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By: Anusha Rajbhandari

Cancеr, a malignant disease that claims countless lives globally, has instigated considerable research to find effective treatments. The startling figure that one in every three people will develop cancer at some time in their lives makes the need for a viable solution evident.  Despite advancements in cancer treatment, most current techniques fall short of giving complete protection. Thе rеcеnt dеvеlopmеnt of genetic technologies shows that cancеr stеm cеlls themselves play an intеgral part in cancеr thеrapy, shifting our focus toward pеrsonalizеd trеatmеnts.

According to several recent studies, cancerous cells often arise from a single cancer cell that exhibits stem cell properties. Hence, targeting the origin of cancer stem cells instead of traditional techniques, which typically fail to eradicate the root of tumours, is a promising way to battle cancer recurrence after standard treatments. Furthermore, since abnormal epigenetic modifications in key signalling pathways promote the production of cancer stem cells, epigenetic modification research has gained attention in cancer therapy. 

Cancer Stem Cells

Cancer stem cells (CSCs) are a major factor in tumour initiation, progression, metastasis, and recurrence. CSCs are a subpopulation of bulk tumours. They have stem cell-like properties, tumourigenic capacities, and the ability to self-renew and differentiate, which enable them to form heterogeneous cancer cell lineages and resist anti-tumour therapy: the standard chemotherapy and radiation treatments. Their heterogeneous nature and migratory capacity allow them to spread to distant organs and form metastatic tumours, posing treatment challenges. 

The first proper evidence of CSCs was discovered in acute myeloid leukaemia (AML) in 1994. Prospective CSCs were identified as a significant tumour-initiating subgroup of cancer cells using cell surface markers that identify normal hematopoietic stem cells with the same markers (CD34+ and CD38) which are prone to developing leukaemia. Cancer in the brain, breast, liver, ovary, and colon were later discovered to have comparable tumour-initiating populations of abnormal cells.

Although the origin of cancer stem cells is still under investigation, it is hypothesised that CSCs are derived from either tissue cells that have undergone genetic mutations or cancer cells that have developed stem cell qualities.

Models of Carcinogenesis: Stochastic vs. Hierarchical

Tumour heterogeneity refers to the differences among cancer cells within a tumour. To explain tumour heterogeneity, the following two models of carcinogenesis have been proposed.

a) The stochastic model

According to the stochastic model, all cancer cells have an equal ability to induce carcinogenic growth (form heterogeneous tumours) if a particular set of mutations is acquired.

b) The hierarchical model

The hierarchical model assigns a specific group of cancer stem cells as the originators of new tumours. Unlike their non-tumorigenic cells, these cells can accelerate tumour growth and progression.

The ability of CSCs to regenerate an identical phenotypic duplicate of the original tumour in an orthotopic transplantation model is one of the most important criteria for functionally identifying CSCs within a cancer population. Non-CSCs, in contrast, cannot produce tumours in the transplantation model.

Commonly employed cancer treatments include surgery, chemotherapy and radiotherapy. The combination of surgery, chemotherapy and radiotherapy known as multimodality treatment often yields better outcomes. While surgery effectively removes cancer from the body, recent chemotherapeutic agents have demonstrated success against primary tumour lesions and residual cancer post-surgery or post-radiotherapy. Unfortunately, chemotherapy can lead to tumour heterogeneity, involving both normal and cancer cells. This intratumoral heterogeneity diminishes the effectiveness of chemotherapy, contributing to treatment failures and disease progression. Chemoresistance, a significant issue in cancer treatment, occurs when cancer cells develop resistance to the agents used in therapy, thereby limiting the efficacy of chemotherapy. Moreover, chemoresistance is associated with the transformation of tumours into more aggressive or metastatic forms.


Targeting CSCs through the epithelial-mesenchymal transition (EMT) pathways introduces a ground-breaking dimension in cancer therapy research. This therapeutic approach aims to curb the aggressiveness of cancer and counteract the acquired drug resistance observed in cancer stem cells.

