Colorectal cancer initiation and progression: the role of low oxygen levels in cancer cell survival

IBBL and the Luxembourg Institute of Health (LIH) supported the University of Luxembourg in unravelling the mechanisms by which low oxygen levels trigger a series of cellular changes leading to the survival, renewal and growth of colorectal cancer cells. The findings further reinforce current knowledge on the initiation and progression of the disease and may contribute to opening up new treatment avenues for patients.

Colorectal cancer (CRC) is one of the most common types of cancers globally, being responsible for about 600,000 deaths annually. Advances in the understanding of its initiation and development have been provided by the identification of a specific subtype of cancer cells that display tumour-initiating properties. These so-called tumour-initiating cells (TICs) or cancer stem cells (CSCs), which are also associated with cancer progression and increased resistance to anti-cancer drugs, are often located in low oxygen regions within the tumour. Indeed, this situation of hypoxia[1] has been shown to be associated with a more aggressive cancer behaviour, increased invasiveness, greater resistance to chemo- and radiotherapy, as well as an increased rate of tumor recurrence, consequently resulting in poor patient outcomes.

In this context, a team of researchers from the Life Sciences Research Unit (LSRU) of the University of Luxembourg — together with the Luxembourg Institute of Health (LIH), the Integrated Biobank of Luxembourg (IBBL), the Centre Hospitalier Emile Mayrisch (CHEM), the Laboratoire National de Santé (LNS) and the Luxembourg Centre for Systems Biomedicine (LCSB) — used patient-derived CRC cultures rich in TICs to elucidate the link between hypoxia, TICs and increased cancer malignancy. Namely, the team observed that hypoxia triggers the expression of a series of genes involved in the activation of autophagy in TICs. Autophagy is a cellular survival process triggered by stress conditions, such as starvation and low oxygen levels, that causes the ‘autodigestion’ of intracellular proteins and other components, which become an energy source to sustain cellular metabolism. The team also found that hypoxia-induced autophagy in turn induces specific modifications to a particular protein, ezrin (EZR), through the action of an intermediate protein (PRKCA). This modification ‘activates’ the EZR protein, which is known to be involved in cell survival, and therefore results in the increased resistance and self-renewal capacity of TICs, leading to metastatic tumour growth.

As part of the study, IBBL was involved in the set-up of the collection of colon tissue samples and in the immunohistochemical staining – from the optimisation of the antibodies to the staining and analysis of tissue slides. LIH performed microarray gene expression profiling experiments, while the Tumor Microenvironment (TIME) unit of the LIH Department of Oncology (DONC), headed by Dr. Bassam Janji, collaborated with the LSRU to understand the extent of autophagy in TICs under hypoxia.

“We are honoured to have contributed to this study. It represents a true example of multidisciplinary collaboration between all major players in the national biomedical research landscape and of high-impact research ‘made in Luxembourg’”, says Dr. Yervand Karapetyan, Pathologist at IBBL.

“Up until now, we knew that hypoxia and autophagy were associated with increased tumour malignancy, but the mechanisms and the exact correlation between these factors were still unclear. Our work provides an explanation to this research conundrum. We showed that TICs upregulate autophagy under low oxygen conditions to survive this stress, which in turn ‘switches on’ the EZR protein involved in their survival and growth”, explains Dr. Elisabeth Letellier, Principal Investigator in the Life Sciences Research Unit of the University of Luxembourg and corresponding author of the publication. “The study also suggests that this link between hypoxia, autophagy and EZR activation could be ‘broken’, either by genetically targeting the genes involved in triggering autophagy, or by pharmacologically inhibiting the PRKCA and EZR proteins. This would reduce the tumour-initiating action of TICs, slowing down its progression and thus potentially representing a promising therapeutic strategy for cancer patients”, she concludes.

The full publication is available here.

[1] A condition of inadequate oxygen availability at the tissue level, resulting from an imbalance between oxygen supply and consumption by diving cells.