Search for new cancer biomarker propelled by detailed exploration of cell structures

Advances in science, diagnosis and treatment mean that more people than ever before are surviving cancer. But with an increase in survival rates comes an increase in the possibility that for some people, cancer will recur later in life. This presents a continuing challenge for cancer research – biomedical scientists at Bristol University are finding new ways to find a solution.

An estimated 80 per cent of cancers are categorised as carcinomas – cancers which begin in the epithelial cells, the most prolific of the four major tissue types in the human body, which line the cavities and surfaces of the structures throughout the body.

“Although primary tumours can now be diagnosed earlier and treated with surgery, chemotherapy, radiotherapy, or new biologically based treatments, a major problem still remains in terms of recurrence,” explains Jo Adams, Professor of Cell Biology in the School of Biochemistry. “This happens as a result of cells escaping from the primary tumour and then residing in the tissues. Cells can also move to different sites in the body and then start to grow a metastatic tumour years, or even decades later, and this is what often turns out to be fatal.”

The primary interest of Professor Adams’ lab is in understanding how cells interact within the extracellular matrix (ECM), the structure and composition of which regulates a cell’s behaviour. In cancer, and particularly in metastasis, the composition of the extracellular matrix can be altered. Genetic changes in carcinoma cells also often lead to altered interactions of the cells with the ECM – for example, carcinoma cells may actively migrate through ECM that would keep a normal cell in static adhesion.

Over the last ten years, Professor Adams’ lab has been investigating an actin-bundling protein, fascin-1, and its role in carcinoma cell movement, starting with cell biological studies and analysis of samples from human tumours that were carried out while she was a faculty member at the Lerner Research Institute, Cleveland Clinic, USA. These studies showed that fascin-1 is upregulated in the worst cases of breast and colon carcinomas. Her work has since developed in collaboration with colleagues in epidemiology, enabling her to combine the findings of cell biology experiments with the wealth of data gathered about carcinoma from human samples.

This research could ultimately develop into a novel route for the treatment of cancer. There are already strong early indications that fascin-1 might be an effective biomarker for diagnosing aggressive tumours at an early stage, or even as a therapeutic target to arrest the development of metastatic cells.

Professor Adams, who is also affiliated with the Bristol Heart Institute (BHI), says: “The metastatic stage of cancer is so debilitating. So if it were possible to recognise cancers that are more prone to metastasis early after diagnosis it would be a great step for therapy – if someone can be in remission for longer or continue a good quality of life that would be a huge achievement.”

A recent collaboration with Professor Richard Martin, from the School of Social and Community Medicine, examined the role of fascin-1 in five of the most prevalent forms of carcinoma. After collating and analysing data from series of papers on each of the cancers (carcinomas of the breast, colon, lung, oesophagus and stomach) Professors Adams and Martin and their colleagues found strong evidence to confirm the clinical relevance and prospective value of analyzing the role of fascin-1, especially in colorectal carcinomas. At the very least, their research – published in the BMC Medicine journal (11:52, March 2013) – highlighted the need for more studies and more data about metastasis.

“Clarifying the capabilities of proteins at the basic science stage in this manner is very important,” explains Professor Adams. “Many potential new targets fail in clinical trials, which is a very costly process.

“The functionality of the ECM, along with the workings of the cytoskeleton (the scaffolding contained with a cell’s cytoplasm), combined with the multiple variants of cancer, make this an enormously complicated area to work in.  Equally, the potential impact cannot be over-stated.”

“In science we have to go carefully from one piece of proof to the next; research can take a painfully long time compared to the course of a disease,” adds Professor Adams. “Understanding how the cell – as the core unit of life – operates and interacts within tissues is essential. The fundamental molecular knowledge is vital if we are to develop new biomarkers or new targets to combat metastasis.”

The wet-laboratory-based molecular knowledge is being propelled by complementary studies of the evolution of the ECM. By examining which ECM proteins are conserved throughout animals, from the sponge to the human, it is possible to make models about the roles of different proteins in the evolution of ECM and how this has contributed to the evolution of animals with complex tissues.

One group of multifunctional ECM proteins that Professor Adams has identified as being preserved throughout evolution are thrombospondins. Her lab is now investigating the molecular mechanisms by which thrombospondins accumulate in the ECM through interactions with cell surfaces and other ECM components.

Professor Adams adds: “We think of evolution as very slow but given the incredibly fast pace at which data is emerging, due to the DNA sequencing of more and more animal genomes, we’re at a stage where our research has constantly to be updated in line with the latest developments.”

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