Functional neuronal circuits promote disease progression in cancer

Abstract

The molecular and functional contributions of intratumoral nerves to disease remain largely unknown. We localized synaptic markers within tumors suggesting that these nerves form functional connections. Consistent with this, electrophysiological analysis shows that malignancies harbor significantly higher electrical activity than benign disease or normal tissues. We also demonstrate pharmacologic silencing of tumoral electrical activity. Tumors implanted in transgenic animals lacking nociceptor neurons show reduced electrical activity. These data suggest that intratumoral nerves remain functional at the tumor bed. Immunohistochemical staining demonstrates the presence of the neuropeptide, Substance P (SP), within the tumor space. We show that tumor cells express the SP receptor, NK1R, and that ligand/receptor engagement promotes cellular proliferation and migration. Our findings identify a mechanism whereby intratumoral nerves promote cancer progression.

Brain-wide neuronal circuit connectome of human glioblastoma

“…Given that rabies virus does not label all synaptic inputs of starter cells 68,69 , our observation may still represent an underestimation. Our findings thus significantly expand the notion that tumor cells may be innervated and regulated by myriad neuronal subtypes [70][71][72][73] , such as those comprising neuromodulatory systems 74,75 that signal through metabotropic neurotransmitter receptors. Given the ability of glioma to bidirectionally interact with neuronal circuits 19,20,76,77 combined with established roles of diffuse neuromodulatory projections in memory and behavior 43,78 , our discoveries also provide a foundation to investigate whether feedback to neurons that innervate GBM cells might explain generalized patient symptoms such as cognitive dysfunction, sleep disturbances, seizures, or behavioral deficits that affect quality of life [79][80][81][82] and to develop corresponding therapeutic interventions.…”

Tumor-infiltrating nerves functionally alter brain circuits and modulate behavior in a mouse model of head-and-neck cancer

“…MOC2-7 cells are HNSCC cancer cells derived from a CXCR3 null mouse under a C57BL6 background 29 . Their implantation in male mice results in dense innervation of tumors with nociceptor neurons 38,39 . To define the timing of tumor innervation, wildtype male mice were orthotopically implanted with MOC2-7 cells in the oral cavity, and tumors were collected on days 4-, 10-, and 20-days post-implantation.…”

Acid-sensing ion channels and downstream signalling in cancer cells: is there a mechanistic link?

“…Thus, the main function of ASICs appears to be the mediation of phasic responses to synaptic fluctuations in the proton concentration. Intriguingly, in recent years it has become apparent that many tumours are innervated and that neuronal input drives tumour progression [ 56 , 63 , 77 – 79 , 89 ]. Thus, it is an exciting possibility that ectopic expression of ASIC1a in tumour tissues contributes to the response of tumour cells to synaptically released protons.…”