Sympathetic modulation of tumor necrosis factor alpha-induced nociception in the presence of oral squamous cell carcinoma

Abstract

Supplemental Digital Content is Available in the Text.Oral cancer mouse models were used to demonstrate that sympathetic neurotransmission modulates oral cancer pain and tumor growth through adrenergic signaling in the tumor microenvironment.

Lingual innervation in male and female marmosets

“…7 ); however expression of TH was found to be in very few TG neurons indicating that TH + nerves in the tongue are not sensory fibers ( Fig S3 A). This is in accordance to what we and others have observed in mice ( Atherton et al 2023 ; Wu et al 2018 ). Instead, our data confirmed that TH + nerve filaments were surrounding blood vessels indicative of sympathetic innervation ( Fig S3 B) .…”

“…We also tested for expression of TH expressing fibers in the tongue of marmosets as TH can be expressed in sensory neurons in mice ( Usoskin et al 2015 ) as well as is considered a marker for sympathetic innervation that has been shown to contribute to peripheral nociception ( Atherton et al 2023 ; Fan et al 2018 ). TH + fibers were indeed expressed in marmoset tongue and quantification of these fibers in the tongue showed no difference in the number of TH fibers (( Fig.…”

“…We used GFAP as a pan-nerve filament marker as it is known to stain myelinating and non-myelinating Schwann cells ( Bianchini et al, 1992 , McKenzie et al, 2006 , Yang and Wang, 2015 ). However, PGP9.5 which is a widely used pan-neuronal marker ( Boyd et al 2021 ; Lindquist et al 2021 ; Brady et al 2004 ; Chou et al 2001 ; Atherton et al 2023 ; Agelopoulos et al 2023 ), also stained well and can also be used as an alternate, for marmoset tongue tissues ( Fig S4 ). We did not find any evidence of pan-nerve fiber staining of human tongue tissues, although we speculate that both GFAP and PGP9.5 can potentially be used as pan-nerve markers in human tongue as well.…”

The impact of tumor immunogenicity on cancer pain phenotype using syngeneic oral cancer mouse models

“…Reverse transcription was performed with Quantitect Reverse Transcription Kit (Qiagen Inc.) according to the manufacturer's instructions. For single cell analysis, DiI-positive single neurons were dissociated as previously described ( 19 , 21 , 22 ), identified using fluorescence microscopy, and limited to ≤ 25 μm in diameter. Cells were then picked up using glass capillaries (World Precision Instruments) which were held by micromanipulator (Sutter Instruments), headstage (EPC10 HEKA) and electrode holder under brightfield optics.…”

The 3D's of Neural Phenotypes in Oral Cancer: Distance, Diameter, and Density

“…However, Atherton et al identified postganglionic sympathetic nerves in C57Bl/6 mouse tongue tumors using a retrograde tracer that labeled neurons in the superior cervical ganglion. [51] Importantly, increased TH-positive nerve density is associated with aggressive OSCC. [49] Adv.…”