Research reveals 'seeds' of liver cancer recurrence

Patients with liver cancer eventually develop resistance to chemotherapy—the Achilles’ heel of cancer treatment. Now researchers have identified how this resistance occurs in liver cancer. Reversing it would restore chemotherapy’s ability to treat the disease, the researchers reported in the January 12, 2016 issue of the journal Cell Metabolism.

“There are bad seeds in cancer,” said the study’s senior author Keigo Machida, PhD, Associate Professor of Molecular Microbiology and Immunology at the University of Southern California’s Keck School of Medicine, in Los Angeles, CA. “Even though we treat patients with chemotherapy, those bad seeds survive and force relapse. That’s why we would like to target the bad seeds in cancer to eradicate recurrence problems and metastasis.”

The bad seeds in liver cancer, the researchers found, are the stem cell marker NANOG along with the highly malignant tumor-initiating stem-like cells (TICs).

In this study, which involved patient-derived stem cells and hundreds of mice with liver tumors, the researchers determined that NANOG reprograms mitochondrial metabolism, which spurs TICs to be self-renewing, tumorigenic, and resistant to chemotherapy. Specifically, NANOG uses oxidative phosphorylation and fatty acid oxidation as oncogenic pathways. This finding, the researchers said, is the “Achilles’ heel” in cancer therapy.

Yet, this discovery also makes NANOG a prime therapeutic target. “If you reduce the cellular response to mitochondrial oxidative phosphorylation/fatty acid oxidation molecules, NANOG will not be able to promote cancer progression,” said study co-author Vasu Punj, PhD, Lead Bioinformatician at the USC Epigenome Center.

Dr. Machida added, “If we shut down this alternative pathway, the liver cancer will become sensitized to chemotherapy again.”

He envisions a novel treatment that would target NANOG and eliminate TICs: “In the future, we might be able to give liver cancer patients a shot that will infuse NANOG-targeted therapy into the bloodstream. Wherever blood circulates, we will be able to deliver new instructions to the bad seeds of cancer.”

That would be a timely intervention because hepatocellular carcinoma, the world’s third-deadliest cancer, is on the rise. The 5-year survival rate is only about 17%, and an estimated 24,550 Americans died of the disease in 2015, according to the National Cancer Institute.