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

Background: The presence of circulating tumor cells (CTCs) in the peripheral blood is a prerequisite for the formation of distant metastases. Transforming growth factor-beta eta (TGF-beta) 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-beta and CXCL1 are predictors of CTC seeding in preferential distant sites in patients with metastatic breast cancer. Materials and 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-beta 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-beta and CXCL1 are predictive for the detection of CTCs. In particular, patients with CK3(+) CTCs and plasma concentrations of TGF-beta and CXCL1 higher than the median value had a poor prognosis in comparison to patients with CK1(+/-) CTCs and TGF-beta and CXCL1 concentrations below the median value. Conclusion: Our study shows that elevated circulating levels of TGF-beta 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.