Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Ryota Takahashi
 -- 2482 2022-09-14 14:35:27 |
2 format change
Peter Tang
 Meta information modification 2482 2022-09-15 03:13:31 |

Video Upload Options

We provide professional Video Production Services to translate complex research into visually appealing presentations. Would you like to try it?
No, upload directly Yes

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Takahashi, R.;  Ijichi, H.;  Fujishiro, M. Neural Signaling in the Pancreatic Cancer Microenvironment. Encyclopedia. Available online: https://encyclopedia.pub/entry/27168 (accessed on 18 December 2024).
Takahashi R,  Ijichi H,  Fujishiro M. Neural Signaling in the Pancreatic Cancer Microenvironment. Encyclopedia. Available at: https://encyclopedia.pub/entry/27168. Accessed December 18, 2024.
Takahashi, Ryota, Hideaki Ijichi, Mitsuhiro Fujishiro. "Neural Signaling in the Pancreatic Cancer Microenvironment" Encyclopedia, https://encyclopedia.pub/entry/27168 (accessed December 18, 2024).
Takahashi, R.,  Ijichi, H., & Fujishiro, M. (2022, September 14). Neural Signaling in the Pancreatic Cancer Microenvironment. In Encyclopedia. https://encyclopedia.pub/entry/27168
Takahashi, Ryota, et al. "Neural Signaling in the Pancreatic Cancer Microenvironment." Encyclopedia. Web. 14 September, 2022.
Neural Signaling in the Pancreatic Cancer Microenvironment
Edit
This entry is adapted from the peer-reviewed paper 10.3390/cancers14174269

Pancreatic cancer is one of the most lethal malignant diseases. Various cells in the tumor microenvironment interact with tumor cells and orchestrate to support tumor progression. Several kinds of nerves are found in the tumor microenvironment, and each plays an essential role in tumor biology. Studies have shown that sympathetic, parasympathetic, and sensory neurons are found in the pancreatic cancer microenvironment. Neural signaling not only targets neural cells, but tumor cells and immune cells via neural receptors expressed on these cells, through which tumor growth, inflammation, and anti-tumor immunity are affected. Thus, these broad-range effects of neural signaling in the pancreatic cancer microenvironment may represent novel therapeutic targets. The modulation of neural signaling may be a therapeutic strategy targeting the whole tumor microenvironment.

pancreatic ductal adenocarcinoma tumor microenvironment stroma nerve

1. Introduction

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers and is estimated to be the second leading cause of cancer-related deaths in the United States by 2040 [1]. Despite the advances in diagnosis and treatment, the 5-year survival rate still stands at 11% [2].
The tumor has a heterogeneous population of tumor cells and stromal cells called tumor microenvironment, which includes immune cells, fibroblasts, endothelial cells, extracellular matrix, and secreted factors [3]. The tumor microenvironment of PDAC is characterized by its dense stroma with various cells such as fibroblasts, immune cells, blood vessels, and nerves [4][5]. These cells in the tumor microenvironment and tumor cells interact with each other to form a complex network and support tumor progression by providing nutrition [6], growth factors, and cytokines/chemokines [7], suppressing anti-tumor immunity [8], and inhibiting efficient drug delivery [9].
The role of nerves in cancer has been implicated, because the infiltration of nerves in tumor stroma and neural invasion is often found in many cancers, including PDAC [10][11]. Recent studies have demonstrated the important roles of autonomic nerves such as sympathetic and parasympathetic nerves in the tumorigenesis of prostate cancer [12][13], ovarian cancer [14], gastric cancer [15][16], and basal cell carcinoma [17].

2. Nerves in the Normal Pancreas and PDAC

Sympathetic and parasympathetic nerves innervate the pancreas [18]. Both exocrine and endocrine cells are regulated by sympathetic and parasympathetic nerve systems. Sympathetic nerve stimulation leads to a decrease in insulin and an increase in glucagon to maintain glycemic levels during stressful conditions [19][20][21]. Parasympathetic nerve activation increases insulin secretion [22]. The vagal nerve regulates pancreatic exocrine secretion [23]. In addition, sensory nerves also innervate the pancreas and may be involved in perceiving pain associated with chronic pancreatitis [24]. Neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, and NT-4, play key roles in inducing nerve growth and axonal guidance in normal conditions [25]. For example, NGF is known to attract sympathetic and sensory nerves [26][27]. These molecules bind to different receptors, including the tropomyosin-related kinase (TRK) family of tyrosine receptor kinases and the low-affinity p75NTR [28].
Tumoral innervation is reportedly associated with patient prognoses in many cancers, such as breast [29][30][31][32], gastric [15][16], head and neck [33][34], ovarian [35], prostate [12][13][36][37][38], and pancreatic cancer [39][40][41][42][43]. Especially in the PDAC microenvironment, tumoral innervation is an important hallmark: increased neural density and hypertrophy compared with a normal pancreas was observed in a PDAC specimen and was associated with a poor prognosis [27][44]. These studies suggest a tumor-promoting interaction between nerves and cancer cells (Figure 1). In addition, perineural invasion is another important feature of PDAC, which is a disseminating process through lymphatic vessels along nerves supported by various cells in the perineural niche [45][46]. Intra- and extra-pancreatic perineural invasion by cancer cells is present in 70–100% of PDAC resection specimens and is associated with worse prognoses such as tumor recurrence and shorter patient survival [47][48]. Notably, the prevalence and severity of perineural invasion in PDAC were reported to be the highest among gastrointestinal malignancies [47], suggesting the highly neurotropic feature of PDAC.
Figure 1. The interaction of neural cells and tumor cells. A schematic figure depicting the interaction of cancer cells and neural cells via various molecules.

3. The Effect of Neural Signaling on Tumor Progression

Molecules released by various neural cells infiltrating the tumor microenvironment, such as neurotransmitters, have been shown to affect various aspects of tumor cell activity, such as migration, invasion, and metastasis [49][50]. Accumulating evidence suggests that nerves can directly promote cancer cell proliferation, as suggested by studies in which the co-culturing of dorsal root ganglia (DRG) and cancer cells led to the increased proliferation of prostate and PDAC cells [38][43]. Subsequent studies have shown that various molecules secreted from nerves affect both tumor and non-tumor cells in the tumor microenvironment (Table 1). PDAC is innerved by sympathetic nerves, parasympathetic nerves, and sensory nerves, which have different roles in the tumor microenvironment (Figure 2).
Figure 2. The signaling from nerves into pancreatic tumor microenvironment. A schematic figure showing signaling molecules from various nerves into pancreatic cancer cells and other components in the tumor microenvironment to regulate tumor progression. ADRB2, beta 2 adrenergic receptor. Ach, Acetylcholine. Question marks indicate effects reported in cancers other than PDAC.
Table 1. Molecules secreted by nerves and their effects on target cells.

