Cancer Stem Cells : A formidable force
Cancer Stem Cells (CSCs) are a rare sub-population of tumour cells with the ability to self-renew and differentiate into multiple cell types.CSCs are resistant to traditional radio and chemotherapy and are thought to serve as tumour initiating cells in various cancers that give rise to the bulk of the heterogenous tumour mass. These slow-cycling cells characteristically modulate signalling networks and their niche to maintain stem-cell properties, avoid apoptosis and regenerate tumours. Hence CSCs are being increasingly implicated in metastasis and tumour relapse in patients that have undergone systemic therapy. This review attempts to emphasize their clinical relevance as drivers of cancer progression and explore avenues to specifically target CSCs for cancer therapy.
What are Cancer Stem Cells (CSCs)?
Malignant cancer cells characteristically display uncontrolled division with an invasive streak. Though there have been numerous treatments based on the type and progressive stage of cancer, in all instances, the numbers show a dramatically low survival rate for patients post metastasis. In the 1990s, a hierarchical concept of a ‘cancer stem cell’ was introduced by Dick and colleagues in acute myeloid leukaemia (AML) that could potentially explain this clinical phenomenon of relapse. Their study demonstrated a minor self-renewing cell population (CD34++ CD38−) within the tumour with proliferative and differentiating potential that gave rise to AML in immunodeficient mice. Predictably, the 2000s saw a rush in academic and pharmaceutical investigations into this cancer sleeper cell population. Since then, Cancer Stem Cells have been popularly defined as a dedicated subset in the tumour population with the capacity for self-renewal, differentiation and serving as the origin for a heterogenous tumour population[3,4•]. These malignant counterparts of stem cells are being implicated as tumour initiating cells in haematological cancers and have since been shown to extend to other tumour types including solid tumours[5,6]. CSCs are usually quiescent and hence refractory to conventional therapies targeting the proliferative tumour bulk. However, cues within the tumour niche are known to trigger CSC divisions and metastasis which has significant weightage in the clinical prognosis[7••].
Cancer Stem Cell origin theories have contemplated multiple models such as mutational transformation events, de-differentiation of tumour cells, metabolic reprogramming etc. but without consensus. A popular theory suggests that CSCs arise due to mutations in normal stem cells or the progenitor cells from normal stem cells[9,10].Literature also points towards a model of cellular plasticity where cancer cells shift dynamically between a differentiated state and an undifferentiated CSC state with high tumorigenic potential. It hints at cancer cell (non-CSC) de-differentiation into a CSC in response to conditions in the tumour niche such as hypoxia, epithelial-to-mesenchymal transition (EMT) factors et cetera[11,12,13]. Other origin models detailing metabolic priming, cell fusions etc. have also been aired but lack concrete evidence. Research describing the sequence of events or uncovering possible overlap in the models would be a crucial step towards understanding tumour biology.
Why do they matter?
The existence of Cancer Stem Cells and validation of the CSC model for tumour propagation will have profound implications in oncology; Beyond gaining an understanding of clinical relapse and metastasis, the allure of the CSC hypothesis is in the idea that specifically targeting them would allow for complete remission of the cancer. However, the hierarchical CSC model has been met with debate that raises concerns over its definition, its bearing in solid tumours, the physiological relevance of xenograft studies and the non-specificity of CSC markers.That said, modern technology including techniques like genetic labelling have helped to address concerns and provide overwhelming evidence for the existence and viability of CSCs. Studies used clonal analysis to identify a fraction of persistent stem-cell-like proliferative cells that beget differentiated tumour cells in skin and intestine solid tumours[3,15].Another study in glioblastomas using transgenic labelling, highlighted a relatively quiescent sub-set of tumour cells that hierarchically (through transit amplifying cells) propagates tumours post chemotherapy. Furthermore, literature links Epithelial to Mesenchymal Transition (EMT) progressions in tumours to CSC plasticity which allows it to differentiate into various cell types and generate tumour heterogeneity. This behaviour coupled with their rapid clonal evolution is key to explain the aggressive mobility of tumours[17,18,19••].
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In the clinical setting, the most significant characteristic of CSCs is their resistance to chemo and radiation therapy. The assumption is that CSCs remain dormant and endure therapy following which, this enriched population self-renews and differentiates into a heterogenous tumour. Multiple mechanisms have been implicated in this phenomenon: upregulation of drug transporters or metabolising proteins allowing an efflux of drug molecules (for example the promiscuous ABC transporter or ALDH enzyme family); heightened DNA damage repair mechanisms including increased expression of intracellular ROS scavengers, activation of DNA damage checkpoints; EMT induction; increased expression of hypoxic signals; evading cell death (for example by releasing interleukins or endogenous caspase inhibitors) et cetera[21-26].Beyond mediating normal stem cell signalling pathways such as Notch and Wnt, the induction of quiescence by mechanisms like chromatin remodelling or activation of TGF-β seems key in the CSC modus operandi[27,28] since this dormant/G0 state is unaffected by therapies targeting actively proliferating cells. Thus, even with the disillusionment over CSCs, the clinical implications of this resistant fraction of tumour cells cannot be overlooked if we hope to prevent patient relapse.
