Abstract
Tumor recurrence is a paradoxical function of a machinery, whereby a small proportion of the cancer cell population enters a resistant, dormant state, persists long-term in this condition, and then transitions to proliferation. The dormant phenotype is typical of cancer stem cells, tumor-initiating cells, disseminated tumor cells, and drug-tolerant persisters, which all demonstrate similar or even equivalent properties. Cancer cell dormancy and its conversion to repopulation are regulated by several protein signaling systems that inhibit or induce cell proliferation and provide optimal interrelations between cancer cells and their special niche; these systems act in close connection with tumor microenvironment and immune response mechanisms. During dormancy and reawakening periods, cell proteostasis machineries, autophagy, molecular chaperones, and the unfolded protein response are recruited to protect refractory tumor cells from a wide variety of stressors and therapeutic insults. Proteostasis mechanisms functionally or even physically interfere with the main regulators of tumor relapse, and the significance of these interactions and implications in the tumor recurrence phases are discussed in this review.
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Abbreviations
ATGs, autophagy-related genes; BM, bone marrow; CQ, сhloroquine; CRC, colorectal cancer cells; CSCs, cancer stem cells; CTCs, circulating tumor cells; DAMPs, damage-associated molecular patterns; DTCs, disseminated tumor cells; DTPs, drug-tolerant persisters; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EMT, epithelial-to-mesenchymal transition; ER, endoplasmic reticulum; ERAD, ER-associated degradation; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; GRP94, glucose-regulated protein 94 kDa; GIST, gastrointestinal stromal tumor; HCC, hepatocellular carcinoma; HCQ, hydroxychloroquine; HNSCC, head and neck squamous cell carcinoma; HIF1α, hypoxia-inducible factor 1α; HMGB1, high-mobility group box 1; HSP, heat shock protein; LKB1, liver kinase B1; MAPK, mitogen-activated protein kinase; MICs, metastasis-initiating cells; MLCK, myosin light chain kinase; MSCs, mesenchymal stem cells; NICD, NOTCH intracellular domain; NR2F1, Orphan nuclear receptor 1; NSCLC, non-small cell lung cancer; PDAC, pancreatic ductal adenocarcinoma; PDI, protein disulfide isomerase; PDX, patient-derived xenografts; PGCCs, polyploid giant cancer cells; PSA, prostate-specific antigen; ROS, reactive oxygen species; SPARC, secreted protein acidic and rich in cysteine; TBK1, Tank binding kinase 1; TEAD, transcriptional enhanced associated domain; TICs, tumor-initiating cells; TME, tumor microenvironment; TNBC, triple-negative breast cancer; TRAP1, Tumor necrosis factor receptor-associated protein 1; UPR, unfolded protein response; YAP, YES-associated protein; ZEB2, zinc finger E-box binding homeobox 2; 3-MA, 3-methyladenine
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The work was supported by the Ministry of Science and Higher Education of the Russian Federation (Grant No. 075-15-2020-773).
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Alhasan, B., Mikeladze, M., Guzhova, I. et al. Autophagy, molecular chaperones, and unfolded protein response as promoters of tumor recurrence. Cancer Metastasis Rev 42, 217–254 (2023). https://doi.org/10.1007/s10555-023-10085-3
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DOI: https://doi.org/10.1007/s10555-023-10085-3