Abstract
PurposePerineural invasion (PNI) by cancer cells is an ominous clinical event that is associated with increased local recurrence and poor prognosis. Although radiation therapy (RT) may be delivered along the course of an invaded nerve, the mechanisms through which radiation may potentially control PNI remain undefined.Experimental DesignAn in vitro co-culture system of dorsal root ganglia (DRG) and pancreatic cancer cells was used as a model of PNI. An in vivo murine sciatic nerve model was used to study how RT to nerve or cancer affects nerve invasion by cancer.ResultsCancer cell invasion of the DRG was partially dependent on DRG secretion of glial-derived neurotrophic factor (GDNF). A single 4 Gy dose of radiation to the DRG alone, cultured with non-radiated cancer cells, significantly inhibited PNI and was associated with decreased GDNF secretion but intact DRG viability. Radiation of cancer cells alone, co-cultured with non-radiated nerves, inhibited PNI through predominantly compromised cancer cell viability. In a murine model of PNI, a single 8 Gy dose of radiation to the sciatic nerve prior to implantation of non-radiated cancer cells resulted in decreased GDNF expression, decreased PNI by imaging and histology, and preservation of sciatic nerve motor function.ConclusionsRadiation may impair PNI through not only direct effects on cancer cell viability, but also an independent interruption of paracrine mechanisms underlying PNI. RT modulation of the nerve microenvironment may decrease PNI, and hold significant therapeutic implications for RT dosing and field design for patients with cancers exhibiting PNI.
Highlights
Perineural invasion (PNI) has been broadly defined as tumor cell invasion, in, around and through nerves [1]
Cancer cell invasion of the dorsal root ganglia (DRG) was partially dependent on DRG secretion of glial-derived neurotrophic factor (GDNF)
In vitro model of nerve invasion by cancer To investigate dynamic relationships between cancer and nerves, we developed a co-culture model using an insert divider as a temporary barrier that is removed to permit the onset of interactions between cancer cells and DRG within a drop of Matrigel (Fig. 1A)
Summary
Perineural invasion (PNI) has been broadly defined as tumor cell invasion, in, around and through nerves [1]. PNI is a frequent clinical and pathological finding in head and neck, pancreatic, prostate, and other cancers [2], and has been shown to be a marker of poor outcome, with increased locoregional recurrence rates and decreased survival [3,4,5]. Support for the clinical application of radiation therapy (RT) in the treatment of cancers with PNI is derived primarily from limited retrospective series demonstrating improved local control rates following radiation of neurotrophic cancers [6,7,8,9]. We currently lack a biological understanding of how radiation treatment of PNI translates into improved disease control. In current head and neck cancer clinical practice, full therapeutic doses of radiation may be applied to cranial nerves exhibiting PNI along the entire course of the nerve to the skull base. A mechanistic justification for such clinical practice, is lacking
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