Field cancerisation in colorectal cancer: a new frontier or pastures past?

Abstract

Despite considerable advances in our understanding of cancer biology, early diagnosis of colorectal cancer remains elusive. Based on the adenoma-carcinoma sequence, cancer develops through the progressive accumulation of mutations in key genes that regulate cell growth. However, recent mathematical modelling suggests that some of these genetic events occur prior to the development of any discernible histological abnormality. Cells acquire pro-tumourigenic mutations that are not able to produce morphological change but predispose to cancer formation. These cells can grow to form large patches of mucosa from which a cancer arises. This process has been termed "field cancerisation". It has received little attention in the scientific literature until recently. Several studies have now demonstrated cellular, genetic and epigenetic alterations in the macroscopically normal mucosa of colorectal cancer patients. In some reports, these changes were effectively utilised to identify patients with a neoplastic lesion suggesting potential application in the clinical setting. In this article, we present the scientific evidence to support field cancerisation in colorectal cancer and discuss important limitations that require further investigation. Characterisation of the field defect is necessary to enable early diagnosis of colorectal cancer and identify molecular targets for chemoprevention. Field cancerisation offers a promising prospect for experimental cancer research and has potential to improve patient outcomes in the clinical setting.

Keywords: Biomarkers; Carcinogenesis; Colorectal cancer; Epigenetics; Synchronous.

Figure 1

Schematic representation of proposed mechanisms for formation of field defect. A: A mutation or epigenetic alteration in a stem cell (depicted in red) is inherited by all cells within the crypt through niche succession. Crypt fission results in several crypts becoming biologically altered creating a patch defect. Further mutation within this field of altered mucosa leads to malignant transformation; B: Tumour secretes chemical signals that alter the adjacent mucosa resulting in a field defect; C: Malignant cells shed from a tumour travel in the bloodstream and seed in a distant site rendering the mucosa susceptible to malignant transformation.

Figure 2

Changes in crypt morphology, cellular ultrastructure and epigenetic modulation in the field defect. A, B: Changes in crypt morphology characterised by increased branching and distension of crypts, increased cell division and a change in proportion of cells with increase in goblet cells; C, D: Changes in the cell cytoskeleton, organelles and nuclear composition; E, F: Epigenetic modulation of DNA leading to transcriptional silencing of certain genes involved in regulation of cell division, apoptosis and DNA repair.