title: Nerve fibers infiltrate the tumor microenvironment and are associated with nerve growth factor production and lymph node invasion in breast cancer.
abstract: Infiltration of the tumor microenvironment by nerve fibers is an understudied aspect of breast carcinogenesis. In this study, the presence of nerve fibers was investigated in a cohort of 369 primary breast cancers (ductal carcinomas in situ, invasive ductal and lobular carcinomas) by immunohistochemistry for the neuronal marker PGP9.5. Isolated nerve fibers (axons) were detected in 28% of invasive ductal carcinomas as compared to only 12% of invasive lobular carcinomas and 8% of ductal carcinomas in situ (p = 0.0003). In invasive breast cancers, the presence of nerve fibers was observed in 15% of lymph node negative tumors and 28% of lymph node positive tumors (p = 0.0031), indicating a relationship with the metastatic potential. In addition, there was an association between the presence of nerve fibers and the expression of nerve growth factor (NGF) in cancer cells (p = 0.0001). In vitro, breast cancer cells were able to induce neurite outgrowth in PC12 cells, and this neurotrophic activity was partially inhibited by anti-NGF blocking antibodies. In conclusion, infiltration by nerve fibers is a feature of the tumor microenvironment that is associated with aggressiveness and involves NGF production by cancer cells. The potential participation of nerve fibers in breast cancer progression needs to be further considered.
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia.
authors.forename: Jay
authors.initials: J
authors.lastname: Pundavela
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia.
authors.forename: Severine
authors.initials: S
authors.lastname: Roselli
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia.
authors.forename: Sam
authors.initials: S
authors.lastname: Faulkner
authors.affiliation: Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia; School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Attia
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia.
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Scott
authors.affiliation: Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia.
authors.forename: Rick F
authors.initials: RF
authors.lastname: Thorne
authors.affiliation: Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia; School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Forbes
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Bradshaw
authors.affiliation: Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia; School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia.
authors.forename: Marjorie M
authors.initials: MM
authors.lastname: Walker
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia.
authors.forename: Phillip
authors.initials: P
authors.lastname: Jobling
authors.affiliation: School of Biomedical Sciences and Pharmacy, Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, New Lambton Heights, NSW 2305, Australia. Electronic address: hubert.hondermarck@newcastle.edu.au.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hondermarck
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000378:metabolism / Q000473:pathology; D018275:Carcinoma, Lobular / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D061986:MCF-7 Cells; D008875:Middle Aged; D009412:Nerve Fibers / Q000473:pathology / Q000502:physiology*; D009414:Nerve Growth Factors / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D059016:Tumor Microenvironment
chemical_list: D009414:Nerve Growth Factors
keywords: Breast cancer; Nerve fibers (axons); Nerve growth factor; Tumor microenvironment