A research team from Yonsei University College of Medicine has discovered the survival mechanism of cancer stem cells and a corresponding anticancer drug combination that can kill them, Severance said Tuesday.

Stem cells, which can repeat the process of growth and regeneration, are found in tissues in the body, including in cancer tissues. Up to 2 percent of cancer tissues are comprised of cancer stem cells that can regenerate and differentiate into other cells. Cancer stem cells, which often exhibit strong resistance to anticancer drugs and conventional chemotherapy, are the cause of cancer recurrence and metastasis, according to Severance.

The team led by Professors Cheong Jae-ho and Park Ki-cheong found how cancer stem cells survive extreme pressure applied by anticancer drugs while also discovering the primary cause of cancer drug resistance to be their ability to increase the amount of the protein called sarco/endoplasmic reticulum Ca2+-ATPase (SERCA). SERCA is involved in transporting and storing intercellular calcium ions.

Anticancer drugs kill cancer cells by applying extreme stress. The cancer cell dies after an excess amount of calcium ions secreted from the endoplasmic reticulum accumulate in the mitochondria.

The research showed cancer stem cells survived the stress by reducing excessive calcium ion secretion while simultaneously controlling calcium ion concentration by increasing the number of SERCA proteins that have the ability to return the excess amount of calcium ions to the endoplasmic reticulum.

Based on the observed survival principle, the research team studied the effect of a SERCA inhibitor called Thapsigargin along with Metformin and 2-deoxyglucose (2DG). Findings from animal experiments showed that administering a 2DG, Metformin and Thapsigargin combination marked a slower growth of cancer stem cell tumors compared to a 2DG and Metformin combo.

In the 2DG and Metformin arm, the cancer stem cell tumor, which is around 200 cubic millimeters on average, increased to about 525 mm³ after 20 days, 1,082 mm³ after 30 days, and 2,963 mm³ after 40 days. The tumor in the 2DG, Metformin, and Thapsigargin arm showed much more limited growth with the tumor increasing to around 372 mm³ after 20 days, 489 mm³ after 30 days, and 520 mm³ after 40 days.

The results of the study have been patented and used in a technology transfer to develop anticancer drugs, Severance said, noting that it may speed up the development of therapeutic agents for patients with refractory cancer. The results of the study can be applied to not only cancer stem cells but also to other intractable cancers that display resistance to anticancer drugs, the hospital said.

"This study has enabled us to gain an in-depth understanding of adaptation mechanisms to artificial stressors such as anticancer drugs and environmental stress, allowing us to provide experimental evidence for treating cancer stem cells,” Professor Cheong said. “We will open a new chapter in chemotherapy that targets cancer stem cells by clarifying in detail the survival mechanisms.”

The results of the study were published in the online edition of Clinical Cancer Research.