Cancers are composed by a multiplicity of different cells that are similar to normal tissue. However, tumors are constituted by heterogeneous cells. Within them there is a group of cells – cancer stem cells (CSCs) - that exhibit particular characteristics:
1. Self Renewal capacity
2. Ability to initiate a tumor when injected in animal models
3. Ability to recapitulate phenotypically the tumor of origin (TIC)
Conventional anticancer therapies kill rapidly dividing cancer cells and cause initial tumor regression... However, since these stem cells are not dividing and make up just 1-2% of the population, they are thought to be a potential source of treatment resistance via clonal selection.
In the prostate gland, the prostate cancer stem cells are mainly located at the basal layer and display a multiplicity of different markers. These markers have been used to isolate and characterize PCSCs that should maintain their specific characteristics - self-renewal, multipotency and resistance to therapy.
Dr. Leao then went on to focus on the evidence in the literature supporting the theory that CSCs lead to treatment resistance.
Hormonal therapy - Several in vitro and in vivo studies were done. The results from different studies showed that hormonal depletion induced a clonal selection and a consequent enrichment of more tumorigenic cells. In a study by Seiler et al (2013), cell lines deprived of androgen media do not express PSA but are more tumorigenic than the cell line of origin that did not originate tumors when injected in mice.
Chemotherapy (Doxetaxel) - When treated with docetaxel, Dr. Leao’s group noted a decrease in the number of viable cells. However, the reduced number of viable cells displayed:
a higher expression of ALDH (cancer stem cell marker and marker associated with treatment resistance) when compared with non treated cells. 2. A similar number cells expressing CD44+ when compared to the non-treated ones as well, All together these results emphasize that conventional therapies do not eradicate all tumour cells and provides a clonal selection favouring cell with CSC markers and tumorigenic.
The mechanisms of resistance of CSCs are thought to entail the following:
Efficient DNA repair machinery, Resistance to oxidative and DNA damage, Slow cell cycle kinetics, Intrinsic expression of anti-apoptotic proteins, Increased expression of drug-resistance proteins (MDR and ABC transporters), among others.
As such, current therapies remain insufficient for PCa treatment and although we achieve a good initial response with androgen-therapy or chemo, the disease always progresses. We need to target the proliferating bulk of the tumor in addition to a CSC-directed therapy directed at eliminating this critical cell population.
Next we moved on to how to best target this population. In other malignancies, there are numerous ongoing studies looking at targeting CSCs. The majority of the studies in prostate cancer are still pre-clinical and aim to target PCSCS through different strategies: CSCs metabolism – chemotherapy and radiotherapy sensitizers, tumor microenvironment, cellular superficial markers, signaling pathways, ABC transporters, miRNA manipulation, Nanomedicine – target delivery drugs.
He was then able to review some ongoing studies targeting some of these pathways:
1) NCT01677897 (MetAb-Pro) – use of metformin in metastatic PCa - Metformin has been shown to have anti-neoplastic properties and inhibits the proliferation of human prostate cancer cell lines and also reduced tumor growth in LNCaP xenografts.
2) NCT02095249 – Pimonidazole – this targets the tumor microenvironment. The group from Toronto plans to evaluate the effect of hypoxia on CSCs numbers and characteristics and correlate with biochemical relapse.
3) Targeting signaling pathways is probably the most used way to treat CSCs. In vitro studies have shown that several pathways are upregulated in CSCs. Basically Hedgehog, Wnt, Notch and NF-kB are involved in CSCs mechanisms that lead to proliferation, survival, metastasis, and treatment resistance. Multiple ongoing trials.
More recent studies have even begun to use CSC monitoring as a predictor of treatment response.
His conclusions were as follows:
1. CSCs hypothesis offers an explanation for treatment resistance and disease progression
2. Proper characterization of CSCs is crucial to address efficacious strategies - Treatment and Monitoring
3. Primary evidence suggest CSCs-targeted therapy is plausible
4. Future treatment of PCa may combine conventional treatments with cancer stem cells targeted therapies, but the clinical results have not confirmed yet the preclinical hopes
Speaker: Ricardo Leão, Canada and Portugal
Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 37th Congress of Société Internationale d’Urologie - October 19-22, 2017- Lisbon, Portugal