title: Cerebrospinal fluid protein dynamic driver network: At the crossroads of brain tumorigenesis.
abstract: To get a better understanding of the ongoing in situ environmental changes preceding the brain tumorigenesis, we assessed cerebrospinal fluid (CSF) proteome profile changes in a glioma rat model in which brain tumor invariably developed after a single in utero exposure to the neurocarcinogen ethylnitrosourea (ENU). Computationally, the CSF proteome profile dynamics during the tumorigenesis can be modeled as non-smooth or even abrupt state changes. Such brain tumor environment transition analysis, correlating the CSF composition changes with the development of early cellular hyperplasia, can reveal the pathogenesis process at network level during a time before the image detection of the tumors. In our controlled rat model study, matched ENU- and saline-exposed rats' CSF proteomics changes were quantified at approximately 30, 60, 90, 120, 150 days of age (P30, P60, P90, P120, P150). We applied our transition-based network entropy (TNE) method to compute the CSF proteome changes in the ENU rat model and test the hypothesis of the critical transition state prior to impending hyperplasia. Our analysis identified a dynamic driver network (DDN) of CSF proteins related with the emerging tumorigenesis progressing from the non-hyperplasia state. The DDN associated leading network CSF proteins can allow the early detection of such dynamics before the catastrophic shift to the clear clinical landmarks in gliomas. Future characterization of the critical transition state (P60) during the brain tumor progression may reveal the underlying pathophysiology to device novel therapeutics preventing tumor formation. More detailed method and information are accessible through our website at http://translationalmedicine.stanford.edu.
authors.affiliation: Hangzhou Normal University, Zhejiang 311121, China; Stanford University, Stanford, CA 94305, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Stanford University, Stanford, CA 94305, USA; South China University of Technology, Guangzhou 510640, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.affiliation: Stanford University, Stanford, CA 94305, USA; Tsinghua University, Beijing 100084, China.
authors.forename: Le
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Stanford University, Stanford, CA 94305, USA.
authors.forename: Shiying
authors.initials: S
authors.lastname: Hao
authors.affiliation: Stanford University, Stanford, CA 94305, USA; Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Changlin
authors.initials: C
authors.lastname: Fu
authors.affiliation: Stanford University, Stanford, CA 94305, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Stanford University, Stanford, CA 94305, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Deng
authors.affiliation: Stanford University, Stanford, CA 94305, USA.
authors.forename: Taichang
authors.initials: T
authors.lastname: Jang
authors.affiliation: Stanford University, Stanford, CA 94305, USA.
authors.forename: Milton
authors.initials: M
authors.lastname: Merchant
authors.affiliation: Stanford University, Stanford, CA 94305, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Whitin
authors.affiliation: Shanghai Jiao Tong University, Shanghai 200240, China.
authors.forename: Minyi
authors.initials: M
authors.lastname: Guo
authors.affiliation: Stanford University, Stanford, CA 94305, USA.
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Cohen
authors.affiliation: Stanford University, Stanford, CA 94305, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Recht
authors.affiliation: Stanford University, Stanford, CA 94305, USA. Electronic address: bxling@stanford.edu.
authors.forename: Xuefeng B
authors.initials: XB
authors.lastname: Ling
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000134:cerebrospinal fluid* / Q000139:chemically induced / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D002556:Cerebrospinal Fluid Proteins / Q000096:biosynthesis*; D005038:Ethylnitrosourea / Q000633:toxicity; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000134:cerebrospinal fluid* / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D009374:Neoplasms, Experimental / Q000134:cerebrospinal fluid* / Q000139:chemically induced; D020543:Proteome / Q000235:genetics; D051381:Rats
chemical_list: D002556:Cerebrospinal Fluid Proteins; D020543:Proteome; D005038:Ethylnitrosourea
keywords: Critical transition; Dynamical driver network (DDN); Network entropy; Transition state; Tumorigenesis progressing