Type of Nerves

Name of Molecules

Target Cells

Effect

References

sympathetic nerves

norepinephrine, epinephrine

cancer cells

tumor progression

[29][35][39][51][52][53][54]
   

immune cells

immune suppression

[29][55][56][57]
   

endothelial cells

angiogenesis

[13][14][58][59]
 

GABA

cancer cells

tumor suppression

[60]
     

tumor progression

[61]
 

dopamine

endothelial cells

suppression of angiogenesis

[62][63][64][65]
 

NGF, BDNF

cancer cells

tumor progression

[66][67]
 

GFRα1

cancer cells

tumor progression

[68][69]
 

CX3CL1

cancer cells

tumor progression

[70]

parasympathetic nerves

acetylcholine

cancer cells

tumor progression

[12][16][71][72]
   

cancer cells

tumor suppression

[29][40][73]
   

immune cells

immune activation

[29][40][74]

sensory nerves

substance P

cancer cells

tumor progression

[34][75][76][77][78][79]
   

endothelial cells

suppression of angiogenesis

[77][80]
 

CGRP

endothelial cells

angiogenesis

[81]
 

CCL/CXCL chemokines

immune cells

immune suppression

[82]

sympathetic/sensory nerves

serine

cancer cells

tumor progression

[83]

4. The Effect of Neural Signaling on Non-Tumor Cells

As mentioned above, autonomic neural signals can not only affect tumor cells but also other types of cells, especially immune cells. The inflammatory status in the body is regulated via humoral and neuronal pathways [84][85][86].

4.1. Immune Cells

Associations between neuronal and immune systems have been reported to influence tumor immunity [87][88]. Neurogenic signatures were shown to be associated with immunosuppressive phenotypes [89].
The function of T cells, especially cytotoxic CD8+ T cells, is critical for anti-tumor immunity [90]. Some studies have suggested that neural signaling plays a role in controlling anti-tumor T cell functions. The ablation of sympathetic nerves decreased programmed death-1 (PD-1) and FOXP3 expression on T cells in breast cancer [29]. Accordingly, the parasympathetic stimulation of breast cancer cells decreased PD-L1 expression on tumor cells and PD-1 on T cells and increased CD8+/regulatory T (Treg) cells [29]. Another study demonstrated that the inhibition of β2-adrenergic receptor signaling on immune cells led to increased CD8+ T cells and decreased PD-1 expression on T cells [55]. In prostate cancer, PD-L1 expression on nerves in the tumor microenvironment was inversely correlated with the prevalence of CD8+ T cells and patient prognosis [91].
Macrophages infiltrating the tumor microenvironment are called tumor-associated macrophages (TAMs), which exert various effects to promote tumor initiation and progression [92]. In breast cancer, β-adrenergic nerve stimulation induces infiltration and the differentiation of tumor-promoting macrophages in the tumor microenvironment, leading to tumor progression and angiogenesis [56]. In contrast, cholinergic signaling suppresses the CD11b+ myeloid cell population and TNFα expression in the PDAC microenvironment, indicating the tumor suppressive and anti-inflammatory effect of cholinergic signaling [40]. Macrophages in the PDAC microenvironment are recruited by C-C chemokine receptor type 2 (CCR2) and colony-stimulating factors and secrete GDNFs to promote cancer migration and nerve invasion [93].
Myeloid-derived suppressor cells (MDSCs) are activated neutrophils and monocytes which have immune suppressive functions to promote tumor progression [94]. In melanoma, inhibition of β3-adrenergic receptor signaling attenuated regulatory T cells and MDSC increased the number and cytotoxicity of natural killer (NK) cells and increased the ratio of M1/M2 macrophages and N1 granulocytes [57]. Sensory neurons have been reported to secrete several CCL and CXCL chemokines in the melanoma microenvironment, attracting MDSCs to promote immune-tolerant conditions [82]. In colon cancer, cholinergic stimulation prevents colon cancer progression by inducing anti-inflammatory peptide trefoil factor 2 secretion from memory T cells to suppress MDSC expansion [74].
NK cells also play an important role in innate tumor immunity [95]. NK cells and nerves interact in the context of the degeneration of damaged sensory neurons through the NK cell receptor NKG2D and retinoic acid early-inducible 1 (RAE1) gene [96]. Due to β2 adrenergic receptor signaling, NK cells and other leukocytes are mobilized into circulation [97].
Eosinophils are granulocytes involved in innate immunity and have been shown to interact with neurons [98]. Nerves recruit eosinophils through the stimulation of neuropeptides, cytokines, and chemokines; eosinophils release cationic proteins, neurotrophins/neuropeptides, and ROS to induce nerve growth and neuropeptide synthesis. In the tumor microenvironment, the role of eosinophils seems to be context-dependent [99]. In some cancers, including melanoma, eosinophils exhibit anti-tumorigenic roles in mouse models, suggesting a novel therapeutic strategy.

4.2. Tumor Endothelial Cells (TECs)

Angiogenesis during tumor development has also been reported to be promoted by neural inputs. Vascular organization during development has been shown to be affected by sensory neurons [100], as well as signaling via neuropeptide Y [101]. In the tumor microenvironment, sympathetic nerve signaling induces angiogenesis, and TECs, in turn, promote tumorigenesis by secreting cytokines and growth factors [58]. Systemic sympathetic nerve stimulation by the chronic restrain model revealed increased vascular endothelial growth factor (VEGF) expression and angiogenesis via β2-adrenergic receptor signaling in ovarian tumor cells [14]. Catecholamines signaling through β-adrenergic receptors also induced expression of VEGF and IL-6 in breast cancer cells [59]. In prostate cancer, β2-adrenergic receptor signaling on endothelial cells promoted tumor angiogenesis and tumor progression [13], suggesting a mechanism involving immune regulation by sympathetic nerves through endothelial cells. In addition, catecholamine treatment induced the alternatively activated M2 polarization of macrophages to secrete VEGF and promote tumor angiogenesis in a lung cancer mouse model [102]. On the other hand, dopamine, a neurotransmitter of sympathetic nerves, downregulates VEGF receptor 2 signaling in endothelial cells [62] and inhibits colon cancer angiogenesis and growth [63]. Similarly, gastric cancer and ovarian cancer mouse models have shown decreased tumor angiogenesis and tumor growth after dopamine treatment [64][65]. Collectively, in the tumor microenvironment, sympathetic innervation promotes angiogenesis supporting tumor progression.

