Circulating Tumor Cells Enumeration from the Portal Vein for Risk Stratification in Early Pancreatic Cancer Patients

Abstract

Background. Effective biomarkers are needed to enable personalized medicine for pancreatic cancer patients. This study analyzes the prognostic value, in early pancreatic cancer, of single circulating tumor cell (CTC) and CTC clusters from the central venous catheter (CVC) and portal blood (PV). Methods. In total, 7 mL of PV and CVC blood from 35 patients with early pancreatic cancer were analyzed. CTC were isolated using a positive immunomagnetic selection. The detection and identification of CTC were performed by immunocytochemistry (ICC) and were analyzed by Epi-fluorescence and confocal microscopy. Results. CTC and the clusters were detected both in PV and CVC. In both samples, the CTC number per cluster was higher in patients with grade three or poorly differentiated tumors (G3) than in patients with well (G1) or moderately (G2) differentiated. Patients with fewer than 185 CTC in PV exhibited a longer OS than patients with more than 185 CTC (24.5 vs. 10.0 months; p = 0.018). Similarly, patients with fewer than 15 clusters in PV showed a longer OS than patients with more than 15 clusters (19 vs. 10 months; p = 0.004). These significant correlations were not observed in CVC analyses. Conclusions. CTC presence in PV could be an important prognostic factor to predict poor prognosis in early pancreatic cancer. In addition, the number of clustered-CTC correlate to a tumor negative differentiation degree and, therefore, could be used as a diagnostic biomarker for pancreatic cancer.

Association of Adjuvant Chemotherapy in Patients With Resected Pancreatic Adenocarcinoma After Multiagent Neoadjuvant Chemotherapy

“…Within the context of this result, AC is recommended after NAC and resection regardless of node and margin status. Other studies also have provided scientific evidence supporting the results presented in this study. The subgroup with higher pathological T category or higher tumor differentiation grade, which showed significant associations with lower mortality by AC, has been reported to have more circulating tumor cells …”

Pancreatic Ductal Adenocarcinoma (PDAC) circulating tumor cells influence myeloid cell differentiation to support their survival and immunoresistance in portal vein circulation

“…In contrast, CTC released from tumors as pre-formed clusters, where CTC and myeloid cells are already aggregated together, may use GM-CSF to alter the function of the myeloid cells toward a more stromal-like role that promotes inflammation and prevents cytotoxic T cell-induced apoptosis in the portal microenvironment. Recent reports on CTC detection in multiple cancer types have suggested that the epithelial to mesenchymal transition phenotype of CTC may be indicative of further development of aggressive CTC subpopulations with high metastatic potential [ 9 , 42 – 47 ]. Using our FACS selection panels of CD44+CD147+EPCAM+/CK+CD45- for portal blood CTC in this and previous studies of PDAC CTC [ 7 , 11 ] we have collected both EPCAM+ and CK+ populations of CTC whenever possible but have routinely not examined the characteristics of EPCAM+CK- and EPCAM-CK+ subpopulations within the portal blood.…”

“…Addition of more selective markers as they are discovered could allow for better definition of the metastatic potential of individual CTC clones within the portal blood population. Interstitial biomarkers such as Twist and Vimentin have been found advantageous to detection of aggressive CTC in lung [ 45 , 47 ], breast [ 45 ], and recently, pancreatic cancers [ 42 – 46 ] in fluorescence immunohistochemical (IHC) staining and microscopy-based selection methods. Intracellular staining for vimentin has been suggested for distinguishing tumor cells from fibroblasts by IHC or flow cytometry.…”

“…[ 44 ] Since stable intracellular staining for flow cytometric and IHC analyses requires fixation of cells, we were unable to find a workable antibody conjugate reagent and permeabilization method to detect such interstitial biomarkers to incorporate into our live CTC FACS selection panel that would maintain viability of CTC for the ex vivo culture analyses used in these current studies. Development of such biomarkers for future viable cell studies could be a beneficial addition to further define the PDAC CTC subpopulations most likely to migrate out of the portal blood and metamorphosize into metastatic seeding clones [ 15 , 42 – 47 ].…”

Clinical implications and perspectives of portal venous circulating tumor cells in pancreatic cancer

“…The number of CTCs also did not differ between the two sampling sites in this study. A study by Padillo-Ruiz et al [ 38 ] also reported no differences between the portal and peripheral blood in terms of the detection rate (100% vs 100%) and number of CTCs (median 310 vs 405.7, P = 0.239). A comparison of the CTC detection rate and number between the portal vein and peripheral blood in patients with PC is summarized in Table 1 .…”