Date Published: April 15, 2019
Publisher: Public Library of Science
Author(s): Chisato Sumi, Yoshiyuki Matsuo, Munenori Kusunoki, Tomohiro Shoji, Takeo Uba, Teppei Iwai, Hidemasa Bono, Kiichi Hirota, Ferenc Gallyas.
The possibility that anesthesia during cancer surgery may affect cancer recurrence, metastasis, and patient prognosis has become one of the most important topics of interest in cancer treatment. For example, the volatile anesthetic isoflurane was reported in several studies to induce hypoxia-inducible factors, and thereby enhance malignant phenotypes in vitro. Indeed, these transcription factors are considered critical regulators of cancer-related hallmarks, including “sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, angiogenesis, invasion, and metastasis.” This study aimed to investigate the impact of isoflurane on the growth and migration of derivatives of the renal cell line RCC4. We indicated that isoflurane treatment did not positively influence cancer cell phenotypes, and that hypoxia-inducible factors (HIFs) maintain hallmark cancer cell phenotypes including gene expressions signature, metabolism, cell proliferation and cell motility. The present results indicate that HIF activity is not influenced by the volatile anesthetic isoflurane.
The hypothesis that anesthesia during cancer surgery may affect tumor recurrence, metastasis, and patient prognosis [1, 2] is gaining currently increasing importance . Accordingly, numerous recent in vitro, in vivo, retrospective, and translational studies have investigated the effect of anesthetics on perioperative immunity and cancer metastatic potential. For example, isoflurane was reported in several studies to induce hypoxia-inducible transcription factors (HIFs), and thereby enhance malignant phenotypes in vitro [4–6]. HIF-1 was originally cloned as a driver of erythropoietin expression [7–10]; however, shortly thereafter, it was reportedly associated with the tumor grade in various cancers . Indeed, HIFs are now well-known as critical regulators of cancer hallmarks, including “sustained proliferative signaling, evasion of growth suppressors, resistance to cell death, replicative immortality, angiogenesis, invasion, and metastasis” [12, 13]. Moreover, tumor suppressors such as TP53 and PTEN regulate HIFs. Another striking example of the physiological significance of HIFs is von Hippel-Lindau (VHL) disease, a hereditary cancer syndrome predisposing individuals to highly angiogenic tumors, wherein the constitutive overexpression of vascular endothelial growth factor and glucose transporter 1 can be rectified corrected by functional VHL protein, a tumor suppressor that targets HIFs for degradation. This study aimed to investigate the effect of the volatile anesthetic isoflurane on growth and migration of derivatives of the renal cell line RCC4 that express (RCC-VHL) or do not express (RCC4-EV) VHL . The present results indicate that HIFs significantly influence cancer cell growth and migration; however, isoflurane does not affect HIF-dependent phenotypes.
This study shows that transcription factor HIFs maintain hallmarks of cancer cell phenotypes including gene expression signatures, metabolism, cell proliferation, and cell motility, and HIF activity is not influenced by the volatile anesthetic isoflurane.