4.3. Cancer-Associated Fibroblasts (CAFs)

CAFs are key components in the tumor microenvironment and have been extensively investigated and shown to have various functions, including modifying matrix deposition, reciprocal signaling, and interacting with cancer cells and immune cells to promote cancer progression [103]. CAFs have also been shown to secrete several axon-guidance molecules. Exosomes derived from head and neck cancer cells induced NGF expression in fibroblasts [104]. Pancreatic stellate cells also produce neurotrophic factors NGFs and artemin in response to transforming growth factor β (TGF-β) to induce neurite outgrowth [105][106][107]. In pancreatic cancer, CAFs expressing NetrinG1, an axon-guidance molecule, have been shown to metabolically support tumor growth by affecting glutamate/glutamine metabolism and inhibiting NK-cell-mediated tumor killing via the Akt and p38 pathways [108]. CAFs in the pancreatic cancer microenvironment have been reported to secrete an axon guidance molecule, SLIT2, to induce neural outgrowth [109]. These studies suggest that CAFs are an important mediator of tumor innervation and neural remodeling in the tumor microenvironment.

4.4. Cancer-Associated Adipocytes(CAAs)

In adipocytes, β-adrenergic signaling, especially β3, is involved in the lipolytic mobilization of fatty acids [110][111]. In the cancer microenvironment, CAAs have been reported to promote tumor growth, angiogenesis, and migration through the secretion of hormones, cytokines, adipokines, and growth factors [112].

5. Origins of Nerves in the Tumor Microenvironment

The mechanism of how neural cells expand in the tumor microenvironment is not clearly understood. One possibility is that pre-existing nerves directly innervate from the surrounding tissue. Co-culturing neural ganglia and cancer cells promote neurite outgrowth [38][39]. Such innervation might be induced by neurotrophins including nerve growth factors. Another possibility is the trans-differentiation of cells in the tumor microenvironment. Amit and colleagues reported that loss of TP53 in oral cancer induced the trans-differentiation of tumor-associated sensory neurons into adrenergic neurons [34]. Another study suggested the possibility of the trans-differentiation of cancer cells into neural cells in the tumor microenvironment of prostate cancer [113]. Lastly, neural progenitor cells might be recruited to the tumor microenvironment from distant organs. Mauffrey and colleagues reported that doublecortin (DCX)-positive neural progenitors from the central nervous system infiltrated prostate primary tumors and metastases [114].

6. The Molecular Mechanisms Involved in Nerve Expansion in the Tumor Microenvironment

Various molecules, including neurotrophins, axon guidance molecules, and cytokines, are reportedly involved in the development and function of nerves in the tumor microenvironment (Figure 3).
Figure 3. Molecular mechanism of the expansion of tumor-associated nerves. A schematic diagram showing the interaction of nerves, pancreatic cancer cells, and CAFs via neurotrophins and other molecules which induce nerve growth.

7. Clinical Applications of Nerve-Targeting Therapy

Revealing the molecular mechanisms underlying nerves in the tumor microenvironment leads to novel therapeutic targeting, although only a limited number of molecular-targeting drugs have been approved in the field of tumor-associated nerves. Inhibitors of TRK receptors (pan-TRK inhibitors; entrectinib and larotrectinib) have been approved for solid tumors with TRK fusion [115][116][117]. The effect of a multi-kinase inhibitor sitravatinib, which also inhibits Trk activity, on advanced solid tumors is currently being investigated (NCT02219711) [118]. Although these drugs target TRK receptor signaling in cancer cells, they may exert inhibitory effects on innervation and tumor–nerve interactions in the tumor microenvironment, which should be determined in future studies.
Clinical trials to examine the effects of muscarinic agonists on PDAC (NCT03572283) and β-blockers in both non-metastatic and metastatic prostate and pancreatic cancer patients (NCT02944201, NCT03152786, NCT03838029, and NCT04245644) are ongoing. In addition, NK-1R antagonists have been suggested to exert anti-cancer effects both in a pre-clinical and clinical setting [119]. Although these studies mainly target neural signaling in cancer cells, autonomic nerve signaling may also affect other targets including immune systems. In addition, CCR2 inhibitor treatment has been reported to enhance anti-tumor immunity in PDAC [120], and has shown tolerability in PDAC patients [121], possibly also having inhibitory effects on neural invasion or tumor innervation.
The most commonly observed serious treatment-related events were cognitive disorders in entrectinib [116], suggesting a possible adverse effect on neural cells outside tumors by nerve-targeting drugs; moreover, muscarinic agonists or β-blockers may affect the cardiovascular function and bowel movements via autonomic nerve signaling. As such, for novel therapeutic agents targeting nerves, attention should be focused on avoiding adverse effects on normal neural activity.
Future studies should test multiple pathways and interactions in the tumor microenvironment discussed above. Surgical or pharmacological denervations of sympathetic/parasympathetic nerves or sensory neurons, and targeting immune–nerve or CAF–nerve interactions, may warrant future clinical studies. Overcoming suppressed anti-tumor immunity by modulating neural signaling may pave the way for novel immunotherapies in PDAC or other immunologically “cold” tumors. Metabolites secreted from nerves may also be an important therapeutic target, as the PDAC tumor microenvironment places a high demand on nutrients and might be dependent on the continuous supply of metabolites from stroma, including nerves.
Due to the complexity of the heterogeneity in the tumor microenvironment, determining an appropriate target is a critical process for developing novel therapeutic agents. Considering the higher incidence of perineural invasion and its impact on patient prognosis [47][48], it is important to elucidate the PDAC-specific mechanism by which PDAC becomes a more neurotropic tumor. One possibility may be the contribution of desmoplastic stroma, which characterizes PDAC. CAFs in PDAC have been shown to be a highly heterogeneous population [122].

