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Cancer cell plasticity, stem cell factors, and therapy resistance: how are they linked?

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Abstract

Cellular plasticity can occur naturally in an organism and is considered an adapting mechanism during the developmental stage. However, abnormal cellular plasticity is observed in different diseased conditions, including cancer. Cancer cell plasticity triggers the stimuli of epithelial-mesenchymal transition (EMT), abnormal epigenetic changes, expression of stem cell factors and implicated signaling pathways, etc., and helps in the maintenance of CSC phenotype. Conversely, CSC maintains the cancer cell plasticity, EMT, and epigenetic plasticity. EMT contributes to increased cell migration and greater diversity within tumors, while epigenetic changes, stem cell factors (OCT4, NANOG, and SOX2), and various signaling pathways allow cancer cells to maintain various phenotypes, giving rise to intra- and inter-tumoral heterogeneity. The intricate relationships between cancer cell plasticity and stem cell factors help the tumor cells adopt drug-tolerant states, evade senescence, and successfully acquire drug resistance with treatment dismissal. Inhibiting molecules/signaling pathways involved in promoting CSCs, cellular plasticity, EMT, and epigenetic plasticity might be helpful for successful cancer therapy management. This review discussed the role of cellular plasticity, EMT, and stem cell factors in tumor initiation, progression, reprogramming, and therapy resistance. Finally, we discussed how the intervention in this axis will help better manage cancers and improve patient survivability.

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Abbreviations

AKT:

     Protein kinase B

BCRP:

   Breast cancer resistance protein

CSC:

     Cancer stem cells

CaP:

      Prostate cancer

DVL:

    Dishevelled

EGFR:

  Epidermal growth factor receptor

ESC:

     Epithelial stem cells

EMT:

    Epithelial-mesenchymal transition

FOXC1:

Forkhead box c1

FZ:

        Frizzled

HIF:

      Hypoxia-induced factor

IL:

        Interleukin

JAK:

    Janus kinase

KLF4:

   Krüppel-like factor

KRAS:

  Kirsten rat sarcoma

MRP1:

  Multidrug resistance protein 1

OCT4:

   Octamer-binding transcription factor 4

P-gp:

     P-glycoprotein

PI3K:

    PhosphatidylInositol 3-kinase

ROS:

    Reactive oxygen species

STAT:

   Signal transducer and activator of transcription

SMO:

    Smoothened

SOX:

    SRY-related HMG-box

TGF:

    Tumor growth factor

TKI:

     Tyrosine kinase inhibitor

ZEB:

     Zinc finger transcription factor

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Acknowledgements

The authors are thankful to Aligarh Muslim University, India, for providing the necessary facilities. HF expresses her sincere gratitude for the fellowship to UGC (F.82-27/2019(SA-III)), India. HRS is grateful to The UGC (Grant no.F.30-377/2017(BSR)) and DST-SERB (Grant no. EMR/2017/001758), New Delhi, India, for providing financial help.

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    Homa Fatma & Hifzur R. Siddique

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Fatma, H., Siddique, H.R. Cancer cell plasticity, stem cell factors, and therapy resistance: how are they linked?. Cancer Metastasis Rev 43, 423–440 (2024). https://doi.org/10.1007/s10555-023-10144-9

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