Abstract
Colorectal cancer stem cells have been proposed to drive disease progression, tumour recurrence and chemoresistance. However, studies ablating leucine rich repeat containing G protein-coupled receptor 5 (LGR5)-positive stem cells have shown that they are rapidly replenished in primary tumours. Following injury in normal tissue, LGR5+ stem cells are replaced by a newly defined, transient population of revival stem cells. We investigated whether markers of the revival stem cell population are present in colorectal tumours and how this signature relates to chemoresistance. We examined the expression of different stem cell markers in a cohort of patient-derived colorectal cancer organoids and correlated expression with sensitivity to 5-fluorouracil (5-FU) treatment. Our findings revealed that there was inter-tumour variability in the expression of stem cell markers. Clusterin (CLU), a marker of the revival stem cell population, was significantly enriched following 5-FU treatment and expression correlated with the level of drug resistance. Patient outcome data revealed that CLU expression is associated with both lower patient survival and an increase in disease recurrence. This suggests that CLU is a marker of drug resistance and may identify cells that drive colorectal cancer progression.
Highlights
Colorectal cancer (CRC) is the most frequently diagnosed cancer of the digestive tract and a principal cause of cancer-related deaths worldwide [1,2]
In order to determine whether CRC patient-derived colorectal cancer organoids (PDCOs) are robust models for examining the expression pattern of stem cell markers, we first compared the biological characteristics of primary tumours and their matched PDCOs
The histological profile of the primary tumour was generally well maintained in PDCOs, with organoids typically having a more cuboidal appearance, but present otherwise similar cellular morphology to the primary specimen
Summary
Colorectal cancer (CRC) is the most frequently diagnosed cancer of the digestive tract and a principal cause of cancer-related deaths worldwide [1,2]. The majority of deaths from CRC can be attributed to cancer recurrence after initial treatment, which presents as distant metastases in secondary sites such as the liver or lung. The 5 year survival rate of patients with metastatic. CRC can be as low as 5% [3,4]. Combined chemotherapy treatment, which includes the commonly used drug 5-fluorouracil (5-FU), can help to increase this survival rate [5,6]. Development of more targeted and personalised treatments are necessary to decrease overall CRC mortality [7]. Understanding the mechanisms underlying resistance to common treatments incorporating 5-FU is complex and requires further elucidation in models that recapitulate the diversity of primary tumours arising [8]
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