Extracellular Matrix

How The Scaffolding Supporting Our Cells Can Help Cancers Spread

Posted on 8 September 2021

90% of cancer deaths are the consequence of metastasis – when cancer cells leave the primary site of the tumour to spread to other sites throughout the body. Aside from the obvious problem of multiple tumours being harder to treat than just one, metastatic tumours also tend to be more deadly than the original tumour that gave rise to them. It is now understood that the cancer cells which form these secondary tumours don’t necessarily grow unaided – before metastasis occurs, primary tumours are able to cause changes in other organs to make them into more favourable sites for the growth of a new tumour. These sites have been called ‘premetastatic niches’. One of the ways in which these niches are prepared for ‘seeding’ by metastasising cancer cells is through changes to the meshwork that holds our cells together – the extracellular matrix or ECM.

All of the cells that make up our tissues and organs are supported and anchored together by a strong but flexible scaffold of proteins called the extracellular matrix. In addition to its structural role, the ECM is also important for communication between different cells as it can store, transport, and affect the diffusion of signalling molecules. Some ECM proteins become signalling molecules themselves when broken down. Migrating cells are also able to use the stiffness of the ECM in order to navigate through the tissue, with ECM proteins providing them with homing sites and anchorage points.

The extracellular matrix and cell wall (article) | Khan Academy
A diagram showing how cells are anchored to ECM components at the cell membrane. Collagen and proteoglycan complexes are shown, but there are many other ECM components. Integrins are molecules embedded in the cell membrane to which ECM proteins are anchored. They allow the cell to sense both chemical and mechanical cues such as stretching of the ECM.
Source

So why is the ECM important in cancer? Just as ECM proteins can provide structural support and signals that aid growth and migration of healthy cells, so too can the ECM support the growth of tumours. It seems that prior to metastasis, the primary tumour can release signals that can change the composition and structure of the ECM in other organs, making them more hospitable for metastasising cancer cells. For example, the initial cancer may release signals that alter the behaviour of stromal cells (a group of stem cells that can produce ECM proteins), causing the composition of the ECM to change. The excessive deposition of proteins like collagen (the main component of the ECM in most organs) and accompanying stiffening of the tissue can attract cancer cells and prevent them from undergoing apoptosis (cell suicide.) Cells responsible for remodelling the ECM also communicate with immune cells to promote inflammation, which further encourages tumour growth.

Cross-talks between cancer cells, stromal cells, and immune cells promotes changes to the extracellular matrix that are favourable for cancer cells.
Source

On the flip side, degradation of some ECM components can release stored growth factors which aid the development of cancer. Destruction of the ECM also helps cells to breach epithelial barriers and escape the site of the primary tumour and into the blood.

Learning more about exactly how the ECM changes in these premetastatic niches and how this supports tumour development could help us to treat cancer more effectively. Research suggests that unfortunately, some chemotherapy might cause metastasis-promoting changes to the ECM at the same time as treating the primary tumour. We also know that the ECM is remodelled during ageing, which contributes to increased susceptibility to both cancer and metastasis in the elderly. However, the ways in which the ECM can promote metastasis varies from tissue to tissue, and important gaps in our knowledge remain for some organs. In particular, we don’t yet have a good understanding of how this ECM remodelling occurs in bone tissue and in the brain, which are two frequent sites of metastasis. It is hoped that as techniques for studying the ECM improve, we will gain a better understanding of how this often fatal process can be prevented.


References

A glitch in the matrix: organ-specific matrisomes in metastatic niches: https://doi.org/10.1016/j.tcb.2021.08.001

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