary adenocarcinoma induced by MDA-MB-231HM cell line in nude mice [118].

The role of dopamine in cancer metastasis is not clear. Low levels of dopamine have been reported in stressed mice with ovarian carcinoma [119]. In contrary, in hepatocellular carcinoma (HCC) patients dopamine levels are elevated in the blood samples compared to healthy individuals [120]. Moreover, enzymes such as monoamine oxidase A (MAOA) degrading catecholamines and serotonin [121] may also play an important role in influencing cancer metastasis [122124]. Studies have demonstrated that MAOA expression is decreased in HCC patients; it suppresses HCC cell metastasis by inhibiting adrenergic and epidermal growth factor receptor (EGFR) signaling pathways [125]. Inhibition of MAOA stimulates malignant behavior in MDA-MB-231 breast cancer cells [126]. On the other hand, high expression of MAOA in human tissues correlates with poor prognostic in prostate cancer patients and increased tumor metastasis in xenograft mouse model of prostate cancer via HIF1-α/VEGF-A/FOXO1/TWIST1 signaling pathway [124]. These limited studies on the role of MAOA in cancer metastasis are controversial.

γ-Aminobutyric acid (GABA)

Plays a role in cancer metastasis via activation of ionotropic (GABAA) and metabotropic (GABAB) receptors [127]. It has been demonstrated that GABA mediates its inhibitory effect through GABAA receptor. For example, HCC cell lines and human adjacent non-tumor liver tissues, express GABAA receptor. GABA inhibits HCC cell migration through the activation of GABAA receptor [128]. However, there are studies demonstrating that GABAA receptor enhances metastasis. The activation of GABAA receptors upregulates brain metastasis of breast cancer patients [129]. Expression of the GABAA receptor subunit, Gabra3, which is normally not present in breast epithelial cells, is increased in human metastatic breast cancer which correlated with poorer patients survival [108]. Gabra3 overexpression promotes migration and metastasis of breast cancer cells via activating serine/threonine kinase or protein kinase B (AKT) signaling pathway demonstrated in a mouse orthotopic model induced by MCF7 and MDA-MB-436 breast cancer cell lines [108]. Mechanistically, the activation of AKT signaling pathway enhances metastasis via downstream molecules such as focal adhesion kinase and MMPs [130131]. Therefore, it could be speculated that the effect of GABAA receptor depends on the activated downstream molecules and signalling pathways. Murine (4 T1) and human (MCF7) breast cancer cell lines and human breast cancer tissues express GABAB receptor [107]. In mice, GABAB receptor mediates 4 T1 cell invasion and pulmonary metastasis via ERK1/2 signaling [107]. GABAB activation inhibits migration of PLC/PRF/5 and Huh 7 malignant hepatocyte cell lines in vitro [132].

Acetylcholine (ACh)

Plays a functional role in cellular proliferation, differentiation and apoptosis. In HCC, the release of ACh acting on androgen receptor promotes SNU-449 cell invasion and migration via activation of AKT and signal transducer and activator of transcription 3 (STAT3) signaling pathways [133]. Nicotine stimulation of nicotinic acetylcholine receptor (nAChRs) enhances SW620 and LOVO colorectal cancer cell invasion and metastasis in vitro via the activation of p38 mitogen-activated protein kinases (MAPK) signaling pathway [112]. Similarly, nicotine pretreatment stimulates the activation of α9-nAChR which mediates MCF-7 and MDA-MB-231 breast cancer cell migration via the expression of epithelial mesenchymal transition markers [134]. Furthermore, implantation of CD18/HPAF pancreatic cancer cells into immuno-deficient mice, demonstrates that nicotine treatment activates α7-nAChR and mediates tumor metastasis via Janus kinase 2 (JAK2)/STAT3 signaling in synergy with mitogen activated protein kinase (Ras/Raf/MEK/ERK1/2) signalling pathway [135]. ACh promoted cancer metastasis and associate with poor clinical outcomes in prostate adenocarcinoma via M1R; and pharmacological blockade or genetic disruption of the M1R inhibit tumor invasion and metastasis leading to improved survival of the mice-bearing PC-3 prostate tumor xenografts [93]. In addition, ACh acting on M3 muscarinic receptor (M3R) associates with metastasis and low survival rate of NSCLC patients [136]. M3R activation increases invasion and migration of NSCLC cells and increased release of interleukin (IL)-8 via the activation of EGFR/PI3K/AKT pathway [137]. In human SNU-C4 and H508 colon cancer cell lines, administration of muscarinic receptor inhibitor, atropine, abolished SNU-C4 cell migration, however, H508 cell migration requires the activation of MMP7 [138139].


