Hypoxia After Liver Surgery Imposes an Aggressive Cancer Stem Cell Phenotype on Residual Tumor Cells

Abstract

Surgery-generated hypoxia in the liver causes rapid dedifferentiation of tumor cells into immature CSCs with high clone- and metastasis-forming capacity. The results help explain the phenomenon of aggressive local tumor recurrence after liver surgery and offer a potential strategy to kill aggressive CSCs by hypoxia-activated prodrugs.

Maintenance of Clonogenic KIT+ Human Colon Tumor Cells Requires Secretion of Stem Cell Factor by Differentiated Tumor Cells

“…It induces de-differentiation of metastatic colorectal tumor cells and causes them to adopt an aggressive stem-like phenotype 9,27 . The present report shows that SCF/KIT signaling is an integral part of hypoxia-induced de-differentiation and increased aggressiveness in colorectal cancer.…”

“…ISCK03 or the SCF-neutralizing antibody also abrogated hypoxia-induced colony forming potential ( Figure 7B). To study the relationship between hypoxia and KIT expression in vivo, colonosphere-induced liver tumors were exposed to a vascular clamping protocol to induce hypoxia and a stem-like tumor cell phenotype 9 . RT-qPCR analysis revealed high KIT expression in tumors isolated from the clamped liver lobes along with markers of hypoxia (HK2, HIF1A) and EMT (increased ZEB1, SNAI1, CDH2) ( Figure 7C).…”

“…For instance, the tumor-initiating/stem-like cell phenotype can be installed by hepatocyte growth factor produced by stromal fibroblasts 7 or by Notch ligand produced by endothelial cells 8 . In addition, we have recently shown that hypoxia is a major inducer of the stem-like clonogenic phenotype of colorectal tumors in vitro and in vivo 9 .…”

Matrix stiffness-mediated effects on stemness characteristics occurring in HCC cells

“…Hypoxia can induce stem cell markers such as octamer-binding transcription factor 4 (OCT4), NANOG, SOX2, kruppel-like factor 4 (KLF4), c-MYC, and microRNA-302 in 11 cancer cell lines including HCC cells through hypoxia-inducible factor (HIF) [57]. Low oxygen level after liver surgery may cause rapid loss of differentiation markers of tumor cells and increase the expression of CSC markers and the clone-forming capacity [58]. Interleukin-6 (IL-6)/STAT3 signaling upregulate the expression of CD133 in HCC cells and promote HCC progression [59].…”

Cancer stem cells and their vascular niche: Do they benefit from each other?

“…A more hypoxic microenvironment induced by vessel regression is believed to be the important cause of a switch to a more invasive program [61,63]. Further, hypoxia leads to enrichment of CSCs, with a more invasive phenotype [64]. Thus, how to prune excessive vessels but not aggravate hypoxia should be taken into account in exploring new anti-angiogenic strategy.…”