Innervation of cervical carcinoma is mediated by cancer-derived exosomes

Abstract

• Exosomes from cervical cancer cell lines with integrated HPV promote neurite outgrowth of PC12 cells. • Exosomes from cervical cancer cell lines with episomal HPV fail to promote neurite outgrowth of PC12 cells. • Cervical cancers are innervated with sensory nerves. • The integrated HPV status of cervical cancer may modulate tumor innervation mediated by tumor-released exosomes.

Tumor-infiltrating nerves create an electro-physiologically active microenvironment and contribute to treatment resistance

“…To test this, we turned to a previously generated set of isogenic cell lines in which the parental cell line (A2780) is platinum sensitive, while two independently derived lines (C30, CP-70) are platinum resistant [55, 56]. Purified sEVs from these cell lines express EV markers (Figure 8F); equal amounts were tested on PC12 cells as previously described (Figures 3 & Supplemental 3) [18, 19]. While sEVs from the CP70 treatment resistant line induced significantly more neurite outgrowth from PC12 cells than sEVs from the treatment sensitive parental A2780 line, sEVs from the second treatment resistant line, C30, did not (Figure 8G).…”

“…The presence of nerves within HNSCC and cervical cancer patient samples were recently identified by IHC staining for the pan-neuronal marker, β-III tubulin. These tumor-infiltrating nerves are IHC positive for the transient receptor potential vanilloid type 1 channel (TRPV1), a nociceptive sensory marker, but negative for tyrosine hydroxylase (TH, sympathetic marker) and vasoactive intestinal polypeptide (VIP, parasympathetic marker) [18, 19]. To define if other solid tumors are similarly innervated, we surveyed a collection of cancers in a similar fashion.…”

“…Likewise, pain in recurrent or late stage cervical cancer remains a challenge [68-70]. As opposed to the sensory innervation we identified in cancers [18, 19], several groups have identified sympathetic and parasympathetic innervation in other tumors (prostate, liver and breast) [3, 5, 17, 71]. Recent work demonstrates varying roles for sympathetic/parasympathetic tumor-infiltrating nerves including modulation of inflammation [72], immune cell functions [17] and mediating stress effects on disease progression [73-75].…”

“…Three reports in squamous cell carcinomas show that tumor-released small EVs (sEVs) promote innervation in cancer [18-20]. Moreover, highly innervated tumors grow faster and are more metastatic than sparsely innervated disease and sEVs directly contribute to this phenotype [18-20]. Based on these findings, we assessed innervation in other solid tumors (breast, prostate, pancreatic, lung, liver, ovarian and colon) and found that all are innervated.…”

“…While communication between cancer and the nervous system is appreciated, the potential that extracellular vesicles (EVs, vesicles released by cells) are vehicles of this communication was only recently discovered. Three reports in squamous cell carcinomas show that tumor-released small EVs (sEVs) promote innervation in cancer [18-20]. Moreover, highly innervated tumors grow faster and are more metastatic than sparsely innervated disease and sEVs directly contribute to this phenotype [18-20].…”