Expression of SP is shown to exert functional effects on small cell lung cancer [140], pancreatic [141], colon [142], prostate [143144] and breast cancer [145] cells. SP acting on neurokinin-1 (NK-1) receptors enhances pancreatic cancer cell migration and perineural invasion to the dorsal root ganglia (DRG) mediated by MMP-2 demonstrating its essential role in metastasis [146]. Enhanced expression of SP correlated with lymph node metastasis and poor prognosis in colorectal cancer patients [142]. NPY modulates cell proliferation, differentiation and survival via acting on its G protein-coupled receptors designated Y1R–Y5R leading to the development of metastasis [147148]. High levels of systemic NPY associates with metastatic tumors as noted in Ewing sarcoma patients [149]. Similarly, in the SK-ES1 xenograft model, elevated levels of NPY associates with bone invasion and metastases [150]. NPY mediates 4 T1 cell proliferation and migration via the activation of NPY Y5 receptor [148]. Neurotensin mediates metastasis by binding to neurotensin receptors 1 (NTSR1). In breast cancer, the expression of NTSR1 correlates with lymph node metastasis [151]. These studies demonstrate the important role of neuropeptide signaling in cancer metastasis.Go to:

Concluding remarks and future directions

Metastasis continues to be the main cause of cancer-related death. Although genetic compartments that influence metastasis have been identified, there are still needs to conduct comprehensive evaluation of the factors that contribute to cancer metastasis. This review demonstrates that the nervous system influences cancer metastasis through the release of neurotransmitters and neuropeptides leading to metastasis. However, sensory nerve fibres have been given less attention. Sensory stimuli activate pain transmission pathways which result in acute or chronic pain depending on the intensity and the nature of the stimulus [152153]. Cancer-related pain is linked to accelerating cancer progression and metastasis. Sensory nerves can innervate primary tumors and metastases, thus contributing to tumor-associated pain as demonstrated in pancreatic [61] and prostate cancer [154]. Therefore, a possible involvement of sensory fibers in tumor progression and metastasis, although not well demonstrated at this stage, cannot be excluded.

In conclusion, cancer cells can transduce neurotransmitter-mediated intracellular signaling pathways which lead to their activation, growth and metastasis. The findings reported here are primarily done in cancer cell lines and animal models. Therefore, better understanding the interaction between these signaling molecules and tumor cells in human cancers would enhance our knowledge on pathways promoting cancer metastasis.Go to:


NK was supported by an Australian Postgraduate Research Award, LS and KN was supported by the College of Heath and Biomedicine Victoria University, Australia and VA was supported by the Centre for Chronic Disease, Victoria University, Australia.Go to:

Authors’ contributions

NK wrote the manuscript. LS, VA and KN revised and corrected the manuscript. All authors read and approved the final manuscript.Go to:


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Competing interests

The authors confirm that this article content has not competing interests.Go to:

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Go to:


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How the body’s nerves become accomplices in the spread of cancer

By Kelly ServickSep. 12, 2019 , 10:35 AM

In 1998, Gustavo Ayala, a young pathologist, landed at Baylor College of Medicine in Houston, Texas, ready to start to see patients. But his state medical license was delayed, and during 4 months of unexpected freedom, he found himself hunched over lab dishes, absorbed by a strange kind of cellular courtship.

Ayala hadn’t planned to do research full time, but a little-explored feature of cancer enticed him: the tendency of some cancer cells to wrap around nerves and grow along them. He had seen that “perineural invasion” in cancer patients and knew it often signaled an aggressive tumor and a poor prognosis. “But nobody knew how it happened,” Ayala says. “There was no biology.”