CSCs as a viable therapeutic targets.
Traditionally, cancer therapies have targeted the bulk of the tumour as if it were a clonal disease but now, there is irrefutable proof of the existence of tumour sub-populations with differing drug responses, immunogenicity and proliferative potentials. To add a layer of complexity, there is considerable cross-talk between these populations implying that tumorigenesis could be a collaborative effort. Furthermore, there is the worrying observation that chemotherapy (particularly those inducing senescence) and radiotherapy unwittingly create a microenvironment that is conducive for metastasis by upregulating growth factors and chemokines that induce cellular reprogramming to form de-novo CSCs or initiate chemotaxis[4,29•].Thus, evidence clearly associates intra-tumour heterogeneity (reflecting the phenotypic diversity) with disease progression and resistance. Undoubtedly, the medical community must develop integrated regimens targeting both CSCs and non-CSCs to effectively combat cancer.
CSC Marker based strategies.
Thinking of therapeutic strategies, a major challenge has been to specifically target CSCs within a tumour without affecting the normal stem cells in the tissue. A majority of the CSC marker expression patterns are shared by their non-malignant counterparts and hence there is a lack of distinguishing CSC biomarkers. Currently, the more viable CSC markers include upregulated intracellular ALDH protein, onco-foetal stem cell markers and EMT markers like vimentin. Glycans have also been explored since aberrant glycosylation of certain surface stem cell markers such as mucins is commonly observed in malignant cancers[30,31,32].Additionally, some CSC markers have been used to develop immunotherapies including CTLA-4 inhibitors, antibody-drug conjugates (ADC), chimeric antigen receptor T-cells (CAR-T) and vaccines for selective ablation. For example,5T4 Trophoblast glycoprotein is an onco-foetal marker that is downregulated in adult tissue but re-expressed in cancers overlapping with typical tumour cell characteristics such as cytoskeletal alterations, downregulation of E-cadherin and increased motility. Studies using ADCs and targeted to 5T4 successfully showed a significant reduction in tumour-initiating cells.Other strategies targeting 5T4 expression including a vaccine (TroVax®) and CAR-T have also shown clinical benefits.
Targeting signalling cascades.
Several signal transduction pathways such as STAT3, Notch, Wnt/β-catenin, P13K etc. known to regulate CSC identity and function are being evaluated as potential targets: Abnormal activation of STAT3 has been associated with the inactivation of TGF-β signalling, aberrant proliferation and EMT induction in tumours. Studies show that its inhibition in CSCs results in apoptosis and decreased tumour cell invasion. In fact, in Wilms tumours, treatment with a STAT3 inhibitor (stattic) reduced tumour formation and progression in animal models.
Notch activation in CSCs plays a vital role in maintaining the stem-cell identity, cell fate decisions and inducing hypoxic conditions in the tumour microenvironment. Inhibitors such as γ-secretase inhibitors (GSIs) or monoclonal antibodies usually target Notch receptor cleavage or obstruct ligand interactions. Thus, they initiate tumour necrosis by reducing CSC numbers and inhibiting angiogenesis.
The Wnt/β-catenin pathway is another developmental pathway involved in maintaining a CSC phenotype, particularly, self-renewal. Both canonical and non-canonical Wnt are known to enhance EMT programmes. Wnt pathway inhibitors usually aim to obstruct its nuclear/cytol signal components or receptor (e.g. Fzd,LRP) interactions. Recently, lung cancer cell lines dosed with small molecule-Verrucarin J (VJ) that is known to induce ROS and DNA damage showed downregulated Wnt/β-catenin and Notch1 pathways which resulted in apoptosis and decreased proliferation of the cell lines.
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P13K/mTOR signalling pathway is abnormally activated in cancers and involved in promoting cell proliferation and angiogenesis. Targeting its components depletes the CSC population thus inhibiting tumour initiation and proliferation. Investigations into targeting other pathways involved in maintaining malignant phenotypes such as TGF- β and Hedgehog (popularly using chemo-agent-Vismodegib) have also shown good clinical promise.
Targeting CSC metabolism
CSC metabolism is another subject under active research considering the specific metabolic adaptations required in a stressful tumour microenvironment. Studies have shown that an oxidative phenotype characterised by upregulated mitochondrial oxidative phosphorylation (OXPHOS) pathway as well as a healthy mitophagy flux is key in CSC survival. Drugs inhibiting OXPHOS or antagonising mitochondrial function (e.g. tigecycline) induce apoptosis and decrease tumour formation indicating that they can be utilised for therapy.Similarly, a class of small-molecule ferroptotic agents have shown promise-they exploit aspects of CSC metabolism in the mesenchymal state and harness toxic ROS in an iron-dependent manner to selectively kill CSCs[40•].
