Changes in cellular mechanical properties during onset or progression of colorectal cancer

Abstract

Colorectal cancer (CRC) development represents a multistep process starting with specific mutations that affect proto-oncogenes and tumour suppressor genes. These mutations confer a selective growth advantage to colonic epithelial cells that form first dysplastic crypts, and then malignant tumours and metastases. All these steps are accompanied by deep mechanical changes at the cellular and the tissue level. A growing consensus is emerging that such modifications are not merely a by-product of the malignant progression, but they could play a relevant role in the cancer onset and accelerate its progression. In this review, we focus on recent studies investigating the role of the biomechanical signals in the initiation and the development of CRC. We show that mechanical cues might contribute to early phases of the tumour initiation by controlling the Wnt pathway, one of most important regulators of cell proliferation in various systems. We highlight how physical stimuli may be involved in the differentiation of non-invasive cells into metastatic variants and how metastatic cells modify their mechanical properties, both stiffness and adhesion, to survive the mechanical stress associated with intravasation, circulation and extravasation. A deep comprehension of these mechanical modifications may help scientist to define novel molecular targets for the cure of CRC.

Keywords: Atomic force microscopy; Biomechanics; Colorectal cancer; Mechanical signalling; Pressure; Wnt.

Figure 1

Canonical Wnt signaling pathway (reproduced with permission from[95]). the WNT pathway consist of two states, one referred to as “off” state where the small lipid modified Wnt protein does not bind to frizzled receptors (A), the other refereed as to “on state” when Wnt binds to frizzled (B). In the off state a large destruction complex is formed by the APC, Axin and GSk3β proteins. This complex binds to free β-catenin, phosphorylates it, thus triggering its degradation and preventing it from entering the nucleus. In the on-state dishevelled is activated, inhibits the formation of the destruction complex and leads to an abundance of cytoplasmic β-catenin, some of which enters the nucleus, binds with TCF, leading to cell proliferation.

Figure 2

Novel method by Fernández-Sánchez et al[5] to deliver a defined mechanical pressure in vivo (reproduced with permission from[5]). A: Strain maps of non-magnetized (left) and magnetized (right) colon crypt injected with ultra-magnetic liposomes; B: Top: immunefluorescence of Myc expression in APC deficient crypts 1 mo after the ULM injection, in control (left), non-magnetized (middle) and magnetized (left) tissues; Bottom: β-catenin Y654 phosphorylation after 15 d under UML in control (left), non-magnetized (middle) and magnetized (left) tissues.