Abstract
Endoplasmic reticulum (ER) proteostasis is often altered in tumor cells due to intrinsic (oncogene expression, aneuploidy) and extrinsic (environmental) challenges. ER stress triggers the activation of an adaptive response named the Unfolded Protein Response (UPR), leading to protein translation repression, and to the improvement of ER protein folding and clearance capacity. The UPR is emerging as a key player in malignant transformation and tumor growth, impacting on most hallmarks of cancer. As such, the UPR can influence cancer cells’ migration and invasion properties. In this review, we overview the involvement of the UPR in cancer progression. We discuss its cross-talks with the cell migration and invasion machinery. Specific aspects will be covered including extracellular matrix (ECM) remodeling, modification of cell adhesion, chemo-attraction, epithelial-mesenchymal transition (EMT), modulation of signaling pathways associated with cell mobility, and cytoskeleton remodeling. The therapeutic potential of targeting the UPR to treat cancer will also be considered with specific emphasis in the impact on metastasis and tissue invasion.
Highlights
Cell migration/invasion is one of the cancer hallmarks that drives cancer progression leading to tumor expansion of the adjacent tissues and/or to tumor dissemination through metastasis.These properties compromise the efficacy of the anti-cancer therapeutic approaches such as surgery or irradiation that rely on the existence of defined and limited zones within the tumor site
Upon accumulation of misfolded proteins in the Endoplasmic reticulum (ER) lumen, GRP78 is released from the ER stress sensors which leads to their activation by allowing IRE1 and PERK dimerization/oligomerization and ATF6 export to the Golgi apparatus [87,97]
The three sensors of the Unfolded Protein Response (UPR) have been recently linked to tumor cell migration/invasion processes such as extracellular matrix (ECM) and actin cytoskeleton remodeling and cytoskeleton reorganization, modification of cellular adhesion, activation of signaling pathways associated with cell mobility, and epithelial-mesenchymal transition (EMT) [7,91,94,95]
Summary
Cell migration/invasion is one of the cancer hallmarks that drives cancer progression leading to tumor expansion of the adjacent tissues and/or to tumor dissemination through metastasis. These properties compromise the efficacy of the anti-cancer therapeutic approaches such as surgery or irradiation that rely on the existence of defined and limited zones within the tumor site. In glioblastoma (GBM), the diffuse infiltration of tumor cells into the cerebral neighboring parenchyma renders the complete and safe tumor resection as almost impossible This leads to the recurrence of GBM [1,2]. We discuss the therapeutic perspectives targeting the UPR/cancer cell migration/invasion links to limit the tumor dissemination
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