So Ayala put spinal nerves from a mouse in a dish next to human prostate cancer cells. What he saw was a symbiotic dance: Before the cancer colony invaded the nerves, the nerves reached out to the cancer. They elongated toward the cancer cells and grew into the colony’s midst. In turn, the cancer cell colony ballooned. The attraction, it seemed, was mutual.


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Since that observation, Ayala’s group and others have discovered that the peripheral nerves that branch through our bodies and regulate our organs are crucial partners to cancer as it grows and spreads. Those nerves churn out molecules that appear to aid the growth of cancer cells, and they alter surrounding tissue in ways that can make it more hospitable to cancer. “They’re not a bystander,” says Paola Vermeer, a cancer biologist at Sanford Research in Sioux Falls, South Dakota, who studies cancer-nerve interaction. “They’re an active participant in the disease process.”

To some experts, those revelations from basic biology help explain a controversial link between chronic stress and cancer progression. The work has also prompted several clinical trials testing whether blocking nerve signaling slows tumors’ spread. Those studies have yet to show long-term benefits for patients, but optimism is high. “The field, I feel, is about to explode,” Vermeer says. “People are starting to take notice.”

Recent studies have revealed many lines of communication between tumors, nerves, and other nearby cells. Their elaborate crosstalk seems to promote the growth and spread of cancer, in part through the release of stress-related hormones.

IT’S NOT OUTLANDISH to think the nervous system could become complicit in cancer’s growth and spread. Cancer is adept at exploiting the body’s normal functions—for example, by stimulating the growth of new blood vessels that nourish the invading cells. The disease manages to “curate the best of the body and use it to promote its survival advantage,” says Paige Green, head of the National Cancer Institute’s research program on basic biobehavioral and psychological sciences in Bethesda, Maryland. By studying how cancer “curates” protective mechanisms in the immune system, scientists have developed powerful drugs to thwart those mechanisms, sparking a multibillion-dollar industry.

The role of nerves has taken longer to emerge, says cancer neurobiologist Hubert Hondermarck of the University of Newcastle in Australia. Before the development of precise ways to label neurons, the small nerve branches in and around tumors were easy to overlook. And even after those tools were available, “There was no particular interest in studying nerves in depth among the cancer community,” Hondermarck says.

Many cancer labs were absorbed in studying genetic mutations in cancer cells themselves, not the body’s cancer-promoting signals, Ayala says. In the early 2000s, his focus on cancer-nerve crosstalk made him an outsider. “I was called the nerve guy.”

But Ayala wasn’t truly alone. Others were studying nerves in hopes of pinning down an elusive connection between cancer and stress. One such researcher was Anil Sood, a cancer biologist at the University of Texas MD Anderson Cancer Center in Houston. He was intrigued by findings that tumors grew bigger and faster in lab animals that were stressed—for example, by being physically restrained or socially isolated. Some studies had even suggested chronic stress in people made cancer more likely to progress. But how those proposed links worked wasn’t clear, he says. Among researchers interested in stress and cancer, “There was a feeling that hardcore scientists would view these kinds of observations to be ‘soft science.’”

So Sood and others went hunting for mechanisms. The researchers focused on the sympathetic nervous system, which orchestrates our “fight or flight” response to a perceived threat. The hormones epinephrine and norepinephrine play a key role in the response, increasing heart rate and blood pressure. Sympathetic nerves, which weave through our organs and signal to them, release those hormones into nearby tissue. (The adrenal glands perched on our kidneys secrete the same hormones into the bloodstream, which distributes them widely.)

Many cells in the body, including many cancer cells, are studded with β-adrenergic receptors, to which epinephrine and norepinephrine bind. And activating those receptors on cancer cells seems to encourage them to grow. In 2006, Sood’s team reported it could prompt a mouse’s ovarian tumor to grow larger by either exposing mice to chronic stress or giving the animal a drug that activates β-adrenergic receptors. Both interventions prompted cancer cells to recruit and nourish nearby blood vessels that, in turn, fueled their growth. Blocking the receptors prevented this growth.

