Background & Aims

Oral cancer patients report severe pain while talking and chewing. Cancer resection cures pain, suggesting pain is initiated and maintained in the cancer microenvironment. Oral cancer pain is attributed to sensitization of primary afferent neurons by mediators released from the cancer microenvironment. We previously identified 40 genes increased in expression in patients with metastatic cancers who also reported high pain. The identified genes are enriched for functions in extracellular matrix organization, lymphangiogenesis and angiogenesis. Fibronectin (FN1), an extracellular matrix glycoprotein, was the most significantly up-regulated “pain and metastasis” gene. There are over 20 alternatively spliced human FN1 isoforms. The EDA isoform of fibronectin (Fn EDA) is expressed in pathological conditions including cancer, but not in normal adult tissues. Our goal is to evaluate whether Fn EDA is a an oral cancer pain mediator.

Methods

FN1 and Fn-EDA expression were evaluated by immunohistochemistry in tissue samples from patients, and in preclinical models. The nociceptive potential of Fn EDA, and impact of blocking Fn EDA were analyzed in preclinical models.

Results

Spatially distinct expression patterns were observed. FN1 was predominantly expressed in the stromal cells, whereas Fn-EDA was expressed in cancer cells and adjacent immune cells. FN1 and Fn-EDA expression correlated with high pain scores (stromal FN1 vs. pain, r = 0.639; cancer-cell Fn-EDA vs. pain, r = 0.554 respectively, n = 10 cases). FN1 and Fn-EDA expression was also spatially distinct in preclinical models of oral cancer pain. Intraplantar injections of Fn-EDA recombinant protein evoked mechanical allodynia. Blocking Fn EDA relieved mechanical allodynia.

Conclusions

Our findings suggest FN1 and Fn-EDA overexpressed in painful and metastatic cancers are potential oral cancer pain mediators. Additional testing is underway to evaluate the impact of Fn EDA on trigeminal neurons.

References

1. Bhattacharya A, Janal MN, Veeramachaneni R, Dolgalev I, Dubeykovskaya Z, Tu NH, Kim H, Zhang S, Wu AK, Hagiwara M, Kerr AR, DeLacure MD, Schmidt BL, Albertson DG. Oncogenes overexpressed in metastatic oral cancers from patients with pain: potential pain mediators released in exosomes. Sci Rep. 2020 Sep 7;10(1):14724. doi: 10.1038/s41598-020-71298-y. PMID: 32895418; PMCID: PMC7477576.

2. Jeske NA, Patwardhan AM, Henry MA, Milam SB. Fibronectin stimulates TRPV1 translocation in primary sensory neurons. J Neurochem. 2009 Feb;108(3):591-600. doi: 10.1111/j.1471-4159.2008.05779.x. Epub 2008 Nov 11. PMID: 19012739; PMCID: PMC2678239.

Presenting Author

Aditi Bhattacharya

Poster Authors

Shailee Patel

Lead Author

Niloofar Ghadirian

PhD

New York University College of Dentistry

Lead Author

Leticia Arbex

New York University

Lead Author

Aida Calderon Rivera

PhD

University of Florida College of Medicine

Lead Author

Kimberly Gomez

PhD

University of Florida College of Medicine

Lead Author

Malvin Janal

PhD

New York University College of Dentistry

Lead Author

May Khanna

PhD

University of Florida College of Medicine

Lead Author

Rajesh Khanna

PhD

University of Florida College of Medicine

Lead Author

Aditi Bhattacharya

MD, PhD

New York University College of Dentistry

Lead Author

Topics

  • Specific Pain Conditions/Pain in Specific Populations: Cancer Pain & Palliative Care