No food to eat? Don’t starve! How starvation drives tumour evolution, therapy resistance and metastasis
Our lives revolve around food. We think about it all of the time (at least I do!). We have to eat to survive and we even plan our lives around it. During festive celebrations such as birthdays or Christmas for instance, we stuff our faces with calorie-laden treats. As we evolved, our ancestors adapted to withstand long periods of starvation when food was scarce. But how does nutrient availability relate to cancer? The ability to adapt to changes in our environment such as nutrient deprivation, which has allowed us as a species to survive, also enables cancer cells to survive and spread throughout the body. Our lab focuses on a group of proteins that read our genetic code and control which genes are turned ON or OFF in response to nutrient limitation. These ‘readers’ can be over-expressed and/or hyperactive in cancer. As they control the way cells process nutrients, they also affect the way cells behave.
Most of us have had our lives touched by cancer. But what exactly is cancer? When asking my close friends or family, they often respond with something along the lines of ‘cells that grow uncontrollably and lead to tumour formation’. Cancer itself is a disease initiated by changes in our cells’ genetic code (our DNA), but also from changes to how our DNA is read. We refer to these as genetic and epigenetic changes respectively. These aberrations happen frequently with each cell division providing another chance for a cell to convert mistakes in our DNA to a mutation which can be inherited by all cells that arise from it. Thankfully most of the time, these mistakes are corrected by our cells’ DNA repair machinery. However, sometimes the outcome can be sinister. A change in our DNA that isn’t corrected can have dire consequences for a cell, leading to alterations in their appearance, metabolism and behaviour. If a cell begins to exhibit de-regulated growth and divides independently from external cues, we refer to this as a cancer cell.
The story isn’t quite that simple. Just as humans evolved, with the fittest amongst us surviving and reproducing during famine, cancer cells must sense and adapt to environmental changes or else they will perish. Over time, stressful conditions within tumours such as reduced oxygen or nutrient levels can select for cells with specific genetic or epigenetic variations that confer a survival advantage. By the time a tumour is discovered and biopsied, cancer cells will exhibit substantial genetic and epigenetic heterogeneity, with some cells altering their behaviour to become therapy resistant.
Normal cells are supplied with a steady flow of nutrients from the blood whereas in tumours, cancer cell growth can often exceed the available supply of resources. As long-term starvation is not sustainable, cancer cells use several strategies to try to rectify this problem but if unsuccessful, may face death. In part, adaptation may be achieved through cancer cells in the tumour interacting with, and co-opting, other ‘normal’ cells in the body to promote the formation of new blood vessels to supply them with food, in a process called angiogenesis. However, this process is inefficient and over time tumours deplete their resources, causing some cancer cells to die.
So, without a food supply, tumours should stop growing and die, right? Based on this idea, therapies were designed to essentially starve tumours to death by preventing blood vessel formation. Although they showed promise at first, succeeding in decreasing tumour size, patients would later experience catastrophic relapse with the resilient cancer cells disseminating to other tissues. Why is that? How can cancer cells survive if there is no food left? In adapting to starvation, tumours aim to decrease their nutritional demand and increase their nutritional supply. One way tumour cells can increase their nutrient supply is to move elsewhere, where food is plentiful. Just as we would look in the fridge, realise we have no food and go out for dinner instead. For cells it is more complicated. To move elsewhere, cells must rewire their metabolism to switch from a fast-growing and fast-dividing state (proliferative) to a slow-growing and slow-dividing state (invasive), a process known as ‘phenotype-switching’. Once tumour cells escape from the primary tumour, they can enter the circulatory system and seek nutrients elsewhere. Upon locating a nutrient-rich tissue, cancer cells settle down in their new home, make themselves comfortable and start to proliferate once more to form a new tumour in a process called metastasis. Interestingly, even tumour cells with access to an abundance of nutrients can exhibit a phenomenon known as pseudo-starvation, whereby non-nutritional signals hijack the stress-response to drive invasion, providing an explanation as to why some tumours metastasise early.
Cancer is complicated; we are slowly beginning to unravel the mysteries of how genetic, epigenetic and environmental factors such as nutrient availability influence tumour behaviour. Cancer cell behaviour is highly dynamic and adaptable to long-term stresses including starvation and anti-cancer therapies that evoke similar stress-responses. So how can we harness our knowledge of tumour adaptation to stress to fight cancer and prevent metastasis? Well, starvation isn’t the answer but preventing the adaptive response to starvation may be!
^ HeLa cell lines, derived from the cervical cancer of a woman named Henrietta Lacks, have been used for decades to study resistance to cancer drugs.
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