title: Circulating levels of transforming growth factor-βeta (TGF-β) and chemokine (C-X-C motif) ligand-1 (CXCL1) as predictors of distant seeding of circulating tumor cells in patients with metastatic breast cancer.
abstract: BACKGROUND
  The presence of circulating tumor cells (CTCs) in the peripheral blood is a prerequisite for the formation of distant metastases. Transforming growth factor-βeta (TGF-β) and Chemokine (C-X-C Motif) Ligand-1 (CXCL1) are cytokines involved in the colonization of distant sites by CTCs in several pre-clinical animal models. However, their role is poorly-investigated in patients with metastatic cancer. Here, we investigated whether circulating levels of TGF-β and CXCL1 are predictors of CTC seeding in preferential distant sites in patients with metastatic breast cancer.
  
  
  METHODS
  CTCs were isolated from the peripheral blood of 61 patients with metastatic breast cancer by immunomagnetic separation. Plasma samples were collected from the same patients and assayed for TGF-β and CXCL1 by enzyme-linked immunoassay.
  
  
  RESULTS
  Patients were grouped in CK1+/- (N<10), CK2+ (N ≥ 10<50) and CK3+ (N ≥ 50), according to the number (N) of cytokeratin 7/8-positive CTCs: the highest number of CK7/8-positive CTCs was detected in patients with negative Human epidermal growth factor receptor-2 (HER-2/NEU) status (p<0.0001) antigen, identified by the monoclonal antibody Ki-67 (Ki-67) ≥ 15% (p=0.003), Carcinoma antigen 15-3 (CA-15.3) ≥ 40 U/ml (p=0.004) and those with lung metastases (p=0.01). We found that elevated plasma concentrations of TGF-β and CXCL1 are predictive for the detection of CTCs. In particular, patients with CK3+ CTCs and plasma concentrations of TGF-β and CXCL1 higher than the median value had a poor prognosis in comparison to patients with CK1+/- CTCs and TGF-β and CXCL1 concentrations below the median value.
  
  
  CONCLUSIONS
  Our study shows that elevated circulating levels of TGF-β and CXCL1 are associated with a poor prognosis, and higher detection of CTCs and propensity of these cells to seed lung metastases in patients with breast cancer.
authors.affiliation: Clinical Pathology Laboratory, Department of Experimental Oncology, National Cancer Institute Giovanni Paolo II, Bari, Italy. rosadive@inwind.it
authors.forename: Rosa
authors.initials: R
authors.lastname: Divella
authors.forename: Antonella
authors.initials: A
authors.lastname: Daniele
authors.forename: Eufemia
authors.initials: E
authors.lastname: Savino
authors.forename: Fabiola
authors.initials: F
authors.lastname: Palma
authors.forename: Antonia
authors.initials: A
authors.lastname: Bellizzi
authors.forename: Francesco
authors.initials: F
authors.lastname: Giotta
authors.forename: Giovanni
authors.initials: G
authors.lastname: Simone
authors.forename: Marco
authors.initials: M
authors.lastname: Lioce
authors.forename: Michele
authors.initials: M
authors.lastname: Quaranta
authors.forename: Angelo
authors.initials: A
authors.lastname: Paradiso
authors.forename: Antonio
authors.initials: A
authors.lastname: Mazzocca
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D001859:Bone Neoplasms / Q000097:blood / Q000401:mortality / Q000556:secondary*; D001943:Breast Neoplasms / Q000097:blood / Q000401:mortality / Q000473:pathology*; D054360:Chemokine CXCL1 / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000401:mortality / Q000556:secondary*; D008875:Middle Aged; D009367:Neoplasm Staging; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D011379:Prognosis; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000097:blood*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D016212:Transforming Growth Factor beta