Cancer Stem Cells
Characterizing and Targeting Cancer Stem Cells in Challenging Cancer Models
Over the past few decades, science has made remarkable progress in the understanding and treatment of human cancer, resulting in greatly improved survival for many patients. However, such achievements remain incomplete or out of reach for some hard-to-treat cancers, such as triple-negative breast cancer (5-year survival rate: 77%, compared to 93% for other types of breast cancer), chondrosarcoma (resistant to conventional radiation therapy and chemotherapy; usual treatment is surgery, which sometimes requires amputation), pancreatic cancer (5-year survival rate: less than 5%) or glioblastoma (5-year survival rate: less than 1%). Innovative approaches focusing on those challenging cancer models are therefore highly expected.
There is now wide acknowledgment that tumors are generally heterogeneous and that cancer treatment failure, relapse or metastasis may be related a small population of stem-like cells that are capable of self-renewing and of causing the different lineage of cancer cells comprising a tumor. These cancer stem cells (CSCs, also referred to as “tumor-initiating cells” or stem-like cells) are more radio-resistant than their non-CSC counterparts and have a distinct molecular signature. The development of new therapeutic strategies that selectively target CSCs is currently receiving increasing attention from the academic research community and the pharmaceutical industry (Yoshida and Saya, 2016).
In addition to conventional X-ray radiotherapy, new treatment modalities have been developed and are gaining importance. Particle radiation therapy (using low-LET protons or high-LET heavy ions) is effective at treating various radioresistant tumors and has already achieved promising results. For example, the HIMAC synchrotron at NIRS (Chiba, Japan) has been used for basic and clinical research as well as carbon-ion radiation therapy of more than 9,000 patients since 1994. Approaches combining particle- and targeted-therapy have been suggested for tumors with bad prognosis. Furthermore, carbon-ion therapy may be more efficient at killing CSCs than conventional X-ray therapy (Sai et al., 2015).
Boron neutron capture therapy (BNCT) is an innovative treatment modality that relies on the ability of boron-10 (10B) to capture thermal neutrons, resulting in the release of high-LET α(4He) particles and lithium (7Li) nucleus, with a path length shorter than 10 µm. Therefore it is crucial to maximize the concentration of boron-enriched compounds in tumor tissues while minimizing levels in surrounding normal tissues. Like carbon-ion beams, BNCT releases high-LET radiation (Moss, 2014), suggesting that BNCT might offer similar advantages over conventional radiotherapy, such as an improved relative biological effectiveness (RBE) and a lower oxygen enhancement ratio (OER).
New anti-CSC strategies will require first a better knowledge of their biology in each cancer model. The origin of CSCs (mutated adult stem cell, de-differentiated mutated cells…) is a hotly debated research area, and probably depends on the tumor type (Schulenburg et al., 2015). It is becoming clear that the capacity of CSCs to acquire and retain their tumor-initiating phenotype strongly depends on the microenvironment and is highly dynamic. Like normal stem cells, CSCs can reside in niches which control self-renewal and differentiation potential. For example, as mesenchymal stem cells give rise to chondrocytes, it has been proposed that these cells or their progenitors (mesenchymal chondroprogenitor cells) may constitute the origin of chondrosarcoma stem cells (Rodriguez et al., 2011). Indeed, it was recently demonstrated that normal mesenchymal stem cells may be reprogrammed into cancer stem cells by the modification of expression of the transcription factor EWS-FLI-1 (Riggi et al., 2010). Moreover, a healthy human cartilage is composed of 95-97% of mature chondrocytes and 3-5% of mesenchymal stem cells or chondroprogenitor cells. Thus, cartilage physiology supports recent in vitro findings about origin of chondrosarcoma (ChSC) stem cells.
Furthermore, CSCs and differentiated cancer cells seem to coexist in dynamic equilibrium. For example, based on an inducible breast oncogenesis model based on breast basal-like MCF10A cells, it was shown that the molecular switch between CSC and non-CSC phenotypes is influenced by IL6, several signaling pathways (including NF-κB and PTEN) as well as specific microRNA expression patterns (such as the downregulation of let-7 and miR-200 families or the upregulation of miR-210) (Iliopoulos et al., 2011).
We have also recently described for the first time a new molecular pathway in basal-like cells; the generation of CSCs in the MCF10A cell line by ionizing radiation and progesterone via membrane progesterone receptor, relies on PI3K/Akt signaling pathway and requires the downregulation of miR-29 expression and the upregulation of Klf4 (Vares et al., 2015; Vares et al., 2013). Furthermore, miRNA levels are sometimes directly correlated with CSC phenotype; for example, in our MCF10A model, the inhibition of miR-29 activity is sufficient to trigger CSC properties. Moreover, our new data suggest that administration of miR-29 mimic might improve radiation therapy of triple-negative breast cancer cells.
miRNAs are emerging as playing an essential role in regulating CSC generation, maintenance and behavior, indicating their potential utility for novel cancer therapy strategies. Antagomirs or miRNA mimics have recently started to be tested in mouse or non-human primates models as potential therapeutic tools, but significant challenges remain, such as stability (due to the rapid degradation by endogenous nucleases or elimination though hepatic and renal metabolism) or accessibility to target cells (Ishida and Selaru, 2013). Several methods have been used to address those challenges, such as delivery of RNAs as lipid-based nanoparticles or the use of chemically modified oligonucleotides. Recently, new in vivo delivery reagents have been available commercially for academic research.
In this research program, we are trying to :
1) Understand the biology of CSCs in selected cancer models
2) Target CSCs in combination with new radiation therapy modalities (BNCT and carbon-ion therapy)