Feature: Putting cancer to the test

Although relatively new to his postdoc career, Dr Mark Shackleton, medical oncologist and founder of the Melanoma Research Laboratory at the Peter MacCallum Cancer Centre in Melbourne, has already made his impression on the world of cancer biology.

His research has rapidly expanded current knowledge into how melanomas grow and progress, with the aim of finding better ways to treat and prevent this disease, including those patients under his own care.

Melanoma is an all-too-real disease for many people in Australia. It causes significant morbidity and mortality in this country, being one of the most common causes of cancer deaths in younger adults and therefore also a leading source of productive working years lost.

Despite these sobering statistics, the incidence of melanoma keeps increasing and effective therapies for patients with advanced disease continue to evade scientists and clinicians.

“Conceptually, there are two basic aspects to cancer,” Shackleton explains. “One is the process of a cancer forming – what drives the malignant transformation of a normal cell into a cancer cell. The other one is the means through which a cancer, once it is established, maintains itself, and the extension of that is how they propagate themselves in patients.”

It is these broad biological questions that have occupied Shackleton over several years, first during his postdoc at the University of Michigan in the USA and then back home in Melbourne. He’s also attracted the attention of big pharma for his pioneering research. Shackleton received the prestigious 2011 Pfizer Australia Research Fellowship.

Making models

Numerous models or theories have been proposed to explain how cancers such as melanoma maintain and propagate themselves. According to Shackleton, three main ones have gained traction in the field: the cancer stem cell (CSC) model; clonal evolution; and the newest kid on the block, tumour plasticity.

Probably the most topical one is known as the CSC model. The idea here is that established cancers are maintained by only small subpopulations of cells within those tumours, and that these rare cells are actually the primary drivers of tumour maintenance and spread.

The observational background of this model is that many tumours, from a cellular point of view, are quite heterogenous, with phenotypically distinct types of cancer cells within one tumour when analysed microscopically or by flow cytometry.

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The CSC mode is so-named because it somewhat reflects the idea of normal stem cell biology in organ development, whereby differentiation of a tissue-specific resident stem cell is a hierarchical and unidirectional phenomenon that gives rise to a non-stem cell population.

“The idea has gained a lot of traction in the cancer field over the last 20 years as a result of experimental work that has been enabled by the development of immunocompromised animal models that allow the engraftment of human cells,” Shackleton said.

The observation of physical variation within tumours has actually been reported over many years in a range of cancers. “This concept has always intrigued cancer biologists because cells that look a bit different under the microscope may in fact be functionally different in the way that they contribute to disease progression within patients, that is their tumourigenicity.”

The question of whether such cells are indeed rare also has fundamental implications for therapy. If rare, as the CSC model proposes, then these specific subpopulations should be targeted more specifically and effectively, but if cells with increased potential to cause disease are more common, then a more broad approach is needed to effectively treat the cancer and to better understand cancer biology.

The second, and probably the most widely accepted model of cancer progression, is the clonal evolution model. “This idea is fundamentally different from the CSC model because it says that pretty much every cell in a tumour harbours similar intrinsic tumourigenic potential over time,” Shackleton explained.

“Then, at any point in time, single clones, or at least only a small number of individual clones, may dominate by acquiring additional genetic and maybe heritable epigenetic mutations – changes to the cell’s gene expression not encoded by the genome – that confer on those cells a proliferative or survival advantage.”

This shift in cell potential within a tumour is an evolutionary process such that new favourably adaptive clones are continually being developed in the highly selective environment of the wider organism. Clonal evolution also goes some way to explaining cellular heterogeneity within tumours.

The third, and most recent model for cancer progression, encapsulates the notion of tumour plasticity. “Probably arising out of the stem cell reprogramming era, it is similar to clonal evolution in that pretty much every cell within a tumour harbours some intrinsic tumourigenic and malignant potential, and that cells are basically able to flip flop back and forwards in a plastic fashion between more or less actively malignant states represented by phenotypic differences among cells. So this is primarily like a reversible epigenetically driven process.”