References

  1. Rahib, L.; Wehner, M.R.; Matrisian, L.M.; Nead, K.T. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw. Open 2021, 4, e214708.
  2. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin. 2022, 72, 7–33.
  3. Anderson, N.M.; Simon, M.C. The tumor microenvironment. Curr. Biol. 2020, 30, R921–R925.
  4. Ho, W.J.; Jaffee, E.M.; Zheng, L. The tumour microenvironment in pancreatic cancer-clinical challenges and opportunities. Nat. Rev. Clin. Oncol. 2020, 17, 527–540.
  5. Feig, C.; Gopinathan, A.; Neesse, A.; Chan, D.S.; Cook, N.; Tuveson, D.A. The pancreas cancer microenvironment. Clin. Cancer Res. 2012, 18, 4266–4276.
  6. Gouirand, V.; Guillaumond, F.; Vasseur, S. Influence of the Tumor Microenvironment on Cancer Cells Metabolic Reprogramming. Front. Oncol. 2018, 8, 117.
  7. Thomas, D.; Radhakrishnan, P. Tumor-stromal crosstalk in pancreatic cancer and tissue fibrosis. Mol. Cancer 2019, 18, 14.
  8. Chang, J.H.; Jiang, Y.; Pillarisetty, V.G. Role of immune cells in pancreatic cancer from bench to clinical application: An updated review. Medicine 2016, 95, e5541.
  9. Magri, A.; Baveloni, F.G.; de Camargo, B.A.F.; Chorilli, M. The Emerging Landscapes to Drug Delivery Systems for the Treatment of Pancreatic Cancer. Curr. Med. Chem. 2021, 28, 5411–5430.
  10. Bapat, A.A.; Hostetter, G.; Von Hoff, D.D.; Han, H. Perineural invasion and associated pain in pancreatic cancer. Nat. Rev. Cancer 2011, 11, 695–707.
  11. Boilly, B.; Faulkner, S.; Jobling, P.; Hondermarck, H. Nerve Dependence: From Regeneration to Cancer. Cancer Cell 2017, 31, 342–354.
  12. Magnon, C.; Hall, S.J.; Lin, J.; Xue, X.; Gerber, L.; Freedland, S.J.; Frenette, P.S. Autonomic nerve development contributes to prostate cancer progression. Science 2013, 341, 1236361.
  13. Zahalka, A.H.; Arnal-Estape, A.; Maryanovich, M.; Nakahara, F.; Cruz, C.D.; Finley, L.W.S.; Frenette, P.S. Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science 2017, 358, 321–326.
  14. Thaker, P.H.; Han, L.Y.; Kamat, A.A.; Arevalo, J.M.; Takahashi, R.; Lu, C.; Jennings, N.B.; Armaiz-Pena, G.; Bankson, J.A.; Ravoori, M.; et al. Chronic stress promotes tumor growth and angiogenesis in a mouse model of ovarian carcinoma. Nat. Med. 2006, 12, 939–944.
  15. Hayakawa, Y.; Sakitani, K.; Konishi, M.; Asfaha, S.; Niikura, R.; Tomita, H.; Renz, B.W.; Tailor, Y.; Macchini, M.; Middelhoff, M.; et al. Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling. Cancer Cell 2017, 31, 21–34.
  16. Zhao, C.M.; Hayakawa, Y.; Kodama, Y.; Muthupalani, S.; Westphalen, C.B.; Andersen, G.T.; Flatberg, A.; Johannessen, H.; Friedman, R.A.; Renz, B.W.; et al. Denervation suppresses gastric tumorigenesis. Sci. Transl. Med. 2014, 6, 250ra115.
  17. Peterson, S.C.; Eberl, M.; Vagnozzi, A.N.; Belkadi, A.; Veniaminova, N.A.; Verhaegen, M.E.; Bichakjian, C.K.; Ward, N.L.; Dlugosz, A.A.; Wong, S.Y. Basal cell carcinoma preferentially arises from stem cells within hair follicle and mechanosensory niches. Cell Stem Cell 2015, 16, 400–412.
  18. Borden, P.; Houtz, J.; Leach, S.D.; Kuruvilla, R. Sympathetic innervation during development is necessary for pancreatic islet architecture and functional maturation. Cell Rep. 2013, 4, 287–301.
  19. Dunning, B.E.; Ahren, B.; Veith, R.C.; Taborsky, G.J., Jr. Nonadrenergic sympathetic neural influences on basal pancreatic hormone secretion. Am. J. Physiol. 1988, 255, E785–E792.
  20. Holst, J.J.; Jensen, S.L.; Knuhtsen, S.; Nielsen, O.V. Autonomic nervous control of pancreatic somatostatin secretion. Am. J. Physiol. 1983, 245, E542–E548.
  21. Holst, J.J.; Schwartz, T.W.; Knuhtsen, S.; Jensen, S.L.; Nielsen, O.V. Autonomic nervous control of the endocrine secretion from the isolated, perfused pig pancreas. J. Auton. Nerv. Syst. 1986, 17, 71–84.
  22. Ionescu, E.; Rohner-Jeanrenaud, F.; Berthoud, H.R.; Jeanrenaud, B. Increases in plasma insulin levels in response to electrical stimulation of the dorsal motor nucleus of the vagus nerve. Endocrinology 1983, 112, 904–910.
  23. Chandra, R.; Liddle, R.A. Neural and hormonal regulation of pancreatic secretion. Curr. Opin. Gastroenterol. 2009, 25, 441–446.
  24. Liu, L.; Shenoy, M.; Pasricha, P.J. Substance P and calcitonin gene related peptide mediate pain in chronic pancreatitis and their expression is driven by nerve growth factor. JOP 2011, 12, 389–394.
  25. Huang, E.J.; Reichardt, L.F. Neurotrophins: Roles in neuronal development and function. Annu. Rev. Neurosci. 2001, 24, 677–736.
  26. Aloe, L.; Rocco, M.L.; Bianchi, P.; Manni, L. Nerve growth factor: From the early discoveries to the potential clinical use. J. Transl. Med. 2012, 10, 239.
  27. Ceyhan, G.O.; Bergmann, F.; Kadihasanoglu, M.; Altintas, B.; Demir, I.E.; Hinz, U.; Muller, M.W.; Giese, T.; Buchler, M.W.; Giese, N.A.; et al. Pancreatic neuropathy and neuropathic pain—A comprehensive pathomorphological study of 546 cases. Gastroenterology 2009, 136, 177–186.e1.
  28. Chao, M.V.; Hempstead, B.L. p75 and Trk: A two-receptor system. Trends Neurosci. 1995, 18, 321–326.
  29. Kamiya, A.; Hayama, Y.; Kato, S.; Shimomura, A.; Shimomura, T.; Irie, K.; Kaneko, R.; Yanagawa, Y.; Kobayashi, K.; Ochiya, T. Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression. Nat. Neurosci. 2019, 22, 1289–1305.
