Stem cells, quiescence and rectal carcinoma: an unexplored relationship and potential therapeutic target

Abstract

Stem cells are responsible for maintaining differentiated cell numbers during normal physiology and at times of tissue stress. They have the unique capabilities of proliferation, self-renewal, clonogenicity and multi-potentiality. It is a widely held belief that stem-like cells, known as cancer stem cells (CSCs), maintain tumours. The majority of currently identified intestinal stem cell populations appear to be rapidly cycling. However, quiescent stem cell populations have been suggested to exist in both normal intestinal crypts and tumours. Quiescent CSCs may have particular significance in the modern management of colorectal cancer making their identification and characterisation a priority. In this review, we discuss the current evidence surrounding the identification and microenvironmental control of stem cell populations in intestinal crypts and tumours as well as exploring the evidence supporting the existence of a quiescent stem and CSC population in the gut and other tissues.

Figure 1

The CSC hypothesis and disease recurrence. CSCs are responsible for driving tumour growth. If CSCs rather than other malignant cells evade chemotherapy, then they can be responsible for re-establishing the tumour, clinically presenting as local recurrence or metastatic disease.

Figure 2

Label retaining cell studies. C=cycling cell; Q=quiescent cell. All cells are labelled with a nucleotide analogue or fluorescent reporter protein at T0. Cells that are cycling will subsequently divide thus diluting out the label. Quiescent cells retain the label enabling their isolation from the main population via FACS (fluorescence-activated cell sorting) or identification microscopically in tissue sections.

Figure 3

Functional arrangement of cells within small intestinal crypts. Crypts are glandular monolayer epithelial invaginations in the intestinal wall from which differentiated cells arise. In the small intestine, immunological terminally differentiated Paneth cells (red) reside in the crypt base. Interspersed between the Paneth cells are found intercalated crypt base cells (green), which are marked by Lgr5 and have been shown to be homeostatic stem cells. Above the Paneth and stem cell zone, in the +4 position, is found the location where the majority of label retaining cells (yellow) reside. Above this is known as the transit amplifying zone (brown) through which cells migrate and terminally differentiate on their way to the upper crypt (blue) and eventually the villus.