Tumour Initiation: a Discussion on Evidence for a “Load-Trigger” Mechanism

Abstract

Appropriate mechanical forces on cells are vital for normal cell behaviour and this review discusses the possibility that tumour initiation depends partly on the disruption of the normal physical architecture of the extracellular matrix (ECM) around a cell. The alterations that occur thence promote oncogene expression. Some questions, that are not answered with certainty by current consensus mechanisms of tumourigenesis, are elegantly explained by the triggering of tumours being a property of the physical characteristics of the ECM, which is operative following loading of the tumour initiation process with a relevant gene variant. Clinical observations are consistent with this alternative hypothesis which is derived from studies that have, together, accumulated an extensive variety of data incorporating biochemical, genetic and clinical findings. Thus, this review provides support for the view that the ECM may have an executive function in induction of a tumour. Overall, reported observations suggest that either restoring an ECM associated with homeostasis or targeting the related signal transduction mechanisms may possibly be utilised to modify or control the early progression of cancers. The review provides a coherent template for discussing the notion, in the context of contemporary knowledge, that tumourigenesis is an alliance of biochemistry, genetics and biophysics, in which the physical architecture of the ECM may be a fundamental component. For more definitive clarification of the concept there needs to be a phalanx of experiments conceived around direct questions that are raised by this paper.

A Flexible Microdevice for Mechanical Cell Stimulation and Compression in Microfluidic Settings

“…All these examples point that phenotypes may become dominant over genotypes of the tumor cells depending on the microenvironment [1]. Thus, an altered mechanobiological profile of the cells and microenvironments (a mutationindependent element) is proposed to be necessary to promote development and spread of cancer [8]. However, there are no coherent quantitative data on the nature and level of mechanical forces that influence the interactions between the physical microand nano-environment and cancer cells [7].…”

Bioimprinting: Bringing Together 2D and 3D in Dissecting Cancer Biology

“…The extracellular environment also possesses physical and mechanical characteristics including stiffness, electrostatic charge, elasticity, compression and shear stress, which cooperate with a variety of biological factors and can affect a wide range of cellular behaviors [18][19][20]. Any disruption causing an imbalance in these biomechanical features can switch cell responses from normal to aberrant [21], although details are still unclear as to how cancer cells are affected by this balance. The fibrous constituents of the ECM, like collagen, along with physical characteristics like stiffness or elasticity, provide the ECM with topographical features that can generate a variety of biophysical and biomechanical cues, potentially dependent on size, dimension and type of topographies.…”

A Doctrine of Ovarian Cancer Translational Research Needs Revisiting

“…It has been shown that interrupting aberrant ECM-to-cell signals mediated by integrins may normalize cell behavior and reverse tumor development (14). In addition, it was also suggested that the early development of ovarian cancer is dependent on potential tumor forming cells being bound to the sites in ovarian tissue with permissive, as distinct from tumor-inhibiting, characteristics (15). The commensurate inclusion of ARMs as a strategic component of a multi-targeted approach in larger clinical trials may therefore be warranted in ovarian cancer translation research.…”