  30. Pundavela, J.; Roselli, S.; Faulkner, S.; Attia, J.; Scott, R.J.; Thorne, R.F.; Forbes, J.F.; Bradshaw, R.A.; Walker, M.M.; Jobling, P.; et al. Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer. Mol. Oncol. 2015, 9, 1626–1635.
  31. Zhao, Q.; Yang, Y.; Liang, X.; Du, G.; Liu, L.; Lu, L.; Dong, J.; Han, H.; Zhang, G. The clinicopathological significance of neurogenesis in breast cancer. BMC Cancer 2014, 14, 484.
  32. Austin, M.; Elliott, L.; Nicolaou, N.; Grabowska, A.; Hulse, R.P. Breast cancer induced nociceptor aberrant growth and collateral sensory axonal branching. Oncotarget 2017, 8, 76606–76621.
  33. Madeo, M.; Colbert, P.L.; Vermeer, D.W.; Lucido, C.T.; Cain, J.T.; Vichaya, E.G.; Grossberg, A.J.; Muirhead, D.; Rickel, A.P.; Hong, Z.; et al. Cancer exosomes induce tumor innervation. Nat. Commun. 2018, 9, 4284.
  34. Amit, M.; Takahashi, H.; Dragomir, M.P.; Lindemann, A.; Gleber-Netto, F.O.; Pickering, C.R.; Anfossi, S.; Osman, A.A.; Cai, Y.; Wang, R.; et al. Loss of p53 drives neuron reprogramming in head and neck cancer. Nature 2020, 578, 449–454.
  35. Allen, J.K.; Armaiz-Pena, G.N.; Nagaraja, A.S.; Sadaoui, N.C.; Ortiz, T.; Dood, R.; Ozcan, M.; Herder, D.M.; Haemmerle, M.; Gharpure, K.M.; et al. Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction. Cancer Res. 2018, 78, 3233–3242.
  36. Pundavela, J.; Demont, Y.; Jobling, P.; Lincz, L.F.; Roselli, S.; Thorne, R.F.; Bond, D.; Bradshaw, R.A.; Walker, M.M.; Hondermarck, H. ProNGF correlates with Gleason score and is a potential driver of nerve infiltration in prostate cancer. Am. J. Pathol. 2014, 184, 3156–3162.
  37. Dobrenis, K.; Gauthier, L.R.; Barroca, V.; Magnon, C. Granulocyte colony-stimulating factor off-target effect on nerve outgrowth promotes prostate cancer development. Int. J. Cancer 2015, 136, 982–988.
  38. Ayala, G.E.; Dai, H.; Powell, M.; Li, R.; Ding, Y.; Wheeler, T.M.; Shine, D.; Kadmon, D.; Thompson, T.; Miles, B.J.; et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin. Cancer Res. 2008, 14, 7593–7603.
  39. Renz, B.W.; Takahashi, R.; Tanaka, T.; Macchini, M.; Hayakawa, Y.; Dantes, Z.; Maurer, H.C.; Chen, X.; Jiang, Z.; Westphalen, C.B.; et al. β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. Cancer Cell 2018, 33, 75–90.e7.
  40. Renz, B.W.; Tanaka, T.; Sunagawa, M.; Takahashi, R.; Jiang, Z.; Macchini, M.; Dantes, Z.; Valenti, G.; White, R.A.; Middelhoff, M.A.; et al. Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness. Cancer Discov. 2018, 8, 1458–1473.
  41. Saloman, J.L.; Albers, K.M.; Li, D.; Hartman, D.J.; Crawford, H.C.; Muha, E.A.; Rhim, A.D.; Davis, B.M. Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer. Proc. Natl. Acad. Sci USA 2016, 113, 3078–3083.
  42. Jurcak, N.R.; Rucki, A.A.; Muth, S.; Thompson, E.; Sharma, R.; Ding, D.; Zhu, Q.; Eshleman, J.R.; Anders, R.A.; Jaffee, E.M.; et al. Axon Guidance Molecules Promote Perineural Invasion and Metastasis of Orthotopic Pancreatic Tumors in Mice. Gastroenterology 2019, 157, 838–850.e836.
  43. Dai, H.; Li, R.; Wheeler, T.; Ozen, M.; Ittmann, M.; Anderson, M.; Wang, Y.; Rowley, D.; Younes, M.; Ayala, G.E. Enhanced survival in perineural invasion of pancreatic cancer: An in vitro approach. Hum. Pathol. 2007, 38, 299–307.
  44. Ferdoushi, A.; Griffin, N.; Marsland, M.; Xu, X.; Faulkner, S.; Gao, F.; Liu, H.; King, S.J.; Denham, J.W.; van Helden, D.F.; et al. Tumor innervation and clinical outcome in pancreatic cancer. Sci. Rep. 2021, 11, 7390.
  45. Amit, M.; Na’ara, S.; Gil, Z. Mechanisms of cancer dissemination along nerves. Nat. Rev. Cancer 2016, 16, 399–408.
  46. Liebig, C.; Ayala, G.; Wilks, J.A.; Berger, D.H.; Albo, D. Perineural invasion in cancer: A review of the literature. Cancer 2009, 115, 3379–3391.
  47. Liebl, F.; Demir, I.E.; Mayer, K.; Schuster, T.; D’Haese, J.G.; Becker, K.; Langer, R.; Bergmann, F.; Wang, K.; Rosenberg, R.; et al. The impact of neural invasion severity in gastrointestinal malignancies: A clinicopathological study. Ann. Surg. 2014, 260, 900–907.
  48. Schorn, S.; Demir, I.E.; Haller, B.; Scheufele, F.; Reyes, C.M.; Tieftrunk, E.; Sargut, M.; Goess, R.; Friess, H.; Ceyhan, G.O. The influence of neural invasion on survival and tumor recurrence in pancreatic ductal adenocarcinoma—A systematic review and meta-analysis. Surg. Oncol. 2017, 26, 105–115.
  49. Entschladen, F.; Drell, T.L.T.; Lang, K.; Joseph, J.; Zaenker, K.S. Tumour-cell migration, invasion, and metastasis: Navigation by neurotransmitters. Lancet Oncol. 2004, 5, 254–258.
  50. Schuller, H.M. Neurotransmitter receptor-mediated signaling pathways as modulators of carcinogenesis. Prog. Exp. Tumor Res. 2007, 39, 45–63.
  51. Zhang, X.; Zhang, Y.; He, Z.; Yin, K.; Li, B.; Zhang, L.; Xu, Z. Chronic stress promotes gastric cancer progression and metastasis: An essential role for ADRB2. Cell Death Dis. 2019, 10, 788.
  52. Guo, K.; Ma, Q.; Li, J.; Wang, Z.; Shan, T.; Li, W.; Xu, Q.; Xie, K. Interaction of the sympathetic nerve with pancreatic cancer cells promotes perineural invasion through the activation of STAT3 signaling. Mol. Cancer Ther. 2013, 12, 264–273.
  53. Zhang, D.; Ma, Q.Y.; Hu, H.T.; Zhang, M. beta2-adrenergic antagonists suppress pancreatic cancer cell invasion by inhibiting CREB, NFkappaB and AP-1. Cancer Biol. Ther. 2010, 10, 19–29.
  54. Kim-Fuchs, C.; Le, C.P.; Pimentel, M.A.; Shackleford, D.; Ferrari, D.; Angst, E.; Hollande, F.; Sloan, E.K. Chronic stress accelerates pancreatic cancer growth and invasion: A critical role for beta-adrenergic signaling in the pancreatic microenvironment. Brain Behav. Immun. 2014, 40, 40–47.
