title: The chemokine (CCL2-CCR2) signaling axis mediates perineural invasion.
abstract: Perineural invasion is a form of cancer progression where cancer cells invade along nerves. This behavior is associated with poor clinical outcomes; therefore, it is critical to identify novel ligand-receptor interactions between nerves and cancer cells that support the process of perineural invasion. A proteomic profiler chemokine array was used to screen for nerve-derived factors secreted from tissue explants of dorsal root ganglion (DRG), and CCL2 was identified as a lead candidate. Prostate cancer cell line expression of CCR2, the receptor to CCL2, correlated closely with MAPK and Akt pathway activity and cell migration towards CCL2 and DRG. In vitro nerve and cancer coculture invasion assays of perineural invasion demonstrated that cancer cell CCR2 expression facilitates perineural invasion. Perineural invasion is significantly diminished in coculture assays when using DRG harvested from CCL2(-/-) knockout mice as compared with control CCL2(+/+) mice, indicating that CCR2 is required for perineural invasion in this murine model of perineural invasion. Furthermore, 20 of 21 (95%) patient specimens of prostate adenocarcinoma with perineural invasion exhibited CCR2 expression by immunohistochemistry, while just 3 of 13 (23%) lacking perineural invasion expressed CCR2. In summary, nerve-released CCL2 supports prostate cancer migration and perineural invasion though CCR2-mediated signaling.
  
  
  CONCLUSIONS
  These results reveal CCL2-CCR2 signaling as a key ligand-receptor mechanism that mediates cancer cell communication with nerves during perineural invasion and highlight a potential future therapeutic target.
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York. Department of Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, PR China.
authors.forename: Shizhi
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York. Department of Otolaryngology-Head and Neck Surgery, Anhui Provincial Hospital, Anhui Medical University, Anhui, China.
authors.forename: Shuangba
authors.initials: S
authors.lastname: He
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Chun-Hao
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Deborde
authors.affiliation: Department of Radiation Oncology, Mount Sinai Hospital, New York, New York.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Bakst
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Natalya
authors.initials: N
authors.lastname: Chernichenko
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: William F
authors.initials: WF
authors.lastname: McNamara
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Sei Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Fernando
authors.initials: F
authors.lastname: Barajas
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Nanjing Tongren Hospital, Nanjing, PR China.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Hikmat A
authors.initials: HA
authors.lastname: Al-Ahmadie
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York. wongr@mskcc.org.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wong
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D018920:Coculture Techniques; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D054390:Receptors, CCR2 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C111835:CCL2 protein, human; C515334:CCR2 protein, human; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054390:Receptors, CCR2