Ayala, G. E. et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin. Cancer Res. 14, 7593â7603 (2008).
Huang, D. et al. Nerve fibers in breast cancer tissues indicate aggressive tumor progression. Medicine 93, e172 (2014).
Oertel, H. Innervation and tumour growth: a preliminary report. Can. Med. Assoc. J. 18, 135â139 (1928).
Renz, B. W. et al. β2 adrenergic-neurotrophin feedforward loop promotes pancreatic cancer. Cancer Cell 34, 863â867 (2018).
Latil, A. et al. Quantification of expression of netrins, slits and their receptors in human prostate tumors. Int. J. Cancer 103, 306â315 (2003).
Osswald, M. et al. Brain tumour cells interconnect to a functional and resistant network. Nature 528, 93â98 (2015).
Venkatesh, H. S. et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161, 803â816 (2015).
Venkatesh, H. S. et al. Electrical and synaptic integration of glioma into neural circuits. Nature 573, 539â545 (2019).
Zhao, C. M. et al. Denervation suppresses gastric tumorigenesis. Sci. Transl. Med. 6, 250ra115 (2014).
Magnon, C. et al. Autonomic nerve development contributes to prostate cancer progression. Science 341, 1236361 (2013).
Balood, M. et al. Nociceptor neurons affect cancer immunosurveillance. Nature 611, 405â412 (2022).
Globig, A. M. et al. The β1-adrenergic receptor links sympathetic nerves to T cell exhaustion. Nature 622, 383â392 (2023).
Gerendai, I. et al. Transneuronal labelling of nerve cells in the CNS of female rat from the mammary gland by viral tracing technique. Neuroscience 108, 103â118 (2001).
Hebb, C. & Linzell, J. L. Innervation of the mammary gland. A histochemical study in the rabbit. Histochem. J. 2, 491â505 (1970).
Tavora, B. et al. Tumoural activation of TLR3âSLIT2 axis in endothelium drives metastasis. Nature 586, 299â304 (2020).
Brose, K. et al. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96, 795â806 (1999).
Nguyen-Ngoc, K. V. et al. ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium. Proc. Natl Acad. Sci. USA 109, E2595âE2604 (2012).
Aslakson, C. J. & Miller, F. R. Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Res. 52, 1399â1405 (1992).
Bujak, J. K., Kosmala, D., Szopa, I. M., Majchrzak, K. & Bednarczyk, P. Inflammation, cancer and immunity-implication of TRPV1 channel. Front. Oncol. 9, 1087 (2019).
Liebig, C., Ayala, G., Wilks, J. A., Berger, D. H. & Albo, D. Perineural invasion in cancer: a review of the literature. Cancer 115, 3379â3391 (2009).
Kastin, A. Handbook of Biologically Active Peptides (Academic, 2013).
Otsuka, M. & Konishi, S. Release of substance P-like immunoreactivity from isolated spinal cord of newborn rat. Nature 264, 83â84 (1976).
Eshete, F. & Fields, R. D. Spike frequency decoding and autonomous activation of Ca2+-calmodulin-dependent protein kinase II in dorsal root ganglion neurons. J. Neurosci. 21, 6694â6705 (2001).
Nishikawa, S. et al. Two histidine residues are essential for ribonuclease T1 activity as is the case for ribonuclease A. Biochemistry 26, 8620â8624 (1987).
Robertson, H. D., Webster, R. E. & Zinder, N. D. Purification and properties of ribonuclease III from Escherichia coli. J. Biol. Chem. 243, 82â91 (1968).
Bremnes, R. M., Sirera, R. & Camps, C. Circulating tumour-derived DNA and RNA markers in blood: a tool for early detection, diagnostics, and follow-up? Lung Cancer 49, 1â12 (2005).
Huang, W. et al. Site-specific RNase A activity was dramatically reduced in serum from multiple types of cancer patients. PLoS ONE 9, e96490 (2014).
De Lamirande, G. Action of deoxyribonuclease and ribonuclease on the growth of Ehrlich ascites carcinoma in mice. Nature 192, 52â54 (1961).
Ledoux, L. Action of ribonuclease on two solid tumours in vivo. Nature 176, 36â37 (1955).
Lund, J. M. et al. Recognition of single-stranded RNA viruses by Toll-like receptor 7. Proc. Natl Acad. Sci. USA 101, 5598â5603 (2004).
Kawasaki, T. & Kawai, T. Toll-like receptor signaling pathways. Front. Immunol. 5, 461 (2014).
Ojaniemi, M. et al. Phosphatidylinositol 3-kinase is involved in Toll-like receptor 4-mediated cytokine expression in mouse macrophages. Eur. J. Immunol. 33, 597â605 (2003).
Ha, T. et al. TLR2 ligands induce cardioprotection against ischaemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Cardiovasc. Res. 87, 694â703 (2010).
Hesketh, P. J. et al. The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high-dose cisplatin-the Aprepitant Protocol 052 Study Group. J. Clin. Oncol. 21, 4112â4119 (2003).
Rosso, M., Robles-Frias, M. J., Covenas, R., Salinas-Martin, M. V. & Munoz, M. The NK-1 receptor is expressed in human primary gastric and colon adenocarcinomas and is involved in the antitumor action of L-733,060 and the mitogenic action of substance P on human gastrointestinal cancer cell lines. Tumour Biol. 29, 245â254 (2008).
Munoz, M. & Rosso, M. The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug. Invest. N. Drugs 28, 187â193 (2010).
Nagakawa, O. et al. Effect of prostatic neuropeptides on invasion and migration of PC-3 prostate cancer cells. Cancer Lett. 133, 27â33 (1998).
