Oncogenes overexpressed in metastatic oral cancers from patients with pain: potential pain mediators released in exosomes

Abstract

Oral cancer patients experience pain at the site of the primary cancer. Patients with metastatic oral cancers report greater pain. Lack of pain identifies patients at low risk of metastasis with sensitivity = 0.94 and negative predictive value = 0.89. In the same cohort, sensitivity and negative predictive value of depth of invasion, currently the best predictor, were 0.95 and 0.92, respectively. Cancer pain is attributed to cancer-derived mediators that sensitize neurons and is associated with increased neuronal density. We hypothesized that pain mediators would be overexpressed in metastatic cancers from patients reporting high pain. We identified 40 genes overexpressed in metastatic cancers from patients reporting high pain (n = 5) compared to N0 cancers (n = 10) and normal tissue (n = 5). The genes are enriched for functions in extracellular matrix organization and angiogenesis. They have oncogenic and neuronal functions and are reported in exosomes. Hierarchical clustering according to expression of neurotrophic and axon guidance genes also separated cancers according to pain and nodal status. Depletion of exosomes from cancer cell line supernatant reduced nociceptive behavior in a paw withdrawal assay, supporting a role for exosomes in cancer pain. The identified genes and exosomes are potential therapeutic targets for stopping cancer and attenuating pain.

The Histopathology of Oral Cancer Pain in a Mouse Model and a Human Cohort

“…To determine how nociception and histopathological features of mouse pSCCs compared with patient-reported pain and histopathology of human oral cancers, we compared features that could be measured in the mouse model and in a cohort of 72 oral cancer patients (Bhattacharya et al 2020). Pain scores, pathology, and clinical information were available for these patients (Appendix Table 3).…”

“…Oral cancer patients have function-related mechanical pain (i.e., the highest pain scores were associated with eating and talking) (Connelly and Schmidt 2004; Bhattacharya et al 2020). The dolognawmeter is a validated operant assay and device that measures functional mechanical allodynia and takes advantage of the normal behavior of rodents to escape from confinement (Dolan et al 2010).…”

“…Neuronal density has been associated with pain in pancreatic adenocarcinoma (Bapat et al 2011; Demir et al 2015). Neck lymph node metastasis, a significant predictor of survival in oral cancer, is associated with greater patient-reported pain (Connelly and Schmidt 2004; Bhattacharya et al 2020). Metastasis, however, could not be studied.…”

“…In a previous study (Bhattacharya et al 2020), we assembled a cohort of human oral cancer patients ( n = 72) for study of the association of neck lymph node metastasis with pathologic and clinical features, including pain scores. Pathological data were retrieved from surgical pathology reports.…”

“…Often pain is the first symptom that motivates patients to seek care. Patients with precancerous oral lesions (dysplasia) do not report pain (Lam and Schmidt 2011; Bhattacharya et al 2020). Clinical findings and preclinical studies indicate that cancer pain is initiated and maintained in the cancer microenvironment.…”