When the Cancer World Was Flat

It was not until the circumnavigation of the world, by explorers such as Megellen, and the pioneering work of scientists like Copernicus and Galileo – did the idea that the Earth was indeed round and travelled around the sun, become universally accepted. Before these great men of history, most people thought the Earth was flat, and lived their lives believing so. It is fair to say, that until fairly recently, the majority of cancer biologists and researchers have also lived and existed within a flat world – like in medieval times. Historically, most laboratory based experiments were conducted using single layer sheets of cancer cells grown in a 2D orientation.

Traditional 2D cell cultures
3D Tumour Organoid

 

 

 

 

 

 

 

 

However, tumours grow in the body as 3D amorphous structures displaying a variety of geometrical shapes, and not as flat 2D sheets, as they are often represented in traditional laboratory based cell culture systems. Tumours are greatly influenced by the complex environment in which they grow, known as the microenvironment. Their shape and how they interact and communicate with other cells in their immediate surroundings determines how effective the delivery of nutrients and gases to metabolically hungry cancer cells will be.

Therefore, how cancer cells are grown in the laboratory will profoundly affect their biology and behavior – including how they respond to anti-cancer drugs. Although useful and easy to use, the traditional 2D cell cultures systems of the past, have limited value in informing how tumours really function within the body.

The recent development and ever increasing use of organoid technology, now means that cancer cells can be grown as spheroid-like 3D clusters.  While not perfect, they do represent a more reliable experimental system by which we can better understand the biology of tumours. These new systems better mimic how tumours grow in the body, as their 3D structures provide both volume and depth which have important implications for how oxygen, nutrients and anti-cancer drugs penetrate tumours.

Microscopic Image of Tumour Organoid showing Bowel like structure

Cancer Research Wales was proud to fund the research teams that first brought this technology to Wales. Dr Paul Shaw (consultant oncologist at Velindre Cancer Centre), and the teams at the European Stem Cell Institute who have developed organoid systems specifically to study the biological behavior and treatment response of bowel cancers. A cancer that is Wales’ second leading cause of cancer death.

Dr Paul Shaw

 

Currently, only a small percentage of promising cancer drugs that enter clinical trials make it into the clinic. Most fail because the drugs that work in 2D systems or in animal models fail to have the same effect when trialed on humans. The tumour organoid approach offers an exciting opportunity to personalise and improve efficacy of cancer treatments for diseases such as bowel cancer.  Biopsies can be taken from patients, fragmented, and then re-grown to create 3D tumour organoids. Information about the genetic make-up, shape and behavior of these mini-tumours can then be collected and used to inform treatment decisions.

By analysing these biological characteristics, new cancer drugs can be selected and carefully matched with the biological profile responsible for driving the growth of bowel cancers that will be unique to that patient. This will help ensure patients receive a drug most likely to have the greatest anti-tumour effect for their cancer.

Before drug treatment
After drug treatment

 

In light of this, researchers at the European Cancer Stem Cell Research institute have been studying bowel cancer organoids to explore if they have capacity to predict responses to the treatments administered in the ongoing FOCUS 4 trial for bowel cancer. Essentially, replicating a clinical trial within the research laboratory.

Focus 4 is a trial for patients with advanced or metastatic colorectal cancer whilst they take chemotherapy breaks. During this window, patients will be administered one of several drugs to see if the time taken before the cancer begins to grow again, can be significantly extended. We are excited to see how the results of the FOCUS 4 trial match with the predicted results acquired from the parallel organoid studies.

Whilst mainly focused on bowel cancers, the development of tumour organoids could potentially benefit a range of different cancers in the future. Such systems to better understand how difficult to treat cancers such as lung and pancreatic cancers, respond to new and emerging therapies is greatly welcomed.

As technology advances it is likely we will see tumour organoid systems become ever more sophisticated. Add-ons such as microfluidics, would allow the incorporation of circulating immune cells into these models – mimicking the dynamic interaction that the immune system has with tumours.

I would like to finally thank Professor Matt Smalley and Dr Valerie Meniel who are also funded by Cancer Research Wales, for time and discussions during the writing of this blog.

 

Blog written by third year medical student Hester Lloyd-Cox who is supporting Cancer Research Wales as part of her studies.