Radiation impairs perineural invasion by modulating the nerve microenvironment

Perineural 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 rema...

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Veröffentlicht in:PloS one 2012-06, Vol.7 (6), p.e39925-e39925
Hauptverfasser: Bakst, Richard L, Lee, Nancy, He, Shuangba, Chernichenko, Natalya, Chen, Chun-Hao, Linkov, Gary, Le, H Carl, Koutcher, Jason, Vakiani, Efsevia, Wong, Richard J
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container_issue 6
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container_title PloS one
container_volume 7
creator Bakst, Richard L
Lee, Nancy
He, Shuangba
Chernichenko, Natalya
Chen, Chun-Hao
Linkov, Gary
Le, H Carl
Koutcher, Jason
Vakiani, Efsevia
Wong, Richard J
description Perineural 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. An 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. Cancer 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. Radiation 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.
doi_str_mv 10.1371/journal.pone.0039925
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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. Radiation may impair PNI through not only direct effects on cancer cell viability, but also an independent interruption of paracrine mechanisms underlying PNI. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Bakst, Richard L</au><au>Lee, Nancy</au><au>He, Shuangba</au><au>Chernichenko, Natalya</au><au>Chen, Chun-Hao</au><au>Linkov, Gary</au><au>Le, H Carl</au><au>Koutcher, Jason</au><au>Vakiani, Efsevia</au><au>Wong, Richard J</au><au>Camphausen, Kevin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Radiation impairs perineural invasion by modulating the nerve microenvironment</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2012-06-29</date><risdate>2012</risdate><volume>7</volume><issue>6</issue><spage>e39925</spage><epage>e39925</epage><pages>e39925-e39925</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Perineural 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. An 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. Cancer 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. Radiation 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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22768171</pmid><doi>10.1371/journal.pone.0039925</doi><tpages>e39925</tpages><oa>free_for_read</oa></addata></record>
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identifier ISSN: 1932-6203
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1932-6203
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subjects Animal models
Animals
Biology
Brain-derived neurotrophic factor
Cancer
Cancer therapies
Carcinoma, Adenoid Cystic - metabolism
Carcinoma, Adenoid Cystic - pathology
Cell culture
Cell Line, Tumor
Cell Movement - drug effects
Cell Survival - drug effects
Cell Survival - radiation effects
Cellular Microenvironment - drug effects
Clinical medicine
Coculture Techniques
Dorsal root ganglia
Dose-Response Relationship, Radiation
Experimental design
Ganglia
Ganglia, Spinal - drug effects
Ganglia, Spinal - pathology
Ganglia, Spinal - radiation effects
Glial cell line-derived neurotrophic factor
Glial Cell Line-Derived Neurotrophic Factor - pharmacology
Glial Cell Line-Derived Neurotrophic Factor - secretion
Health aspects
Health physics
Histology
Humans
Implantation
In vivo methods and tests
Inhibition
Kinases
Male
Medicine
Mice
Mice, Inbred BALB C
Neoplasm Invasiveness
Nerve Tissue - drug effects
Nerve Tissue - pathology
Nerve Tissue - radiation effects
Nerves
Nervous system
Neuronal-glial interactions
Pancreatic cancer
Paracrine signalling
Pathogenesis
Preservation
Prognosis
Prostate cancer
Proto-Oncogene Proteins c-ret - metabolism
Radiation
Radiation (Physics)
Radiation dosage
Radiation therapy
Radiotherapy
Rodents
Sciatic nerve
Sciatic Nerve - drug effects
Sciatic Nerve - pathology
Sciatic Nerve - radiation effects
Secretion
Studies
Surgery
Surgical implants
title Radiation impairs perineural invasion by modulating the nerve microenvironment
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