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Platelet-rich plasma and peripheral nerve regeneration: a potential contraindication to its use after tumor excision

Dear Editor, We read with great interest the article by Sánchez et al. [1] titled ‘Platelet-rich plasma, a source of autologous growth factors and biomimetic scaffold for peripheral nerve regeneration.’ The authors state that the ultimate goal of peripheral nerve repair strategy is the restoration of nerve-target organ function, while minimizing therapeutic side effects. We totally agree, but are there any side effects of platelet-rich plasma (PRP) application? What if the nerve injury is due to excision of an invading tumor; is it safe to apply a platelet-rich concentrate full of growth factors on this microenvironment? Let us take for example malignant peripheral nerve sheath tumors (MPNSTs) that arise from major or minor peripheral nerve branches or sheaths of peripheral nerve fibers, and are derived from Schwann cells or pluripotent cells of neural crest origin [2]. Zhou et al. [3] 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. PRP contains a high concentration of several growth factors and contributes to soft-tissue engineering and wound healing. However, the effect of PRP on human dermal fibroblast proliferation and responses is unknown. This was investigated by Hara et al. [4], who reported that PRP induces human dermal fibroblast proliferation via activation of ERK1/2 signaling. Furthermore, 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. [5] 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 associates 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. At this point, and in order tomuddy the waters, we would like tomention the term nerve dependence [6], which has long been described in animal regeneration, where the outgrowth of axons is necessary to the reconstitution of lost body parts and tissue remodeling in various species. Denervation can suppress tumor growth and metastasis, pointing to nerve dependence in cancer. 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. But is this enough in order to consider PRP as a harmful concentrate that could not be applied for peripheral nerve repair? Several studies on cancer growth, progression, recurrence, and postoperative survival rate focus on the tumor stroma, which represents a crucial parameter in tumor development [7]. Much research is now devoted to determining the impact of platelet-derived growth factors on tumor development and progression, and the reciprocal influences of tumor products on the stromal microenvironment. A more detailed understanding of the complex parameters that govern the interactions between the tumor and surrounding compartments has already helped to improve anticancer strategies, not only for treatment but also for preventing recurrence [8]. The release of growth factors stimulates angiogenesis, induces tumor lymphangiogenesis, enhances nodal metastasis rate, and regulates several cell biology processes, including tumorigenesis, proliferation, and survival, and many others such as cell differentiation, migration, and apoptosis [9]. Therefore, we strongly believe that the role of PRP in neurosurgery deserves further experimental investigation and large-scale prospective randomized clinical trials. The neurobiology of cancer is an emerging discipline that opens new perspectives in oncology. The use of novel reversibly switchable in vivo tumor models can elucidate the cause-andeffect chain of processes triggered by acute oncogene activation, providing an indication of the extent to which the tumor cell instructs its microenvironment versus the microenvironment instructing the tumor.