That study and others showed cancer cells were alert to signals from the nervous system. Then, in 2013, research oncologist Claire Magnon and colleagues in the lab of cell biologist Paul Frenette at Albert Einstein College of Medicine in New York City went further. The researchers revealed that the small nerve fibers near a tumor were, at least sometimes, essential to the tumor’s growth. The team grafted human prostate tumors into mice and then either sliced out the surrounding nerves or destroyed them with a toxic chemical. Without neighboring nerves, the tumor failed to grow. In people, the team found that the higher the density of nerves in and around a prostate tumor, the faster the tumor tended to spread outside the prostate and the faster the cancer tended to recur after surgery. Studies by other groups showed that removing nerves could also prevent gastric and pancreatic tumors from forming. And at many other sites—including the breast, colon, and lung—researchers correlated nerve density with more aggressive disease.

Gustavo Ayala has probed basic interactions between nerves and tumor cells that could lead to new therapies. DWIGHT ANDREWS/MCGOVERN MEDICAL SCHOOL AT UTHEALTH

They also began to document the ways that cancer and nerves cozy up. Nerves entwined in blood vessels can hitch a ride into a tumor as it recruits blood vessels to supply it with oxygen. Cancer cells also produce molecular signals that can prompt nearby nerves to form new projections snaking into and around the tumor. Some evidence suggests signals from cancer can even prompt the body to make brand-new neurons from stem cells.

A provocative paper published in Nature this year showed that, in mice, neural precursor cells in the brain appear to migrate to a prostate tumor to supply it with neurons. The study, by Magnon, who is now at the French biomedical research agency INSERM in Paris, and collaborators, pointed to an unexplored path of communication between cancer and the central nervous system.

Why would cancer cells form alliances with nerves in the first place, tuning in to their signals and drawing them close? One idea is that a nerve-rich neighborhood is simply a friendly place for cancer, says Steven Cole, a genomics researcher at the University of California, Los Angeles. Because nerves expand and migrate regularly, they crank out molecules that encourage growth and motility—which a nearby cancer cell will gladly drink up. Cole’s group also found that signals from sympathetic nerves nudge immune cells called macrophages to deconstruct nearby tissue, secrete growth-promoting molecules, and recruit blood vessels. “The cancer cells love it,” he says.

Another idea is that listening to signals from sympathetic nerves helps cancer cells synchronize their invasion to periods of high stress, says neuroimmunologist Shamgar Ben-Eliyahu of Tel Aviv University in Israel. As cancer grows, it risks provoking T cells trained to attack and kill the body’s wayward cells, he explains. But when the body is on high alert and sympathetic nerves are most active, the immune system is tamped down. “If the tumor is smart enough to expose its cells to the immune system only when the immune system is suppressed, then it’s an advantage.”

SOME RESEARCHERS view evidence about the role of nerves as a long-awaited mechanistic link between stress and cancer. “The idea that tumors can be so controlled by these nerves—all of a sudden it really brings some clarity into why various types of stress can be so bad for people,” says Elizabeth Repasky, a cancer researcher at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

Cole notes that when he and others talk of a cancer-promoting stress response, they don’t mean the psychological experience commonly referred to as stress. That fretful, frazzled mental state doesn’t align perfectly with the release of stress hormones into our tissues and veins, he says. Still, he and others believe a state of chronic threat or insecurity—when a person doesn’t know how to meet basic needs such as food, shelter, and companionship—can manifest in a physical reaction that may drive cancer.

“I see these patients … who are taking care of their small children, maybe their parents, are living on aid or assistance, and now have some malignancy,” says Jennifer Knight, a psychiatrist specializing in cancer at the Medical College of Wisconsin in Milwaukee. “They’re in a chronic fight-or-flight mode because they’re under heightened threat, not getting basic needs met.” Knight is investigating whether stress-induced nerve activity could help explain why people of lower socioeconomic status do worse after a cancer diagnosis, even after factors such as access to care are controlled for.

“There are still a lot of unknowns” about the stress-cancer link, Sood says. Nerve activity may promote cancer regardless of whether a person is under particular stress, he says, and nerves may be a driver only at particular stages in a tumor’s evolution.

