title: The presence of clustered circulating tumor cells (CTCs) and circulating cytokines define an aggressive phenotype in metastatic colorectal cancer.
abstract: OBJECTIVE
  Colon carcinoma is a malignant tumor showing a marked preference to metastasize to distant organs. The presence of circulating tumor cells (CTCs) in the peripheral blood is a prerequisite for the formation of distant metastases. However, whether circulating cytokines are linked to the circulation of tumor cells, as individual cells or clusters, remain unclear. In this study, we investigated the circulating levels of TGF-beta, CXCL1, VEGF and PAI-1 as potential bioindicators of the presence of CTCs in patients with metastatic colon cancer.
  
  
  METHODS
  Circulating tumor cells (CTCs) were isolated from peripheral blood by immunomagnetic separation and phenotypically characterized in a cohort of 103 patients with metastatic colon cancer. TGF-beta, CXCL1, VEGF and PAI-1 concentrations were determined by immunoassay in plasma samples from the same patients.
  
  
  RESULTS
  We detected two different populations of CTCs, single cells or clusters in patients with metastatic colon cancer. Importantly, we found that the presence of clustered CTCs is significantly associated with elevated circulating levels of TGF-beta and CXCL1 and with reduced overall survival. Finally, we observed that circulating levels of cytokines are differently associated with the two populations of CTCs.
  
  
  CONCLUSIONS
  Taken together, these findings show that detection of clustered CTCs represents a negative prognostic factor in patients with metastatic colon cancer. The presence of clustered CTCs is associated with elevated circulating levels of cytokines such as TGF-beta and CXCL1. This suggests an additional role for circulating cytokines as predictive tool for cancer prognosis and diagnosis of minimal residual disease as well as assessment of tumor sensitivity to anticancer therapy.
authors.affiliation: Clinical Pathology Laboratory, Department of Experimantal Oncology, National Cancer Institute, Istituto Tumori Giovanni Paolo II, Viale Orazio Flacco, 65, 70100, 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: Ines
authors.initials: I
authors.lastname: Abbate
authors.forename: Antonia
authors.initials: A
authors.lastname: Bellizzi
authors.forename: Eufemia
authors.initials: E
authors.lastname: Savino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Simone
authors.forename: Grazia
authors.initials: G
authors.lastname: Giannone
authors.forename: Francesco
authors.initials: F
authors.lastname: Giuliani
authors.forename: Vito
authors.initials: V
authors.lastname: Fazio
authors.forename: Gennaro
authors.initials: G
authors.lastname: Gadaleta-Caldarola
authors.forename: Cosimo Damiano
authors.initials: CD
authors.lastname: Gadaleta
authors.forename: Ivan
authors.initials: I
authors.lastname: Lolli
authors.forename: Carlo
authors.initials: C
authors.lastname: Sabbà
authors.forename: Antonio
authors.initials: A
authors.lastname: Mazzocca
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D054360:Chemokine CXCL1 / Q000097:blood; D015179:Colorectal Neoplasms / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000401:mortality* / Q000473:pathology; D016207:Cytokines / Q000097:blood; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009360:Neoplastic Cells, Circulating / Q000473:pathology*; D010641:Phenotype; D011379:Prognosis; D016212:Transforming Growth Factor beta / Q000097:blood
chemical_list: D014408:Biomarkers, Tumor; C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D016207:Cytokines; D016212:Transforming Growth Factor beta