Drug Resistance Driven by Cancer Stem Cells and Their Niche

Prieto‐Vila, Marta; Takahashi, Ryou U.; Usuba, Wataru; Kohama, Isaku; Ochiya, Takahiro

doi:10.3390/ijms18122574

Cited by 419 publications

(359 citation statements)

References 172 publications

(213 reference statements)

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“…We can conclude that CSCs are a small population of cancer cells that have self-renewal capacity and differentiation potential, thereby conferring tumor relapse, metastasis, 643 heterogeneity, 644 multidrug resistance, 645,646 and radiation resistance. 647 Several pluripotent transcription factors, including Oct4, Sox2, Nanog, KLF4, and MYC and some intracellular signaling pathways, including Wnt, NF-κB, Notch, Hh, JAK-STAT, PI3K/AKT/mTOR, TGF/Smad, and PPAR, as well as extracellular factors, including vascular niches, hypoxia, TAM, CAF, cancer-associated MSCs, the ECM, and exosomes, are essential regulators of CSCs.…”

Section: Discussionmentioning

confidence: 92%

“…651 Fourth, the environmental factors in CSC niches are not well understood, and the relationship between TAMs/CAFs and CSCs has not been well studied. 645 Fifth, since CSCs also share some signaling pathways with normal stem cells, not all the regulatory factors that contribute to CSCs are appropriate for use as therapeutic targets in cancer treatment. Sixth, whether CSCs should be activated or arrested is an open question in cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

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Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,318

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,318

998

View full text Add to dashboard Cite

show abstract

“…In the context of our findings, cancer stem cells are a particularly intriguing subpopulation of cancer cells [68,69]. Usually quiescent by nature [70], they tend to be relatively resistant to drugs [71,72]. One would expect this resistance to be true for Hsp90 inhibitors as well, although several reports have mentioned that a variety of cancer stems cells can be targeted with Hsp90 inhibitors [73][74][75].…”

Section: Discussionmentioning

confidence: 73%

The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity

Echeverria

Bhattacharya

Joshi

et al. 2018

Preprint

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The molecular chaperone Hsp90 is an essential and highly abundant central node in the interactome of eukaryotic cells. Many of its large number of client proteins are relevant to cancer. A hallmark of Hsp90-dependent proteins is that their accumulation is compromised by Hsp90 inhibitors. Combined with the anecdotal observation that cancer cells may be more sensitive to Hsp90 inhibitors, this has led to clinical trials aiming to develop Hsp90 inhibitors as anti-cancer agents. However, the sensitivity to Hsp90 inhibitors has not been studied in rigorously matched normal versus cancer cells, and despite the discovery of important regulators of Hsp90 activity and inhibitor sensitivity, it has remained unclear, why cancer cells might be more sensitive. To revisit this issue more systematically, we have generated an isogenic pair of normal and oncogenically transformed NIH-3T3 cell lines. Our proteomic analysis of the impact of three chemically different Hsp90 inhibitors shows that these affect a substantial portion of the oncogenic program and that indeed, transformed cells are hypersensitive. Targeting the oncogenic signaling pathway reverses the hypersensitivity, and so do inhibitors of DNA replication, cell growth, translation and energy metabolism. Conversely, stimulating normal cells with growth factors or challenging their proteostasis by overexpressing an aggregation-prone sensitizes them to Hsp90 inhibitors. Thus, the differential sensitivity to Hsp90 inhibitors may not stem from any particular intrinsic difference between normal and cancer cells, but rather from a shift in the balance between cellular quiescence and activity.

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“…One of them, the cancer stem cell (CSC) theory, is based on the capacity of these cells to generate a proliferative progeny, initiating the growth of a heterogeneous tumor [5]. CSCs present chemotherapy resistance, allowing their survival to the treatment with subsequent proliferation and cancer relapse [6]. The role of CSCs in the ovarian cancer was reviewed by Giornelli et al, highlighting the importance of these cells in cancer recurrence and progression [7].…”

Section: Introductionmentioning

confidence: 99%

Linking endoplasmic reticulum stress to polyploidy in ovarian cancer cells

Yart

Bastida-Ruiz

Wuillemin

et al. 2020

Preprint

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Polyploid giant cancer cells (PGCCs) have been observed in epithelial ovarian tumors and have the ability to survive to antimitotic drugs. Their appearance can result from paclitaxel treatment or hypoxia, two conditions known to induce unfolded protein response (UPR) activation. PGCCs produced under hypoxia may be formed by cell fusion and can contribute by bursting and budding to the generation of cancer stem-like cells which have a more aggressive phenotype than the parental cells. Despite the fact that PGCCs may contribute to tumor maintenance and recurrence, they were poorly studied. Here, we confirmed that PGCCs could derive, at least in part, from cell fusion. We also observed that PGCCs nuclei were able to fuse. The resulting cells were able to proliferate by mitosis and were more invasive than the parental cancer cells. Using two different ovarian cancer cell lines (COV318 and SKOV3), we showed that UPR activation with chemical inducers increased cell fusion and PGCCs appearance. Down-regulation of the UPR-associated protein PERK expression partially reversed the UPR-induced PGCCs formation, suggesting that the PERK arm of the UPR is involved in ovarian PGCCs onset. Keywords: ER stress; unfolded protein response; ovarian cancer; PGCC; cell fusion; nuclei fusion; invasion large cells containing several copies of DNA and positive for cancer stem cell markers [10]. Interestingly, the presence of PGCCs in ovarian cancer has been reported preferentially at late disease stages and in high pathological grades [10]. We previously showed that primary EOC cells isolated from malignant ascites were able to spontaneously form PGCCs in culture [11]. However, the origin of PGCCs is controversial since both fusion or endoreplication processes could give rise to them [8,9,12]. Zhang et al., demonstrated that in SKOV3, an EOC cell line established from ascites, the formation of PGCCs was at least partially due to cell fusion events [9]. In the study conducted by Zhang et al., the PGCCs derived from EOC cells had striking properties such as different cell cycle regulation and division profile, changing their daughter generation mechanism from mitosis to budding, which confer these cells the resistance to cytotoxic chemotherapy treatments [9]. Additionally, it was found that hypoxia increased PGCCs formation [9,[13][14][15], but other conditions such as chemotherapy could also favor their production [13].The tumor environment is known to be hypoxic and hypoglycemic due to the low irrigation caused by the fast and erroneous angiogenesis that tumor mass undergo [reviewed at [16]]. These conditions are capable of triggering the endoplasmic reticulum stress (ERS) response or unfolded protein response (UPR) which is essential for cellular adaptation to stressful situations [17]. In homeostatic conditions, the three UPR-associated proteins, protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α) and activating transcription factor 6 (ATF6), remain inactive because of their binding with Gl...

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Drug Resistance Driven by Cancer Stem Cells and Their Niche

Cited by 419 publications

References 172 publications

Targeting cancer stem cell pathways for cancer therapy

Targeting cancer stem cell pathways for cancer therapy

The sensitivity to Hsp90 inhibitors of both normal and oncogenically transformed cells is determined by the equilibrium between cellular quiescence and activity

Linking endoplasmic reticulum stress to polyploidy in ovarian cancer cells

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