A fundamental problem, Hondermarck adds, is that objectively measuring the intensity of stress or defining what kind of stressful experience is relevant to disease is hard. “The potential relationship between stress and cancer has been in the air for a long time,” he says, “but has never been really demonstrated.”

REGARDLESS OF THE ROLE of stress in cancer, targeting the nervous system with drugs might help treat the disease. Knight, Repasky, Frenette, and Sood are all investigating a common class of drugs called β blockers. Used since the 1960s to reduce blood pressure and treat cardiovascular disease, and sometimes prescribed to manage short-term anxiety, they block β-adrenergic receptors to keep heart rate low.

Some retrospective studies have reported that people who happened to be diagnosed and treated for cancer while taking β blockers had better prognoses than patients not taking the drugs. But other studies found no benefit. So, several groups have launched prospective trials to test β blockers more systematically. Ben-Eliyahu has focused on the drugs’ potential to prevent metastasis after surgery, when residual disease often lingers around the surgical site or in distant parts of the body. He wondered whether administering a β blocker alongside another drug to reduce the cancer-promoting inflammatory reaction to surgery could make any leftover cancer less likely to spread.

In 2017, his team published results from a clinical trial, conducted with Cole and other collaborators, that enrolled 38 women with breast cancer who were slated for surgery. Five days before the procedure, half started to take the β blocker propranolol and the anti-inflammatory drug etodolac. The study had too few participants to draw conclusions about survival or disease recurrence. But breast tumors from women getting the drug cocktail expressed fewer genes associated with metastasis than tumors of women taking placebo. Ben-Eliyahu says his group now has similar, unpublished results from 34 people with colorectal cancer.

The field, I feel, is about to explode. People are starting to take notice.Paola Vermeer, Sanford Research

Larger trials are in the works. Ben-Eliyahu and colleagues have launched a trial at Israeli medical centers that aims to recruit 210 people with pancreatic cancer, some of whom will start to take propranolol and etodolac a few days before surgery to remove their tumors. The researchers plan to track survival over 5 years.

But the team is having trouble raising money for the trial, Ben-Eliyahu says. Other groups are struggling, too. “Those trials are really challenging for reasons that are incredibly annoying when you actually think about them,” Cole says: Industry sponsors don’t see a way to profit from drugs that long ago lost patent protection. “It’s hard to even recruit patients because their docs are all putting them on studies of these fabulously remunerative brand-new therapies, as opposed to this β blocker that my grandfather took when he had a heart attack or something,” he says.

β blockers aren’t the only option for targeting the nervous system’s role in cancer. Future studies might also explore the potential of antibodies that bind to and disable proteins released by cancers that promote nerve growth, Hondermarck says. And Cygnal Therapeutics, based in Cambridge, Massachusetts, is pursuing cancer treatments that target the interaction between cancer and nerves, though it has yet to share details of its strategy.

Two decades after his first curiosity project, Ayala—now at McGovern Medical School at the University of Texas Health Science Center in Houston—is still studying the cancer-nerve relationship and has begun to pursue possible therapies. Last year, his team reported in The Prostate that in four men with prostate tumors, injecting the nerve toxin botulinum into one side of the tumor prompted more cancer cells to die there than on the untreated side. He’s preparing to test the approach in a larger group of men.

Ayala is energized by the new enthusiasm for the field. That he has had to spend some time in the academic wilderness is “absolutely normal,” he says. But in his view, studies focused on sympathetic nerves barely scratch the surface of cancer-nerve interactions. Some research has suggested a role for parasympathetic nerves, which counteract sympathetic signals to return the body to rest, and for sensory nerves, which relay various stimuli to the brain. Ayala is preparing to publish a study on the influence of two more nerve types, defined by the proteins they express. He expects that dozens of distinct nerve types form complex—and consequential—partnerships with cancer.

“This is a story to be written by many people over the next 30 years,” he says. “There’s much more out there.”

*Update, 13 September, 11:05 a.m.: This story was updated to mention Claire Magnon’s role in the 2013 study.Posted in: 


Kelly Servick

Kelly Servick

Kelly is a staff writer at Science.

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