Mechanical barrier to cancer cell proliferation

Researchers in NUS discovered the differential effect of extracellular matrix (ECM) topographical cues on healthy and cancer cell proliferation.

The microenvironment that surrounds the cells is composed of the ECM that provides myriads of mechanical and biochemical cues, which can dictate cellular behaviour and phenotype. During breast cancer progression, the ECM fibres align themselves in parallel orientation. This helps the migration of the cancer cells away from the primary tumour. Since cancer cells also possess uncontrolled growth potential, a team led by Prof LOW Boon Chuan from the Department of Biological Sciences in NUS, Prof LIM Chwee Teck at the Department of Biomedical Engineering in NUS and their jointly supervised student, Parthiv Kant CHAUDHURI at the Mechanobiology Institute in NUS questioned whether such changes in the ECM topography during cancer outgrowth could guide the proliferative capacity of cancer cells.

The researchers discovered the existence of a Mechanically Induced Dormancy (MID) where the topographical cues could inhibit normal cell proliferation but the cancer cells could successfully overcome this inhibition and continue uncontrolled growth. Further investigation into the reason behind the inhibition of normal cell proliferation led the research team to discover that the cytoskeleton of normal cells is highly contractile, which generates a mechanical signal that restricts their proliferation. This study reveals a novel mechanism by which normal cells sense external topographical cues and restrict their proliferation in an environment that promotes tumour growth and spreading.

These findings provide an understanding of how the cell’s microenvironment plays a crucial role in maintaining normal tissue homeostasis during healthy conditions. However, during diseased states such as cancer outgrowth, this proliferation inhibitory mechanical cue fails to provide a barrier. This might be one of the contributing factors for the uncontrolled proliferation of cancer cells.

Determining how tumour cells bypass this mechanism of MID may be paramount in the development of novel anti-cancer strategies that target cellular mechanisms altered by physical or mechanical cues during cancer progression.Promising chemotherapeutic agents targeting cellular contractile machineries have already started to emerge, and more are expected to come.

Figure illustrates that topographical cues could inhibit normal cell proliferation (blue nucleus) but cancer cells bypass MID and proliferate (red nucleus). [Image credit: CHUN Xi Wong]

Reference

Chaudhuri PK, Pan CQ, Low BC, Lim CT. “Topography induces differential sensitivity on cancer cell proliferation via Rho-ROCK-Myosin contractility.” Scientific Reports 6 (2016) 19672.