A PSA for prostate cancer stem cells

Author: Sara M. Nolte, 11/26/13

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In honour of Movember – men’s health awareness month – I’m going to talk about prostate cancer. Not in the usual way – PSA (prostate-specific antigen) screens and clinical exams – but rather, from the perspective of cancer stem cells (CSCs), and their role in prostate cancer. This focus is for several reasons: 1) there are many discussions regarding PSA screening out there already (e.g. here and here); 2) Movember is about awareness, so let’s be more aware of the biology behind the disease; and 3) CSC research could lead to new diagnostic and treatment options for prostate cancer, so it’s important to raise awareness for this kind of research too!

Figure 1: A) Simplistic view of the prostate gland structure. B) Cellular organization of the prostate gland structures. There are two types of cells in the prostate: 1) epithelial cells (perform most of the functional ‘gland stuff’) and stromal cells (responsible for structural support). There are two main types of epithelial cells: luminal cells (produce PSA and prostatic secretions, require androgen [e.g. testosterone] signalling to function), and basal cells (form the connecting border between luminal and stromal cells; do not respond to androgens). Prostate stem cells have been found to reside in the basal cell layer.

Figure 1: A) Simplistic view of the prostate gland structure. B) Cellular organization of the prostate gland structures. There are two types of cells in the prostate: 1) epithelial cells (perform most of the functional ‘gland stuff’) and stromal cells (responsible for structural support). There are two main types of epithelial cells: luminal cells (produce PSA and prostatic secretions, require androgen [e.g. testosterone] signalling to function), and basal cells (form the connecting border between luminal and stromal cells; do not respond to androgens). Prostate stem cells have been found to reside in the basal cell layer.

The prostate is a male reproductive gland that produces a sugar and enzyme solution (component of semen) during ejaculation. The gland is composed of several cell types, with a specific cellular organization (see Figure 1). Researchers identified prostate stem cells using cell surface markers (proteins expressed on the outside of the cell membrane) such as CD44 (a glycoprotein involved in cell to cell interactions), CD133 (also a glycoprotein, function unknown), and α2β1 integrin (a protein involved in forming attachments between cells and their environments). These same markers were later found in cancerous prostate cells, indicating the existence of prostate-specific cancer stem cells (scientific reviews of normal prostate stem cells versus prostate CSCs can be found here and here).

CSCs are responsible for initiating tumour growth (see my original post on CSCs) – a property that makes them attractive therapeutic targets: if you can kill the initiators, then there is nothing to sustain the growth of the tumour, allowing for full eradication of the disease and prevention of relapse and/or metastasis.

A research team known for determining the prostate CSC hierarchy recently made some interesting discoveries about prostate CSCs and the expression of PSA (the protein measured during PSA screens). The team was curious to know why recurring prostate cancer becomes insensitive to androgen-deprivation therapy (which mimics castration by blocking the effects of testosterone, as the hormone plays a role in prostate cancer), and they found that cells with low levels of PSA protein (PSAlo) were responsible for the lack of treatment effectiveness.

…the results suggest that PSA levels may not be as dependable as we’d like for predicting prostate cancer, at least for late stage or recurrent cases.”

They performed experiments to assess stem cell-like properties, and determined that not only did PSAlo cells possess a higher capacity for self-renewal, but they were also able to produce cells exactly like themselves (PSAlo) and cells that had higher levels of PSA protein (PSA+ cells). This is known as asymmetrical cell division, a hallmark of stem cells. In contrast, PSA+ cells could only produce more PSA+ cells. Furthermore, PSAlo cells also possessed several other indicators of CSCs: they were quiescent (not actively participating in the cell cycle), chemotherapy-resistant, expressed high levels of stem cell-associated genes, and high levels of CD44 and α2β1 (current markers of prostate stem cells and prostate CSCs, as described above).

While both PSA+ and PSAlo cells had comparable abilities to initiate tumour growth in mice, PSAlo cells were significantly more successful at perpetuating tumour growth after multiple rounds of tumour cell injection (this is called serial transplantation, and is considered the gold-standard for CSC identification), and in mice treated by various means of androgen-deprivation. These results not only demonstrate that PSAlo cells possess CSC capabilities, but that they are also responsible for recurrent disease after androgen-deprivation therapy.

What I find most interesting about this study is that the results suggest that PSA levels may not be as dependable as we’d like for predicting prostate cancer, at least for late stage or recurrent cases. The presence of a CSC population – PSAlo cells – in greater numbers is strongly indicative of more severe disease status. Biologically, this makes sense, as the differentiated luminal cells (see Figure 1) are responsible for PSA production, are sensitive to androgen-deprivation therapy, and likely form the bulk of the tumour mass in early stages. Their susceptibility to current therapies allows them to be killed off, and prevents them from growing back. Meanwhile, treatment-resistant CSCs remain unscathed, and are able to re-grow without expression of PSA and sensitivity to androgen-deprivation therapy (among others): bad news for the patient.

Prostate CSC seem to have high clinical relevance to both disease progression and treatment options/outcomes. In a time where we are more than aware of the controversy surrounding the usefulness of the PSA screen, and still don’t really know what to do with the test, perhaps it’s time to consider prostate cancer stem cells and examine their potential for screening and diagnostic purposes.

References cited:
Taylor R.A., Toivanen R. & Risbridger G.P. (2010). Stem cells in prostate cancer: treating the root of the problem, Endocrine Related Cancer, 17 (4) R273-R285. DOI:
Patrawala L., Calhoun-Davis T., Schneider-Broussard R. & Tang D.G. (2007). Hierarchical Organization of Prostate Cancer Cells in Xenograft Tumors: The CD44+ 2 1+ Cell Population Is Enriched in Tumor-Initiating Cells, Cancer Research, 67 (14) 6796-6805. DOI:
Qin J., Liu X., Laffin B., Chen X., Choy G., Jeter C.R., Calhoun-Davis T., Li H., Palapattu G. & Pang S. & (2012). The PSA−/lo Prostate Cancer Cell Population Harbors Self-Renewing Long-Term Tumor-Propagating Cells that Resist Castration, Cell Stem Cell, 10 (5) 556-569. DOI:
Alison M.R., Lang S., Frame F. & Collins A. (2009). Prostate cancer stem cells, The Journal of Pathology, 217 (2) 299-306. DOI:

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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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