A protective effect after clearance of orthotopic rat hepatocellular carcinoma by nanosecond pulsed electric fields

• Published in: European journal of cancer (1990) Vol. 50; no. 15; pp. 2705 - 2713
• Main Authors: Chen, Ru, Sain, Nova M, Harlow, K. Tyler, Chen, Yeong-Jer, Shires, Peter K, Heller, Richard, Beebe, Stephen J
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Ltd 01.10.2014; Elsevier
• Subjects: Absence of recurrence; Animals; Apoptosis; Biological and medical sciences; Cancer ablation; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Carcinoma, Hepatocellular - therapy; Caspase 3 - metabolism; Caspase 9 - metabolism; Cell Line, Tumor; Disease Models, Animal; Electroporation; Granzyme B; Granzymes - metabolism; Hematology, Oncology and Palliative Medicine; Hepatocellular carcinoma; Humans; Immunity; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver Neoplasms - therapy; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Nanosecond pulsed electric fields; Non-thermal; Orthotopic model; Pharmacology. Drug treatments; Protective Factors; Pulsed Radiofrequency Treatment - methods; Rats, Sprague-Dawley; T-Lymphocytes - metabolism; Time Factors; Treatment Outcome; Tumors; Granzyme B; Non-thermal; Orthotopic model; Absence of recurrence; Hepatocellular carcinoma; Electroporation; Cancer ablation; Nanosecond pulsed electric fields; Immunity; Apoptosis; Relapse; Rat; Protective factor; Hepatic disease; Clearance; Liver cancer; Cancerology; Pulsed field; Protection; Orthotopic; Serine endopeptidases; Enzyme; Rodentia; Malignant tumor; Ablation; Peptidases; Vertebrata; Mammalia; Electric field; Cell death; Animal; Hydrolases; Digestive diseases; Models; Cancer
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2014.07.006

Abstract Strategies for treating liver cancer using radiation, chemotherapy combinations and tyrosine kinase inhibitors targeting specific mutations have provided longer survival times, yet multiple treatments are often needed and recurrences with new malignant phenotypes are not uncommon. New and innovative treatments are undoubtedly needed to successfully treat liver cancer. Over the last decade, nanosecond pulsed electric fields (nsPEFs) have shown promise in pre-clinical studies; however, these have been limited to treatment of skin cancers or xenographs in mice. In the present report, an orthotopic hepatocellular carcinoma (HCC) model is established in rats using N1-S1 HCC cells. Data demonstrate a response rate of 80–90% when 1000 pulses are delivered with 100 ns durations, electric field strengths of 50 kV/cm and repetition rates of 1 Hz. N1-S1 tumours treated with nsPEFs expressed significant number of cells with active caspase-3 and caspase-9, but not caspase-8, indicating an intrinsic apoptosis mechanism(s) as well as caspase-independent mechanisms. Most remarkably, rats with successfully ablated tumours failed to re-grow tumours when challenged with a second injection of N1-S1 cells when implanted in the same or different liver lobe that harboured the original tumour. Given this protective effect, infiltration of immune cells and the presence of granzyme B expressing cells within days of treatment suggest the possibility of an anti-tumour adaptive immune response. In conclusion, NsPEFs not only eliminate N1-S1 HCC tumours, but also may induce an immuno-protective effect that defends animals against recurrences of the same cancer.