Increasing evidence supports the pivotal roles of microRNAs (miRNA) and other categories of long noncoding RNA (lncRNA) in regulating various properties of CSCs. These properties include self-renewal, asymmetric cell division, tumour initiation, drug resistance, and disease recurrence. The utilisation of miRNA as a therapeutic agent targeting CSCs has been shown to halt the initiation of cancer, its progression and its spread.

Thе Rolе of Epigеnеtics and Key Signalling Pathways in Cancеr Stеm Cеlls

Various signalling pathways including Wnt, Hedgehog (Hh), Notch, Hippo, and TGF-β play a critical role in CSC progression when they malfunction. Abnormal activation of these signalling pathways is controlled by epigenetic alterations through DNA mеthylation and histonе modifications (such as acеtylation, mеthylation, phosphorylation, and ubiquitination). Epigenetic modifications are key drivers in the formation and maintenance of CSCs. 

Epigenetic mechanisms such as histone modifications, DNA methylation, chromatin remodelling, and even changes in noncoding RNAs such as microRNAs all work together to manage the ‘epigenome landscape’, which determines cell fate specification without changing DNA sequences. Such genomic alterations are critical throughout normal mammalian development and embryonic stem cell differentiation. 


The deregulation of various epigenetic pathways causes CSCs to proliferate uncontrollably and evade growth suppression mechanisms. Targeting the epigenetic regulators of CSCs signalling pathways has emerged as a promising new strategy to eliminate these deadly cells. Epigenetic drugs may be able to sensitise CSCs to traditional therapies and prevent cancer recurrence. However, CSCs display significant epigenetic heterogeneity between patients which must be taken into account and ways to overcome this should be sought first. 

The link between epigenetics and cancer paves the way for more personalised trеatmеnts. Efforts aim to altеr abеrrant signalling pathways and arе tailorеd to еach individual’s spеcific nееds. Epigenetic changes are crucial in guiding stem cells toward specific cellular and tissue pathways. Abnormal alterations in epigenetics can lead normal stem cells to transform into cancer stem cells, thereby losing their differentiation capacity and adopting stem-like characteristics.

In conclusion, thе discovery of CSCs as key playеrs in carcinogеnеsis, as wеll as thе incorporation of еpigеnеtics, opеns up nеw possibilitiеs for undеrstanding and combating cancеr. With еach discovеry, we еdgе closer to transformative treatments that may onе day thwart thе now pеrvasivе thrеat of cancеr.

Citations:

1 Yu, Z., Pestell, T. G., Lisanti, M. P., & Pestell, R. G. (2012, December). Cancer stem cells. The international journal of biochemistry & cell biology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3496019/ 

2 Kim, W.-T., & Ryu, C. J. (2017, June). Cancer stem cell surface markers on normal stem cells. BMB reports. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498139/#:~:text=The%20first%20prospective%20identification%20of,CD38%E2%88%92%20phenotype%20(3). 

3 Aponte, P. M., & Caicedo, A. (2017, April). Stemness in cancer: Stem Cells, cancer stem cells, and their microenvironment. Stem Cells International. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394399/ 

4 Toh, T. B., Lim, J., & Chow, E. K. (2017, February). Epigenetics in cancer stem cells. Molecular Cancer. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5286794/

5 Keyvani‐Ghamsari, S., Khorsandi, K., Rasul, A., & Zaman, M. K. (2021, May). Current understanding of epigenetics mechanism as a novel target in reducing cancer stem cell resistance. Clinical Epigenetics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164819/

6 Carvalho, L. S. S., Gonçalves, N., Fonseca, N. A., & Moreira, J. N. (2021, January). Cancer stem cells and nucleolin as drivers of carcinogenesis. Pharmaceuticals. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828541/

7 Phi, L. T., Sari, I. N., Yang, Y., Lee, S., Jun, N., Kim, K. S., Lee, Y. K., & Kwon, H. Y. (2018, February). Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells International, 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850899/

Feature images by

https://newatlas.com/stem-cell-cancer-vaccine-stanford/53434/
https://aholdencirm.files.wordpress.com/2015/09/cancer_stem_cells.jpg
https://www.researchgate.net/figure/Hierarchy-model-and-Stochastic-model_fig1_316735848
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