Platelet-Rich Fibrin and Its Contradictory Effect on Peripheral Nerve Repair after Malignant Tumor Resection: Nerve Regeneration versus Cancer Proliferation

Platelet-Rich Fibrin Conduits as an Alternative to Nerve Autografts for Peripheral Nerve Repair

We read with great interest the article by Roth et al[1] titled “Platelet-Rich Fibrin Conduits as an Alternative to Nerve Autografts for Peripheral Nerve Repair.” The authors conclude that vein conduits filled with platelet-rich fibrin (PRF) may be a favorable alternative treatment to nerve grafts for peripheral nerve repair. That might be correct, but is it safe to use a platelet-rich concentrate full of growth factors on a malignant microenvironment after excision of an invading tumor?

To answer this question, we conducted a literature review on this subject. Malignant peripheral nerve sheath tumors (MPNSTs), which arise from major or minor peripheral nerve branches or sheaths of peripheral nerve fibers, are derived from Schwann cells or pluripotent cells of neural crest origin. Zhou et al[2] investigated the role of fibroblast growth factor receptor (FGFR) family members in human MPNSTs via an integrated genomic and molecular study, providing evidence that FGFRs play a role in MPNST prognosis. PRF contains a high concentration of growth factors and contributes to soft-tissue engineering and wound healing. Although the effect of PRF on human dermal fibroblasts is still being investigated, it has been reported that it induces their proliferation via activation of extracellular signal-regulated kinase 1/2 signaling.[3]

Nerves enable cancer progression, as cancers have been shown to extend along nerves through the process of perineural invasion. The innervation of some cancers promotes growth and metastases. It remains unclear, however, how nerves mechanistically contribute to cancer progression. Deborde et al[4] demonstrated that Schwann cells promote cancer invasion through direct cancer cell contact. Histological evaluation of murine and human cancer specimens with perineural invasion uncovered a subpopulation of Schwann cells that associate with cancer cells. Coculture of cancer cells with dorsal root ganglion extracts revealed that Schwann cells direct cancer cells to migrate toward nerves and promote invasion in a contact-dependent manner. Upon contact, Schwann cells induced the formation of cancer cell protrusions in their direction and intercalated between the cancer cells, leading to cancer cell dispersion.[4] Furthermore, denervation can suppress tumor growth and metastasis, pointing to nerve dependence in cancer.[5]

Regeneration and cancer share similarities in regard to the stimulatory role of nerves, and there are indications that the stem cell compartment is a preferred target of innervation. Therefore, we recommend further experimental investigation with novel reversibly switchable in vivo tumor models to elucidate the cause-and-effect chain of processes and provide an indication of the extent to which the tumor cell instructs its microenvironment versus the microenvironment instructing the tumor.

• References

• 1 Roth F, Fernandes M, Valente SG. , et al. Platelet-rich fibrin conduits as an alternative to nerve autografts for peripheral nerve repair. J Reconstr Microsurg 2017; 33 (08) 549-556
• 2 Zhou W, Du X, Song F. , et al. Prognostic roles for fibroblast growth factor receptor family members in malignant peripheral nerve sheath tumor. Oncotarget 2016; 7 (16) 22234-22244
• 3 Hara T, Kakudo N, Morimoto N, Ogawa T, Lai F, Kusumoto K. Platelet-rich plasma stimulates human dermal fibroblast proliferation via a Ras-dependent extracellular signal-regulated kinase 1/2 pathway. J Artif Organs 2016; 19 (04) 372-377
• 4 Deborde S, Omelchenko T, Lyubchik A. , et al. Schwann cells induce cancer cell dispersion and invasion. J Clin Invest 2016; 126 (04) 1538-1554
• 5 Boilly B, Faulkner S, Jobling P, Hondermarck H. Nerve dependence: from regeneration to cancer. Cancer Cell 2017; 31 (03) 342-354