  55. Bucsek, M.J.; Qiao, G.; MacDonald, C.R.; Giridharan, T.; Evans, L.; Niedzwecki, B.; Liu, H.; Kokolus, K.M.; Eng, J.W.; Messmer, M.N.; et al. beta-Adrenergic Signaling in Mice Housed at Standard Temperatures Suppresses an Effector Phenotype in CD8+ T Cells and Undermines Checkpoint Inhibitor Therapy. Cancer Res. 2017, 77, 5639–5651.
  56. Sloan, E.K.; Priceman, S.J.; Cox, B.F.; Yu, S.; Pimentel, M.A.; Tangkanangnukul, V.; Arevalo, J.M.; Morizono, K.; Karanikolas, B.D.; Wu, L.; et al. The sympathetic nervous system induces a metastatic switch in primary breast cancer. Cancer Res. 2010, 70, 7042–7052.
  57. Calvani, M.; Bruno, G.; Dal Monte, M.; Nassini, R.; Fontani, F.; Casini, A.; Cavallini, L.; Becatti, M.; Bianchini, F.; De Logu, F.; et al. beta3 -Adrenoceptor as a potential immuno-suppressor agent in melanoma. Br. J. Pharmacol. 2019, 176, 2509–2524.
  58. Nagl, L.; Horvath, L.; Pircher, A.; Wolf, D. Tumor Endothelial Cells (TECs) as Potential Immune Directors of the Tumor Microenvironment-New Findings and Future Perspectives. Front. Cell Dev. Biol. 2020, 8, 766.
  59. Madden, K.S.; Szpunar, M.J.; Brown, E.B. beta-Adrenergic receptors (beta-AR) regulate VEGF and IL-6 production by divergent pathways in high beta-AR-expressing breast cancer cell lines. Breast Cancer Res. Treat. 2011, 130, 747–758.
  60. Al-Wadei, H.A.; Schuller, H.M. Nicotinic receptor-associated modulation of stimulatory and inhibitory neurotransmitters in NNK-induced adenocarcinoma of the lungs and pancreas. J. Pathol. 2009, 218, 437–445.
  61. Takehara, A.; Hosokawa, M.; Eguchi, H.; Ohigashi, H.; Ishikawa, O.; Nakamura, Y.; Nakagawa, H. Gamma-aminobutyric acid (GABA) stimulates pancreatic cancer growth through overexpressing GABAA receptor pi subunit. Cancer Res. 2007, 67, 9704–9712.
  62. Basu, S.; Nagy, J.A.; Pal, S.; Vasile, E.; Eckelhoefer, I.A.; Bliss, V.S.; Manseau, E.J.; Dasgupta, P.S.; Dvorak, H.F.; Mukhopadhyay, D. The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat. Med. 2001, 7, 569–574.
  63. Tilan, J.; Kitlinska, J. Sympathetic Neurotransmitters and Tumor Angiogenesis-Link between Stress and Cancer Progression. J. Oncol. 2010, 2010, 539706.
  64. Chakroborty, D.; Sarkar, C.; Mitra, R.B.; Banerjee, S.; Dasgupta, P.S.; Basu, S. Depleted dopamine in gastric cancer tissues: Dopamine treatment retards growth of gastric cancer by inhibiting angiogenesis. Clin. Cancer Res. 2004, 10, 4349–4356.
  65. Moreno-Smith, M.; Lee, S.J.; Lu, C.; Nagaraja, A.S.; He, G.; Rupaimoole, R.; Han, H.D.; Jennings, N.B.; Roh, J.W.; Nishimura, M.; et al. Biologic effects of dopamine on tumor vasculature in ovarian carcinoma. Neoplasia 2013, 15, 502–510.
  66. Deborde, S.; Wong, R.J. How Schwann cells facilitate cancer progression in nerves. Cell Mol. Life Sci. 2017, 74, 4405–4420.
  67. Demir, I.E.; Friess, H.; Ceyhan, G.O. Nerve-cancer interactions in the stromal biology of pancreatic cancer. Front. Physiol. 2012, 3, 97.
  68. He, S.; Chen, C.H.; Chernichenko, N.; He, S.; Bakst, R.L.; Barajas, F.; Deborde, S.; Allen, P.J.; Vakiani, E.; Yu, Z.; et al. GFRalpha1 released by nerves enhances cancer cell perineural invasion through GDNF-RET signaling. Proc. Natl. Acad. Sci. USA 2014, 111, E2008–E2017.
  69. Sawai, H.; Okada, Y.; Kazanjian, K.; Kim, J.; Hasan, S.; Hines, O.J.; Reber, H.A.; Hoon, D.S.; Eibl, G. The G691S RET polymorphism increases glial cell line-derived neurotrophic factor-induced pancreatic cancer cell invasion by amplifying mitogen-activated protein kinase signaling. Cancer Res. 2005, 65, 11536–11544.
  70. Marchesi, F.; Locatelli, M.; Solinas, G.; Erreni, M.; Allavena, P.; Mantovani, A. Role of CX3CR1/CX3CL1 axis in primary and secondary involvement of the nervous system by cancer. J. Neuroimmunol. 2010, 224, 39–44.
  71. Song, P.; Sekhon, H.S.; Lu, A.; Arredondo, J.; Sauer, D.; Gravett, C.; Mark, G.P.; Grando, S.A.; Spindel, E.R. M3 muscarinic receptor antagonists inhibit small cell lung carcinoma growth and mitogen-activated protein kinase phosphorylation induced by acetylcholine secretion. Cancer Res. 2007, 67, 3936–3944.
  72. Belo, A.; Cheng, K.; Chahdi, A.; Shant, J.; Xie, G.; Khurana, S.; Raufman, J.P. Muscarinic receptor agonists stimulate human colon cancer cell migration and invasion. Am. J. Physiol. Gastrointest. Liver Physiol. 2011, 300, G749–G760.
  73. Partecke, L.I.; Kading, A.; Trung, D.N.; Diedrich, S.; Sendler, M.; Weiss, F.; Kuhn, J.P.; Mayerle, J.; Beyer, K.; von Bernstorff, W.; et al. Subdiaphragmatic vagotomy promotes tumor growth and reduces survival via TNFalpha in a murine pancreatic cancer model. Oncotarget 2017, 8, 22501–22512.
  74. Dubeykovskaya, Z.; Si, Y.; Chen, X.; Worthley, D.L.; Renz, B.W.; Urbanska, A.M.; Hayakawa, Y.; Xu, T.; Westphalen, C.B.; Dubeykovskiy, A.; et al. Neural innervation stimulates splenic TFF2 to arrest myeloid cell expansion and cancer. Nat. Commun. 2016, 7, 10517.
  75. Garcia-Recio, S.; Fuster, G.; Fernandez-Nogueira, P.; Pastor-Arroyo, E.M.; Park, S.Y.; Mayordomo, C.; Ametller, E.; Mancino, M.; Gonzalez-Farre, X.; Russnes, H.G.; et al. Substance P autocrine signaling contributes to persistent HER2 activation that drives malignant progression and drug resistance in breast cancer. Cancer Res. 2013, 73, 6424–6434.
