New study identifies trigger that turns dormant cancer stem cells into active ones

A new study released in STEM CELLS identifies, for the first time, two morphologically and functionally different types of cancer stem cells found in cervical cancer. Of the two types, one exhibits an overexpression of cPLA2α, a key enzyme that triggers the transformation of dormant cancer stem cells into active ones, resulting in cervical cancer metastasis and recurrence. The information in this study could lead to new targets for treatments to halt tumour recurrence and metastatic spread. Also, it might accelerate the development of combination therapies.

The current standard of treatments for cervical cancer – the second leading cause of cancer death in young women worldwide — is radiotherapy and chemotherapy. However, the cancer’s resistance to chemotherapy and radiation, combined with a tendency to metastasis in the lymph nodes or recur in the pelvis, leaves doctors searching for more effective treatments.

Cervical cancer stem cells (CCSCs) are considered the major culprit behind the cancer’s ability to overcome these treatments. At the same time, a majority of cancer stem-like cells or tumour-initiating cells remain dormant. It takes a change in their microenvironment to spur them to metastasize.

“The mechanisms responsible for this must be identified to design more suitable therapies for the different subpopulations of cancer stem cells (CSCs) in various tissue-specific cancers,” said Hua Guo, PhD, who headed up the investigation along with Yuchao He, PhD. The two are from Tianjin Medical University Cancer Institute and Hospital. Researchers at Tianjin University of Traditional Chinese Medicine and at the Center for Translational Cancer Research, Peking University First Hospital, also participated in the study.

Although several cell surface antigens have been identified in CCSCs, these markers vary among tumours because of CSC heterogeneity. However, whether these markers specifically distinguish CCSCs with different functions is unclear. The study published in STEM CELLS sought to resolve this question. And in fact, its findings demonstrate that CCSCs exist in two biologically distinct phenotypes, characterised by different levels of cPLA2α expression.

“Our study showed for the first time that overexpression of cPLA2α results in a phenotype associated with mesenchymal traits, including increased invasive and migration abilities. On the other hand, CCSCs with cPLA2α downregulation show dormant epithelial characteristics,” said Dr Guo. “In addition, cPLA2α regulates the reversible transition between mesenchymal and epithelial CCSC states through PKCζ, an atypical protein that governs cancer cell state changes.”

Dr He added, “Now that we know cPLA2α triggers this transformation, we believe that cPLA2α might be an attractive therapeutic target for eradicating different states of CCSCs to eliminate tumours more effectively.”

“The novel study by Dr Guo and team is of very high importance in understanding the transition between dormant cancer stem cells, which evade chemotherapy and radiation treatments, and actively dividing cells which can be better targeted, said Dr Jan Nolta, Editor-in-Chief, STEM CELLS. “I applaud the group for this important discovery which will help researchers develop better treatments for cervical cancer.”