Driving Cancer Tumorigenesis and Metastasis Through UPR Signaling

  • Alexandra Papaioannou
  • Eric ChevetEmail author
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 414)


In the tumor microenvironment, cancer cells encounter both external and internal factors that can lead to the accumulation of improperly folded proteins in the Endoplasmic Reticulum (ER) lumen, thus causing ER stress. When this happens, an adaptive mechanism named the Unfolded Protein Response (UPR) is triggered to help the cell cope with this change and restore protein homeostasis in the ER. Sequentially, one would expect that the activation of the three UPR branches, driven namely by IRE1, PERK, and ATF6, are crucial for the adaptation of cancer cells to the changing environment and thus for their survival and further propagation. Indeed, in the last few years, an increasing amount of studies has shown the implication of UPR signaling in different aspects of carcinogenesis and tumor progression. Features such as sustaining proliferation and resistance to cell death, genomic instability, altered metabolism, increased inflammation and tumor-immune infiltration, invasion and metastasis, and angiogenesis, defined as “the hallmarks of cancer”, can be regulated by the UPR machinery. At the same time, new potential therapeutic interventions applicable to different kinds of cancers are being revealed. In order to describe the emerging role of UPR in cancer biology, these are the points that will be discussed in this chapter.

List of Abbreviations


ADAM metallopeptidase domain 17


Protein kinase B (PKB)


Acute lymphoblastic leukemia


Antigen-presenting cells




Apoptosis signal-regulating kinase 1


Activating transcription factor 3


Activating transcription factor 4


Activating transcription factor 6


ATF6 cytoplasmic domain


Autophagy protein 5


Ataxia-telangiectasia mutated (Ser/Thr protein kinase)


Breakpoint cluster region


Binding immunoglobin protein or GRP78


Colitis-associated cancer


Cancer-associated fibroblasts


Chemokine (C-C motif) ligand 2 or MCP-1


Cluster of differentiation 8/28/40/80/86


C/EBP-homologous protein


Central nervous system


Protein phosphatase 1 regulatory subunit 15B (PPP1R15B)




C-X-C motif chemokine ligand 3/8/10/14


Dendritic cells


Family of transcription factors (TF) in higher eukaryotes


Endothelial cells


Extracellular matrix


Epidermal growth factor


Epidermal growth factor receptor


Early growth response protein 1


Guanine nucleotide exchange factor for the eukaryotic initiation factor 2


Eukaryotic initiation factor 2α


Epithelial-to-mesenchymal transition




Endoplasmic reticulum


Estrogen receptor positive


Synonym of EGFR


Endoplasmic reticulum oxidoreductase 1 alpha


Focal adhesion kinase


Fibroblast growth factor


Fibroblast growth factor 2


Forkhead box O


Forkhead box P3


Growth arrest and DNA damage-inducible protein GADD34/Protein phosphatase 1 regulatory subunit 15A (PP1R15A)


Glioblastoma multiforme


Glucose transporter 1


Glycoprotein 96/94 kDa glucose-regulated protein


78 kDa glucose-regulated protein


Histone deacetylase


Hypoxia-inducible factor 1-alpha


Interleukin 1/1β/2/6/8/10/17/23


Endoribonuclease inositol-requiring enzyme 1 alpha


Intestinal stem cells


Integrated stress response inhibitor


c-Jun N-terminal kinase


Kelch-like ECH-associated protein 1


Kinase-inhibiting RNase attenuators


Lysosomal-associated membrane protein 3


Microtubule-associated proteins 1A/1B-light chain 3B


MAF BZIP Transcription Factor


MAF BZIP transcription factor B


Monocyte chemoattractant protein-1 or CCL2


Myeloid-derived suppressor cells


Major histocompatibility complex I/II


Macrophage inflammatory protein-1α/β


Micro RNA


Matrix metalloproteinase


Messenger RNA


Mechanistic target of rapamycin


Mammalian target of rapamycin complex 1



NFκB p65/RelA

Nuclear factor kappa-light-chain-enhancer of activated B cells p65 subunit


Nuclear factor (erythroid-derived 2)-like 2


Tumor protein p53


Valosin-containing protein


Protein disulfide isomerase


Protein disulfide isomerase family A member 5


Protein kinase RNA-like endoplasmic reticulum kinase


Phospholipase C gamma


Protein phosphatase 1 catalytic subunit


Post-translational modification


Ras homolog gene family, member A


Reactive oxygen species


Ribosomal RNA


TRNA-splicing ligase RtcB homolog/C22orf28/HSPC117


RuvB-like 2


Site-1 protease


Sphingosine-1-phosphate receptor 1


Site-2 protease


Squamous cell carcinoma antigen 1


Zinc finger protein SNAI1


Secreted protein acidic and rich in cysteine


Tyrosine-protein kinase Src


Signal transducer and activator of transcription-3/-6


Transit-amplifying cells


Tumor-associated macrophages


T-cell death-associated gene 51 protein




Transforming growth factor beta


Transforming growth factor beta 1


Thrombospondin 1


Triple negative breast cancer


Tumor necrosis factor alpha


TNF receptor-associated factor 2




Twist-related protein 1 (TWIST1)


Unfolded protein response


Vascular endothelial growth factor A


Vascular endothelial growth factor


Vascular endothelial growth factor receptor 2


Wingless-related integration site


WNT family member 11


X-box binding protein 1


Spliced form (active) of X-box binding protein 1



This work was funded by grants from the Institut National du Cancer (INCa) and EU H2020 MSCA ITN-675448 (TRAINERS) to EC.


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© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.Inserm U1242 «Chemistry, Oncogenesis, Stress and Signaling»University of Rennes 1RennesFrance
  2. 2.Centre de Lutte contre le Cancer Eugène MarquisRennesFrance

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