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Review
. 2023 Feb 20:13:1110881.
doi: 10.3389/fonc.2023.1110881. eCollection 2023.

Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells

Hao Wang  1 , Kun Mi  2
Affiliations
Review

Emerging roles of endoplasmic reticulum stress in the cellular plasticity of cancer cells

Hao Wang et al. Front Oncol. .

Abstract

Cellular plasticity is a well-known dynamic feature of tumor cells that endows tumors with heterogeneity and therapeutic resistance and alters their invasion-metastasis progression, stemness, and drug sensitivity, thereby posing a major challenge to cancer therapy. It is becoming increasingly clear that endoplasmic reticulum (ER) stress is a hallmark of cancer. The dysregulated expression of ER stress sensors and the activation of downstream signaling pathways play a role in the regulation of tumor progression and cellular response to various challenges. Moreover, mounting evidence implicates ER stress in the regulation of cancer cell plasticity, including epithelial-mesenchymal plasticity, drug resistance phenotype, cancer stem cell phenotype, and vasculogenic mimicry phenotype plasticity. ER stress influences several malignant characteristics of tumor cells, including epithelial-to-mesenchymal transition (EMT), stem cell maintenance, angiogenic function, and tumor cell sensitivity to targeted therapy. The emerging links between ER stress and cancer cell plasticity that are implicated in tumor progression and chemoresistance are discussed in this review, which may aid in formulating strategies to target ER stress and cancer cell plasticity in anticancer treatments.

Keywords: ER stress; cancer stem cell; cellular plasticity; epithelial-mesenchymal plasticity; resistance; vasculogenic mimicry.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Roles of ER stress in the cellular plasticity of cancer cells. ER stress regulates cancer cell plasticity, including EMP, drug resistance phenotype, CSC phenotype, and VM phenotype plasticity. ER stress can regulate the EMP of cells that migrate along the EMT–MET axis, such as activation, inhibition, and pEMT induction. Several studies have found that ER stress influences the cell fate by promoting or suppressing the susceptibility to drug therapy. ER stress also plays an important role in regulating CSC differentiation and ratio and also regulates CSC plasticity, such as quiescence and activation. The interchange and coexistence of diverse phenotypes need to be studied further. VM is also another remarkable example of tumor cell plasticity. The activation of ER stress inhibits the formation of VM phenotypes in highly aggressive cells, thereby impeding tumor angiogenesis and progression. Created with BioRender.com.
Figure 2
Figure 2
(A) Model of the IRE1–XBP1 axis that regulates EMP. Activation of the IRE1–XBP1 signaling pathway induces the expression of EMT transcription factors, which are direct transcriptional targets of XBP1. Additionally, IRE1α promotes miR-200 degradation via the RIDD process, which results in the derepression of epithelial gene transcriptional repressors. ER accumulation of LOXL2 interacts with HSPA5, activating the IRE1–XBP1 signaling pathway and inducing EMT. (B) Examples of roles of the ER stress inducers thapsigargin and tunicamycin in cancer cell plasticity regulation. Calreticulin promotes TGF-β-induced EMT by repressing E-cadherin and inducing N-cadherin and vimentin. Calreticulin induces EMT via Ca2+-dependent thapsigargin-induced acute ER stress. Moreover, prolonged calcium signaling induces pEMT in carcinoma cells. On the contrary, tunicamycin-induced ER stress inhibits the chemoresistance of hypopharyngeal carcinoma cells in 3D cultures. Furthermore, activation of ER stress inhibits the formation of VM phenotypes in TNBC cells via the TGF-β1/Smad2/3 signaling pathways.Created with BioRender.com.
See this image and copyright information in PMC

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Grants and funding

This work is supported by The National Natural Science Foundation of China (grant no. 81872402) and grants from Sichuan Science and Technology Department Key Research and Development Project Fund (grant no. 2022YFS0215), Sichuan Natural Science Foundation (grant no.2022NSFSC0707) and Medical Science and Technology Project of Sichuan Health Commission (grant no. 21PJ114).

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