Nizam, E. & Erin, N. Differential consequences of neurokinin receptor 1 and 2 antagonists in metastatic breast carcinoma cells; effects independent of substance P. Biomed. Pharmacother. 108, 263â270 (2018).
Le, T. T. et al. Sensory nerves enhance triple-negative breast cancer invasion and metastasis via the axon guidance molecule PlexinB3. NPJ Breast Cancer 8, 116 (2022).
Austin, M., Elliott, L., Nicolaou, N., Grabowska, A. & Hulse, R. P. Breast cancer induced nociceptor aberrant growth and collateral sensory axonal branching. Oncotarget 8, 76606â76621 (2017).
Jurcak, N. R. et al. Axon guidance molecules promote perineural invasion and metastasis of orthotopic pancreatic tumors in mice. Gastroenterology 157, 838â850 (2019).
Kamiya, A. et al. Genetic manipulation of autonomic nerve fiber innervation and activity and its effect on breast cancer progression. Nat. Neurosci. 22, 1289â1305 (2019).
Zahalka, A. H. et al. Adrenergic nerves activate an angio-metabolic switch in prostate cancer. Science 358, 321â326 (2017).
Partecke, L. I. et al. Subdiaphragmatic vagotomy promotes tumor growth and reduces survival via TNFα in a murine pancreatic cancer model. Oncotarget 8, 22501â22512 (2017).
Renz, B. W. et al. Cholinergic signaling via muscarinic receptors directly and indirectly suppresses pancreatic tumorigenesis and cancer stemness. Cancer Discov. 8, 1458â1473 (2018).
Boilly, B., Faulkner, S., Jobling, P. & Hondermarck, H. Nerve dependence: from regeneration to cancer. Cancer Cell 31, 342â354 (2017).
Amit, M. et al. Loss of p53 drives neuron reprogramming in head and neck cancer. Nature 578, 449â454 (2020).
Kalinichenko, V. V., Mokyr, M. B., Graf, L. H. Jr, Cohen, R. L. & Chambers, D. A. Norepinephrine-mediated inhibition of antitumor cytotoxic T lymphocyte generation involves a β-adrenergic receptor mechanism and decreased TNF-α gene expression. J. Immunol. 163, 2492â2499 (1999).
Mohammadpour, H. et al. β2 adrenergic receptor-mediated signaling regulates the immunosuppressive potential of myeloid-derived suppressor cells. J. Clin. Invest. 129, 5537â5552 (2019).
Benci, J. L. et al. Opposing functions of interferon coordinate adaptive and innate immune responses to cancer immune checkpoint blockade. Cell 178, 933â948 (2019).
Cao, Y. Q. et al. Primary afferent tachykinins are required to experience moderate to intense pain. Nature 392, 390â394 (1998).
Wang, Y. et al. Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465, 483â486 (2010).
Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12, 954â961 (1992).
Maroulakou, I. G., Anver, M., Garrett, L. & Green, J. E. Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene. Proc. Natl Acad. Sci. USA 91, 11236â11240 (1994).
Hale, J. J. et al. Structural optimization affording 2-(R)-(1-(R)-3, 5-bis(trifluoromethyl)phenylethoxy)-3-(S)-(4-fluoro)phenyl-4- (3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human NK-1 receptor antagonist. J. Med. Chem. 41, 4607â4614 (1998).
Padmanaban, V. et al. Organotypic culture assays for murine and human primary and metastatic-site tumors. Nat. Protoc. 15, 2413â2442 (2020).
Young, L., Sung, J., Stacey, G. & Masters, J. R. Detection of Mycoplasma in cell cultures. Nat. Protoc. 5, 929â934 (2010).
Foty, R. A simple hanging drop cell culture protocol for generation of 3D spheroids. J. Vis. Exp. https://doi.org/10.3791/2720 (2011).
Heil, F. et al. Species-specific recognition of single-stranded RNA via Toll-like receptor 7 and 8. Science 303, 1526â1529 (2004).
Alexopoulou, L., Holt, A. C., Medzhitov, R. & Flavell, R. A. Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 413, 732â738 (2001).
Hemmi, H. et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat. Immunol. 3, 196â200 (2002).
Jurk, M. et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat. Immunol. 3, 499 (2002).
Maira, S. M. et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol. Cancer Ther. 11, 317â328 (2012).
Davies, B. R. et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol. Cancer Ther. 11, 873â887 (2012).
Folkes, A. J. et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J. Med. Chem. 51, 5522â5532 (2008).
Padmanaban, V. et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature 573, 439â444 (2019).
Krause, S., Brock, A. & Ingber, D. E. Intraductal injection for localized drug delivery to the mouse mammary gland. J. Vis. Exp. https://doi.org/10.3791/50692 (2013).
Jancso, G., Kiraly, E., Such, G., Joo, F. & Nagy, A. Neurotoxic effect of capsaicin in mammals. Acta Physiol. Hung. 69, 295â313 (1987).
Chi, J. et al. Three-dimensional adipose tissue imaging reveals regional variation in beige fat biogenesis and PRDM16-dependent sympathetic neurite density. Cell Metab. 27, 226â236 (2018).
Luppi, P. H., Fort, P. & Jouvet, M. Iontophoretic application of unconjugated cholera toxin B subunit (CTb) combined with immunohistochemistry of neurochemical substances: a method for transmitter identification of retrogradely labeled neurons. Brain Res. 534, 209â224 (1990).
Gee, K. R. et al. Chemical and physiological characterization of fluo-4 Ca2+-indicator dyes. Cell Calcium 27, 97â106 (2000).
Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346â352 (2012).