Could the ‘plasticity’ or ability of cancer cells to change their cellular form, be the key to potentially improving outcomes and even saving lives.
Research by Dr Nataly Stylianou at the Australian Prostate Cancer Research Center – Queensland (APCRC-Q) explored that very question and with a funding boost could be advanced further.
More specifically, Nataly’s work focused on what’s known as EMT or epithelial-mesenchymal transition in prostate cancer. EMT is a biological process in which stationary epithelial cells gain the ability to move and invade, which is reactivated in cancer to promote metastasis. When cancer cells undergo EMT, they lose their epithelial characteristics and gain mesenchymal features like increased migration and invasiveness. This process is linked to tumor progression.
“The area that we focused on was prostate cancer, but this applies across all cancers, most patients will die because they are experiencing metastasis. Metastasis also becomes more resistant over time, or they grow in areas where they shouldn't, disrupting organs and their functions and then patients die,” Dr Stylianou said.
“We looked at what's behind metastases. Some cancers have propensities of metastasizing to specific spots, like castrate-resistant prostate cancer, one of the initial variants of aggressive non-resistant cancer. It's prostate cancer that has stopped responding to the androgen targeted therapies, it can live in the presence of low androgens. It tends to metastasize to the bone.
“Once the cancer cells are in the bloodstream, maybe there's signals coming from other environments that are attractive to the cancer cells and they'll go there. Then once they get there, they need to start growing and forming that secondary tumor. For a cell to be able to do all that, it's hypothesized that they need to shift their profile in some way.
“In the primary site, a majority of the cancer cells are epithelial, they're growing next to each other and touching each other and their shape is, most of the time, described as cuboidal.
“However, for them to be able to detach and be able to travel through the body and get into the vessels, they need to acquire some invasive migratory properties that allow them to break through. Mesenchymal cells have those sorts of properties.
“For epithelial cells, to acquire mesenchymal properties, they need to shift their phenotype through what we've referred to as epithelial-to-mesenchymal transition, or EMT. When cells undergo EMT, they acquire some mesenchymal properties. It gives them some invasive characteristics.
“Alongside EMT comes some chemo-resistant properties, properties that allow them to hide from the immune system. There's a whole bunch of pro-metastatic properties that these cancer cells can acquire. And one of those processes, we think, is through EMT.”
In studying the two different cellular states, Nataly found that not only do the cells need to re-acquire their ability to grow, but as they make transitions and changes, they retain information from the previous form.
Epithelial cells like to grow, they proliferate. When they become mesenchymal, one of the things they lose is their proliferative capacity. They become invasive, but they're not proliferating,” Dr Stylianou explained.
“So once they get to that secondary location, they can either stay in that now mesenchymal state, which is often referred to as metastatic seeds, and they might stay there for a while, dormant, undetectable, then something might happen in the future that triggers them to start growing.
“But for them to start growing and forming a tumor, they need to reacquire their proliferative abilities through what we refer to as a mesenchymal to epithelial transition (MET), so they reverse. And then they grow and they form metastases.
“We hypothesize that the metastases are usually epithelial in nature. So, if you have an epithelial primary and an epithelial metastasis, and we're saying EMTs are involved in metastases, well, why isn't the metastasis mesenchymal? There may be some reversion happening.
“We asked questions like, if a cell undergoes EMT and then MET, and then back to epithelial, is it the same cell as what it started off with? Or now more aggressive? Are they starting to acquire some of those EMT properties? Do they let them go when they reverse back?
“What we found was that when they reverse back, they do maintain a memory of that EMT time, or their time being mesenchymal. We found that some of those properties that they acquired during their EMT, a lot of them they reversed, but a subset of them they kept. We also found there were things that didn't change when they underwent EMT, but then as they were reversing back, they acquired new features, new genes.”
Unfortunately, with research funding always hard to come by, Dr Stylianou has had to pause her work in the field to focus on areas where she has been able to secure funding.
“Our study was one of the first to show when these cells undergo these transitions, they may hold on to the memory of that event, which might also be why the metastases are more resistant to therapies,” she said.
“The limiting step is funding, at the moment this project's not running because we don’t have funding to continue exploring this area more.”
If you’d like to discuss funding for cancer plasticity research, call the Foundation on 07 311840,email general@pafoundation.org.au or simply donate via pafoundation.org.au