  76. Sinha, S.; Fu, Y.Y.; Grimont, A.; Ketcham, M.; Lafaro, K.; Saglimbeni, J.A.; Askan, G.; Bailey, J.M.; Melchor, J.P.; Zhong, Y.; et al. PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk. Cancer Res. 2017, 77, 1868–1879.
  77. Guha, S.; Eibl, G.; Kisfalvi, K.; Fan, R.S.; Burdick, M.; Reber, H.; Hines, O.J.; Strieter, R.; Rozengurt, E. Broad-spectrum G protein-coupled receptor antagonist, SP: A dual inhibitor of growth and angiogenesis in pancreatic cancer. Cancer Res. 2005, 65, 2738–2745.
  78. Li, X.; Ma, G.; Ma, Q.; Li, W.; Liu, J.; Han, L.; Duan, W.; Xu, Q.; Liu, H.; Wang, Z.; et al. Neurotransmitter substance P mediates pancreatic cancer perineural invasion via NK-1R in cancer cells. Mol. Cancer Res. 2013, 11, 294–302.
  79. Friess, H.; Zhu, Z.; Liard, V.; Shi, X.; Shrikhande, S.V.; Wang, L.; Lieb, K.; Korc, M.; Palma, C.; Zimmermann, A.; et al. Neurokinin-1 receptor expression and its potential effects on tumor growth in human pancreatic cancer. Lab. Investig. 2003, 83, 731–742.
  80. Hennig, I.M.; Laissue, J.A.; Horisberger, U.; Reubi, J.C. Substance-P receptors in human primary neoplasms: Tumoral and vascular localization. Int. J. Cancer 1995, 61, 786–792.
  81. Toda, M.; Suzuki, T.; Hosono, K.; Hayashi, I.; Hashiba, S.; Onuma, Y.; Amano, H.; Kurihara, Y.; Kurihara, H.; Okamoto, H.; et al. Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide. Proc. Natl. Acad. Sci. USA 2008, 105, 13550–13555.
  82. Keskinov, A.A.; Tapias, V.; Watkins, S.C.; Ma, Y.; Shurin, M.R.; Shurin, G.V. Impact of the Sensory Neurons on Melanoma Growth In Vivo. PLoS ONE 2016, 11, e0156095.
  83. Banh, R.S.; Biancur, D.E.; Yamamoto, K.; Sohn, A.S.W.; Walters, B.; Kuljanin, M.; Gikandi, A.; Wang, H.; Mancias, J.D.; Schneider, R.J.; et al. Neurons Release Serine to Support mRNA Translation in Pancreatic Cancer. Cell 2020, 183, 1202–1218.e1225.
  84. Tracey, K.J. The inflammatory reflex. Nature 2002, 420, 853–859.
  85. Steinman, L. Elaborate interactions between the immune and nervous systems. Nat. Immunol. 2004, 5, 575–581.
  86. Chavan, S.S.; Tracey, K.J. Essential Neuroscience in Immunology. J. Immunol. 2017, 198, 3389–3397.
  87. Dantzer, R. Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa. Physiol. Rev. 2018, 98, 477–504.
  88. Kuol, N.; Stojanovska, L.; Apostolopoulos, V.; Nurgali, K. Crosstalk between cancer and the neuro-immune system. J. Neuroimmunol. 2018, 315, 15–23.
  89. Jezequel, P.; Kerdraon, O.; Hondermarck, H.; Guerin-Charbonnel, C.; Lasla, H.; Gouraud, W.; Canon, J.L.; Gombos, A.; Dalenc, F.; Delaloge, S.; et al. Identification of three subtypes of triple-negative breast cancer with potential therapeutic implications. Breast Cancer Res. 2019, 21, 65.
  90. Farhood, B.; Najafi, M.; Mortezaee, K. CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review. J. Cell. Physiol. 2019, 234, 8509–8521.
  91. Mo, R.J.; Han, Z.D.; Liang, Y.K.; Ye, J.H.; Wu, S.L.; Lin, S.X.; Zhang, Y.Q.; Song, S.D.; Jiang, F.N.; Zhong, W.D.; et al. Expression of PD-L1 in tumor-associated nerves correlates with reduced CD8+ tumor-associated lymphocytes and poor prognosis in prostate cancer. Int. J. Cancer 2019, 144, 3099–3110.
  92. Noy, R.; Pollard, J.W. Tumor-associated macrophages: From mechanisms to therapy. Immunity 2014, 41, 49–61.
  93. Cavel, O.; Shomron, O.; Shabtay, A.; Vital, J.; Trejo-Leider, L.; Weizman, N.; Krelin, Y.; Fong, Y.; Wong, R.J.; Amit, M.; et al. Endoneurial macrophages induce perineural invasion of pancreatic cancer cells by secretion of GDNF and activation of RET tyrosine kinase receptor. Cancer Res. 2012, 72, 5733–5743.
  94. Veglia, F.; Sanseviero, E.; Gabrilovich, D.I. Myeloid-derived suppressor cells in the era of increasing myeloid cell diversity. Nat. Rev. Immunol. 2021, 21, 485–498.
  95. Liu, S.; Galat, V.; Galat, Y.; Lee, Y.K.A.; Wainwright, D.; Wu, J. NK cell-based cancer immunotherapy: From basic biology to clinical development. J. Hematol. Oncol. 2021, 14, 7.
  96. Davies, A.J.; Kim, H.W.; Gonzalez-Cano, R.; Choi, J.; Back, S.K.; Roh, S.E.; Johnson, E.; Gabriac, M.; Kim, M.S.; Lee, J.; et al. Natural Killer Cells Degenerate Intact Sensory Afferents following Nerve Injury. Cell 2019, 176, 716–728.e718.
  97. Graff, R.M.; Kunz, H.E.; Agha, N.H.; Baker, F.L.; Laughlin, M.; Bigley, A.B.; Markofski, M.M.; LaVoy, E.C.; Katsanis, E.; Bond, R.A.; et al. beta2-Adrenergic receptor signaling mediates the preferential mobilization of differentiated subsets of CD8+ T-cells, NK-cells and non-classical monocytes in response to acute exercise in humans. Brain Behav. Immun. 2018, 74, 143–153.
  98. Salvo-Romero, E.; Rodino-Janeiro, B.K.; Albert-Bayo, M.; Lobo, B.; Santos, J.; Farre, R.; Martinez, C.; Vicario, M. Eosinophils in the Gastrointestinal Tract: Key Contributors to Neuro-Immune Crosstalk and Potential Implications in Disorders of Brain-Gut Interaction. Cells 2022, 11, 1644.
  99. Varricchi, G.; Galdiero, M.R.; Loffredo, S.; Lucarini, V.; Marone, G.; Mattei, F.; Marone, G.; Schiavoni, G. Eosinophils: The unsung heroes in cancer? Oncoimmunology 2018, 7, e1393134.
  100. Mukouyama, Y.S.; Shin, D.; Britsch, S.; Taniguchi, M.; Anderson, D.J. Sensory nerves determine the pattern of arterial differentiation and blood vessel branching in the skin. Cell 2002, 109, 693–705.
