title: The prognostic significance of CXCL1 hypersecretion by human colorectal cancer epithelia and myofibroblasts.
abstract: BACKGROUND
  Clinical therapy for metastatic colorectal cancer (CRC) remains limited, especially when the tumor harbors a KRAS mutation. This study aimed to identify prognostic biomarkers in CRC that are accessible for therapeutic inhibition.
  
  
  METHODS
  Conditioned media from human CRC epithelial cells and myofibroblasts were screened by cytokine arrays for tumorigenic factors. The protein and mRNA expressions of these factors were determined by immunohistochemistry and gene microarrays in human CRC tissues. Prognostic biomarkers were determined by correlation of mRNA expression to overall survival in stage IV CRC patients. Inhibition of CXCL1 was performed with specific neutralizing antibody and lentiviral shRNAs. Malignant growth was assessed by soft agar growth assays and xenograft tumor growth in immunocompromised mice.
  
  
  RESULTS
  CXCL1 was highly secreted by KRAS mutant human CRC cells and myofibroblasts in a complementary adaptive response to serum deprivation. Elevated CXCL1 level promoted anchorage-independent growth of murine fibroblasts and human CRC cells. Inhibition of CXCL1 by neutralizing antibody and specific shRNAs decreased CRC tumor growth. Highly elevated CXCL1 expression significantly correlated with decreased overall survival in stage IV CRC patients (hazard ratio 0.28; 95% CI 0.11-0.72).
  
  
  CONCLUSIONS
  High CXCL1 expression is a poor prognostic biomarker in metastatic CRC. CXCL1 inhibition suppressed tumorigenic growth of KRAS mutant CRC cells.
authors.affiliation: Division of Hematology/Oncology and Chao Family Comprehensive Cancer Center, Department of Medicine, University of California, 839 Health Sciences Road, Sprague Hall Office 116, Irvine, CA, 92697, USA. alerolle@uci.edu.
authors.forename: Anne-France
authors.initials: AF
authors.lastname: le Rolle
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA. thangchiu@yahoo.com.
authors.forename: Thang K
authors.initials: TK
authors.lastname: Chiu
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, NY, 10065, USA. michael.fara@gmail.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Fara
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA. shiaj@mskcc.org.
authors.forename: Jinru
authors.initials: J
authors.lastname: Shia
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA. zengz@mskcc.org.
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA. weiser1@mskcc.org.
authors.forename: Martin R
authors.initials: MR
authors.lastname: Weiser
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA. patyp@mskcc.org.
authors.forename: Philip B
authors.initials: PB
authors.lastname: Paty
authors.affiliation: Division of Hematology/Oncology and Chao Family Comprehensive Cancer Center, Department of Medicine, University of California, 839 Health Sciences Road, Sprague Hall Office 116, Irvine, CA, 92697, USA. vkchiu@uci.edu.
authors.forename: Vi K
authors.initials: VK
authors.lastname: Chiu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D041681:NIH 3T3 Cells; D009367:Neoplasm Staging; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D055815:Young Adult
chemical_list: C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D017077:Culture Media, Conditioned; D016209:Interleukin-8; D012333:RNA, Messenger