What’s in a name? A cancer stem cell by any other name is still a stem cell – or is it?

Author: Sara M. Nolte, 03/23/15

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I have previously written about the phrase “cancer stem cell,” and how it can be misleading for researchers and the public alike. As scientists, we go through great pains to be specific in our use of ‘cancer stem cell’ (CSC), referring to a cell that possesses the stem cell abilities of self-renewal and multi-lineage differentiation, not to describe the origin of a cancer cell (i.e. a stem cell gone bad). While we have yet to see evidence proving CSCs arise from normal stem cells, there is increasing evidence demonstrating a substantial number of genetic, epigenetic, and functional similarities between the two cell groups we are so adamant about keeping separate.

To illustrate this point, I’d like to talk about a gene called Bmi1 (B cell-specific Moloney murine leukemia virus integration site 1 – a ridiculously unhelpful and long name that no one actually uses). This may sound familiar to you – it was predominantly featured in media coverage of Dr. John Dick and Dr. Catherine O’Brien’s paper “Self-renewal as a therapeutic target in human colorectal cancer,” published in Nature Medicine in January of last year.

The Bmi1 gene (and the protein it encodes, Bmi1) was first identified for its role in hematopoietic (blood) stem cells (HSCs). Park and colleagues demonstrated that Bmi1 was necessary for HSCs to retain their ability to self-renew and proliferate; without it, HSCs underwent apoptosis (cell death). The same group later showed that Bmi1 was required for the self-renewal of neural stem cells (NSCs), and without it, mice had depleted numbers of NSCs after birth.

With the emergence of the cancer stem cell hypothesis – a subpopulation of cancer cells possess the ability to self-renew and produce all different cell types of the tumour – scientists began to ask the question of whether the genetic machinery used by normal stem cells was also important to CSCs.

Naturally, CSC researcher attention was drawn to Bmi1, where it was found to have similar self-renewal and proliferative effects in brain tumours, hepatic (liver) carcinoma, among others (check out this review).

So why does all of this matter? How can we use this knowledge to treat cancers?

This is where John Dick and Catherine O’Brien’s paper comes into play. The group from Toronto was interested in not just the role Bmi1 played in colorectal cancer, but in the potential it had as a therapeutic target in colorectal CSCs.

The paper first describes that tumour samples in which Bmi1 gene expression was experimentally reduced (a technique known as gene knockdown), have a reduced ability to survive in culture, and are also unable to form tumours in mice. They explain that this phenomenon is due to a decreased ability of the cells to move forward through the cell cycle (i.e. reduced proliferation), and an increase in apoptosis (cell death). I’ve sketched this out in the figure below (jargon alert!) They also saw that Bmi1 knockdown cells were significantly less able to self-renew in vitro (through reduced limiting dilution sphere formation), as well as in vivo (through reduced serial xenograft transplantation tumour formation).

“Simplified” overview of Bmi1’s role in proliferation (cell cycle) and self-renewal. This figure presents two scenarios of cancer proliferation using the (A) presence or (B) absence of the Bmi1 protein and its downstream effects on the cell cycle. Note: all shapes and short forms represent specific proteins; full names are not written out for simplicity. (A) When Bmi1 is present, it inhibits the expression of the Ink4A/Arf genes, preventing p14 (pink) and p16 (orange) from being made. Without p14, MDM2 can bind p53, preventing it from exerting its inhibitory effects; thus, the cell cycle continues. Without p16, cyclin D and CDK4/6 can interact, and allow progression of the cell cycle via E2F. (B) Without Bmi1, the Ink4A/Arf genes are expressed, producing the p14 (pink) and p16 (orange) proteins. p14 binds to MDM2, preventing it from binding p53; p53 can now stop the cell cycle via p21, or promote apoptosis (cell death). Similarly, p16 binds CDK4/6, preventing it from interacting with cyclin D, which – via Rb protein – inhibits the cell cycle.

“Simplified” overview of Bmi1’s role in proliferation (cell cycle) and self-renewal. This figure presents two scenarios of cancer proliferation using the (A) presence or (B) absence of the Bmi1 protein and its downstream effects on the cell cycle. Note: all shapes and short forms represent specific proteins; full names are not written out for simplicity. (A) When Bmi1 is present, it inhibits the expression of the Ink4A/Arf genes, preventing p14 (pink) and p16 (orange) from being made. Without p14, MDM2 can bind p53, preventing it from exerting its inhibitory effects; thus, the cell cycle continues. Without p16, cyclin D and CDK4/6 can interact, and allow progression of the cell cycle via E2F. (B) Without Bmi1, the Ink4A/Arf genes are expressed, producing the p14 (pink) and p16 (orange) proteins. p14 binds to MDM2, preventing it from binding p53; p53 can now stop the cell cycle via p21, or promote apoptosis (cell death). Similarly, p16 binds CDK4/6, preventing it from interacting with cyclin D, which – via Rb protein – inhibits the cell cycle.

Most excitingly, they identified a drug that is capable of turning the Bmi1 gene ‘off’ in their colorectal cancer cell lines. These cancer cells, which normally produced Bmi1, now had a reduced ability to do so, which led to reduced cell and tumour growth in vitro and in vivo, respectively. Mice with already established tumours that were treated with the drug were found to have reduced tumour growth, better survival, and did not seem to suffer any side effects.

This paper demonstrates that targeting the stem cell-like genetic machinery of CSCs has the potential to be a very successful therapeutic strategy. As you might imagine, a potential pitfall of this approach is that normal stem cells could also be targets of the therapy. While most of today’s current radiation and chemotherapies do not distinguish between cancerous and normal cells, CSC researchers are looking for CSC-specific therapies that have a reduced impact on normal stem cell populations (a topic I will cover in my next post!).

I ask again: what really is in a name? Cancer stem cell, cancer initiating cell, tumour initiating cell – while all referring to something specific scientifically, strip away the nuances, and you’re left with a cancer cell with stem cell properties. As our understanding of CSCs increases, we begin to see that we were more right than we knew in calling them cancer stem cells, as they are continually being shown to likely be misappropriated stem cells. But until the definitive proof arises (e.g. linage tracing in cancer models), we will have to refer to these cells by any other name than stem cell.

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Sara M. Nolte

Sara Nolte holds a Bachelor of Health Sciences and Masters of Science in Biochemistry & Biomedical Sciences from McMaster University. Her MSc research focused on developing of cancer stem model to study brain metastases from the lung. She then spent a year working on developing cell-based cancer immunotherapies. Throughout a highly productive graduate career, Sara became interested in scientific communication and education. She is now involved in developing undergraduate programs and courses in the health sciences at McMaster, and is looking for ways to improve scientific communication with the public. Outside of science, Sara enjoys participating in a variety of sports, and is a competitive Olympic weightlifter hoping to compete at the National level soon!
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