  101. Ekstrand, A.J.; Cao, R.; Bjorndahl, M.; Nystrom, S.; Jonsson-Rylander, A.C.; Hassani, H.; Hallberg, B.; Nordlander, M.; Cao, Y. Deletion of neuropeptide Y (NPY) 2 receptor in mice results in blockage of NPY-induced angiogenesis and delayed wound healing. Proc. Natl. Acad. Sci. USA 2003, 100, 6033–6038.
  102. Xia, Y.; Wei, Y.; Li, Z.Y.; Cai, X.Y.; Zhang, L.L.; Dong, X.R.; Zhang, S.; Zhang, R.G.; Meng, R.; Zhu, F.; et al. Catecholamines contribute to the neovascularization of lung cancer via tumor-associated macrophages. Brain Behav. Immun. 2019, 81, 111–121.
  103. Sahai, E.; Astsaturov, I.; Cukierman, E.; DeNardo, D.G.; Egeblad, M.; Evans, R.M.; Fearon, D.; Greten, F.R.; Hingorani, S.R.; Hunter, T.; et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 2020, 20, 174–186.
  104. Xu, Z.; Zheng, X.; Zheng, J. Tumor-derived exosomes educate fibroblasts to promote salivary adenoid cystic carcinoma metastasis via NGF-NTRK1 pathway. Oncol. Lett. 2019, 18, 4082–4091.
  105. Haas, S.L.; Fitzner, B.; Jaster, R.; Wiercinska, E.; Gaitantzi, H.; Jesnowski, R.; Lohr, J.M.; Singer, M.V.; Dooley, S.; Breitkopf, K. Transforming growth factor-beta induces nerve growth factor expression in pancreatic stellate cells by activation of the ALK-5 pathway. Growth Factors 2009, 27, 289–299.
  106. Ceyhan, G.O.; Bergmann, F.; Kadihasanoglu, M.; Erkan, M.; Park, W.; Hinz, U.; Giese, T.; Muller, M.W.; Buchler, M.W.; Giese, N.A.; et al. The neurotrophic factor artemin influences the extent of neural damage and growth in chronic pancreatitis. Gut 2007, 56, 534–544.
  107. Demir, I.E.; Ceyhan, G.O.; Rauch, U.; Altintas, B.; Klotz, M.; Muller, M.W.; Buchler, M.W.; Friess, H.; Schafer, K.H. The microenvironment in chronic pancreatitis and pancreatic cancer induces neuronal plasticity. Neurogastroenterol. Motil. 2010, 22, 480–490.
  108. Francescone, R.; Barbosa Vendramini-Costa, D.; Franco-Barraza, J.; Wagner, J.; Muir, A.; Lau, A.N.; Gabitova, L.; Pazina, T.; Gupta, S.; Luong, T.; et al. Netrin G1 Promotes Pancreatic Tumorigenesis through Cancer-Associated Fibroblast-Driven Nutritional Support and Immunosuppression. Cancer Discov. 2021, 11, 446–479.
  109. Secq, V.; Leca, J.; Bressy, C.; Guillaumond, F.; Skrobuk, P.; Nigri, J.; Lac, S.; Lavaut, M.N.; Bui, T.T.; Thakur, A.K.; et al. Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling. Cell Death Dis. 2015, 6, e1592.
  110. Correll, J.W. Adipose tissue: Ability to respond to nerve stimulation in vitro. Science 1963, 140, 387–388.
  111. Braun, K.; Oeckl, J.; Westermeier, J.; Li, Y.; Klingenspor, M. Non-adrenergic control of lipolysis and thermogenesis in adipose tissues. J. Exp. Biol. 2018, 221, jeb165381.
  112. Wu, Q.; Li, B.; Li, J.; Sun, S.; Yuan, J.; Sun, S. Cancer-associated adipocytes as immunomodulators in cancer. Biomark. Res. 2021, 9, 2.
  113. Farach, A.; Ding, Y.; Lee, M.; Creighton, C.; Delk, N.A.; Ittmann, M.; Miles, B.; Rowley, D.; Farach-Carson, M.C.; Ayala, G.E. Neuronal Trans-Differentiation in Prostate Cancer Cells. Prostate 2016, 76, 1312–1325.
  114. Mauffrey, P.; Tchitchek, N.; Barroca, V.; Bemelmans, A.P.; Firlej, V.; Allory, Y.; Romeo, P.H.; Magnon, C. Progenitors from the central nervous system drive neurogenesis in cancer. Nature 2019, 569, 672–678.
  115. Cocco, E.; Scaltriti, M.; Drilon, A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat. Rev. Clin. Oncol. 2018, 15, 731–747.
  116. Doebele, R.C.; Drilon, A.; Paz-Ares, L.; Siena, S.; Shaw, A.T.; Farago, A.F.; Blakely, C.M.; Seto, T.; Cho, B.C.; Tosi, D.; et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020, 21, 271–282.
  117. Hong, D.S.; DuBois, S.G.; Kummar, S.; Farago, A.F.; Albert, C.M.; Rohrberg, K.S.; van Tilburg, C.M.; Nagasubramanian, R.; Berlin, J.D.; Federman, N.; et al. Larotrectinib in patients with TRK fusion-positive solid tumours: A pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020, 21, 531–540.
  118. Bauer, T.; Cho, B.C.; Heist, R.; Bazhenova, L.; Werner, T.; Goel, S.; Kim, D.W.; Adkins, D.; Carvajal, R.D.; Alva, A.; et al. First-in-human phase 1/1b study to evaluate sitravatinib in patients with advanced solid tumors. Investig. New Drugs 2022, 40, 990–1000.
  119. Munoz, M.; Covenas, R. The Neurokinin-1 Receptor Antagonist Aprepitant: An Intelligent Bullet against Cancer? Cancers 2020, 12, 2682.
  120. Nywening, T.M.; Belt, B.A.; Cullinan, D.R.; Panni, R.Z.; Han, B.J.; Sanford, D.E.; Jacobs, R.C.; Ye, J.; Patel, A.A.; Gillanders, W.E.; et al. Targeting both tumour-associatedCXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma. Gut 2018, 67, 1112–1123.
  121. Nywening, T.M.; Wang-Gillam, A.; Sanford, D.E.; Belt, B.A.; Panni, R.Z.; Cusworth, B.M.; Toriola, A.T.; Nieman, R.K.; Worley, L.A.; Yano, M.; et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: A single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016, 17, 651–662.
  122. Pereira, B.A.; Vennin, C.; Papanicolaou, M.; Chambers, C.R.; Herrmann, D.; Morton, J.P.; Cox, T.R.; Timpson, P. CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer. Trends Cancer 2019, 5, 724–741.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Gastroenterology & Hepatology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ryota Takahashi
,
Hideaki Ijichi
,
Mitsuhiro Fujishiro
View Times: 639
Revisions: 2 times (View History)
Update Date: 15 Sep 2022
Table of Contents
    1000/1000
    Hot Most Recent
    Video Production Service
    Feedback