Targeting the tumour niche
Factors such as chemo-induced senescence result in heightened inflammatory profiles that contribute to a pro-metastatic environment. Also, growth factors, tumour associated macrophages and cancer associated fibroblasts enhance tumour angiogenesis while suppressing anti-tumour immune responses. Evidently these components play important roles in maintaining stemness and tumorigenic function and thus can be potential therapeutic targets.
Targeting epigenetic regulators.
Recently, research has also focussed on the role of epigenetics in CSC formation and function. Epigenetic mechanisms involving chromatin alterations and DNA methylation have been associated with oncogenic transformation and EMT programmes. Drugs modulating these epigenetic factors can serve as effective adjuvant therapies. For example, the pre-clinical success of Tumour specific inhibitors of bromodomain and extra‐terminal motif (BET) proteins in combination with chemotherapy in both solid and haematological tumours has been encouraging. BET proteins are crucial for cell-cycle regulation and their inhibition results in G1 arrest or the downregulation of important cell-cycle genes thereby preventing cell cycle progression and resulting in tumour regression[41,42].
Challenges and future perspectives.
In terms of developing drugs, a serious limitation has been the use of animal models and xenografts at pre-clinical stages which have certain inadequacies with regards to studying relapse and recapitulating the human tumour microenvironment. Fortunately, the advent of technologies such as gene editing, patient derived human xenografts and organoids has been instrumental in allowing researchers to create physiologically relevant models. That aside, a major challenge in targeted therapy is the quiescent nature of CSCs. In fact, CSC populations in-vivo show a distinctly more quiescent (hence more resistant) fraction separate from a proliferative fraction, each occupying different tumour niches. A solution proposed is to either permanently maintain the dormant/G0 state or use chemicals such as Bisacodyl that are specifically cytotoxic to quiescent cells. Also, a recent study has raised hopes by identifying distinct redox profiles for both CSC states. It suggests combining conventional pro-oxidant therapy with molecules inhibiting the NRF2-mediated antioxidant defence thus allowing us to simultaneously target both states[43,44].However, these are still at tentative pre-clinical stages. Another roadblock in the field has been the phenomenon of cellular plasticity and reversion. Studies suggest that the effect of selective CSC ablation is only temporary and that their populations are restored by non-CSC tumour cells that are reprogrammed to revert into a stem-cell like state owing to their microenvironment[45••].This implies that solely targeting CSCs in a tumour is not sufficient to prevent relapse. Recently, a wave of developments in drug delivery including nanoparticle conjugated drugs and oncolytic adenoviruses promises to improve the efficacy of existing drugs and targeted therapies. However, a better understanding of CSC biology is crucial for clinical translation and we must conceptualise combination therapies that simultaneously target both the tumour life-force i.e. CSCs and the differentiated tumour bulk for a curative solution.
Papers of particular interest have been highlighted as:
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This paper highlights the dynamics between EMT and generation of CSC which contributes to the spatio-temporal heterogeneity of tumours. This cooperatively promotes tumour progression, metastasis and
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This study elucidates the biological functions of the inflammatory cytokine interleukin-17 (IL-17) in gastric cancer metastasis transformation of quiescent gastric CSCs. It shows that invasive gastric CSCs are closely associated with increased metastatic ability and that quiescent gastric CSCs when exposed to specific concentrations of IL-17 downregulate E-cadherin expression while increasing expression of vimentin and N-cadherin. This results in the induction of invasion, migration and tumour formation. Further experiments indicated that the activation of STAT3 TF pathway was facilitated by IL-17 and that the downregulation of STAT3 reversed the EMT-associated properties of quiescent gastric CSCs thus suppressing tumorigenesis and metastasis.
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This study explores the role of cellular senescence in promoting stemness. Components of the senescence pathways like p16INK4a, p53 etc. also regulate stem-cell functions. In-vivo, formerly chemotherapy-induced senescent cells display increased Wnt-mediated proliferative potential unlike the control cells that were never senescent but exposed to chemotherapy. Their results associate senescence with the gain of self-renewing properties in rare malignant cells which is linked to increased tumorigenic potential. Thus they provide another target population for cancer therapy.
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Conventional chemotherapeutic apoptotic drugs are less effective against the dormant quiescent CSC sub-population so there is a need for drug molecules using alternate modes of action. This study highlights a new class of small molecule ferrotopic agents that selectively target these aggressive tumour cells with a the mesenchymal phenotype by harnessing harness ROS created in an iron dependent manner. Experiments suggest that the compounds are Type I inhibitors that block cystine uptake possibly by binding to the xc− transporter. It has potential to be used as an adjuvant with traditional therapies.
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This study highlights the phenomenon of CSC reversion in patient-derived organoids. It provides evidence using lineage tracing experiments of human LGR5+ colorectal cancer cells serving as CSCs with the capacity to self-renew and differentiate. Selective ablation of this population in organoids successfully resulted in tumour regression however, it was followed by tumour regrowth. Tracing of KRT20+ CRC cells post LGR5 ablation allowed the authors to make the assumption that differentiated tumour cells revert to LGR5+ CSCs and replenish the CSC population.
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