Mobilization of tumor cells and hematopoietic progenitor cells into peripheral blood of patients with solid tumors [see comments]

Abstract

Peripheral blood progenitor cells (PBPCs) are increasingly used for autografting after high-dose chemotherapy. One advantage of PBPCs over the use of autologous bone marrow would be a reduced risk of tumor-cell contamination. However, the actual level of tumor cells contaminating PBPC harvests is poorly investigated. It is currently not known whether mobilization of PBPCs might also result in mobilization of tumor cells. We evaluated 358 peripheral blood samples from 46 patients with stage IV or high-risk stage II/III breast cancer, small cell (SCLC) or non- small cell (NSCLC) lung cancer, as well as other advanced malignancies for the detection of epithelial tumor cells. Monoclonal antibodies against acidic and basic cytokeratin components and epithelial antigens (HEA) were used in an alkaline phosphatase-anti-alkaline phosphatase assay with a sensitivity of 1 tumor cell within 4 x 10(5) total cells. Before initiation of PBPC mobilization, circulating tumor cells were detected in 2/7 (29%) patients with stage IV breast cancer and in 2/10 (20%) patients with extensive-disease SCLC, respectively. In these patients, an even higher number of circulating tumor cells was detected after chemotherapy with VP16, ifosfamide, and cisplatin (VIP) followed by granulocyte colony-stimulating factor (G-CSF). This approach has previously been shown to be highly effective in mobilizing PBPCs. In the 42 patients without circulating tumor cells during steady state, tumor cells were mobilized in 9/42 (21%) patients after VIP+G-CSF induced recruitment of PBPCs. The overall incidence of tumor cells varied between 4 and 5,600 per 1.6 x 10(6) mononuclear cells analyzed. All stage IV breast cancer patients and 50% of SCLC patients were found to concomitantly mobilize tumor cells and PBPCs. Kinetic analyses showed two patterns of tumor cell recruitment depending on the presence or absence of bone marrow disease: (1) early after chemotherapy (between days 1 and 7) in patients without marrow infiltration, and (2) between days 9 and 16 in patients with marrow infiltration, ie, within the optimal time period for the collection of PBPCs. We show that there is a high proportion of patients with circulating tumor cells under steady-state conditions, and in addition a substantial risk of concomitant tumor cell recruitment upon mobilization of PBPCs, particularly in stage IV breast cancer patients with bone marrow infiltration. The biologic and clinical significance of this finding is unknown at present.

Clinical and Biological Aspects of Disseminated Tumor Cells and Dormancy in Breast Cancer

“…Beyond lack of efficacy, patient data and experimental models revealed that cytotoxic chemotherapy also has paradoxical effects on tumor relapse, promoting metastasis by enhancing vascular permeability and activation of inflammatory pathways, facilitating intra- and extravasation of cancer cells and promoting tumor dormancy ( D'Alterio et al, 2020 ; Shiozawa et al, 2011 ; Brugger et al, 1994 ; Kurppa et al, 2020 ). A series of preclinical studies indicated that antiangiogenic therapies (e.g., targeting VEGFR) can enhance metastasis, potentially by the induction of hypoxic conditions ( Ebos et al, 2009 ; Pàez-Ribes et al, 2009 ).…”

“…Direct evidence for pro-metastatic effects in humans and clinical scenarios is scarce and challenging to demonstrate conclusively. Nevertheless, indirect yet provocative data exists suggesting, for example, that patients receiving cyclophosphamide, taxanes, epirubicine, 5-fluoroacil exhibit suppressed expression levels of miR-488, an inhibitor of epithelial to mesenchymal transition (EMT) ( Li et al, 2011 ) and that CTC numbers as a surrogate for metastatic spread increase post chemotherapy ( Brugger et al, 1994 ). Together, these results highlight the need for a careful examination of risks versus benefits for standard cancer treatments as well as the need to identify the suitable response biomarkers.…”