Hypoxia as a signal for prison breakout in cancer

Redfern, Andrew; Agarwal, Veenoo; Thompson, Erik W.

doi:10.1097/mco.0000000000000577

Cited by 8 publications

(6 citation statements)

References 130 publications

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“…Moreover, increased ECM deposition and crosslinking compartmentalizes and compresses the tumor as its diverse cellular population proliferates (Tse et al, 2012;Vennin et al, 2018). The destabilized mechanical and biochemical profiles of the TME coalesce to drive pre-metastatic phenomena, such as epithelial-mesenchymal plasticity (EMP) (Redfern et al, 2019). In isolating TME mechanics' effect on tumor progression and metastasis, investigators employ a combination of 2D and 3D hydrogel-based cell culture systems.…”

Section: The Tumor Microenvironmentmentioning

confidence: 99%

The Cancer Microenvironment: Mechanical Challenges of the Metastatic Cascade

Amos

Choi

2021

Front. Bioeng. Biotechnol.

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The metastatic cascade presents a significant challenge to patient survival in the fight against cancer. As metastatic cells disseminate and colonize a secondary site, stepwise exposure to microenvironment-specific mechanical stimuli influences and protects successful metastasis. Following cancerous transformation and associated cell recruitment, the tumor microenvironment (TME) becomes a mechanically complex niche, owing to changes in extracellular matrix (ECM) stiffness and architecture. The ECM mechanically reprograms the cancer cell phenotype, priming cells for invasion. 2D and 3D hydrogel-based culture platforms approximate these environmental variables and permit investigations into tumor-dependent shifts in malignancy. Following TME modification, malignant cells must invade the local ECM, driven toward blood, and lymph vessels by sensing biochemical and biophysical gradients. Microfluidic chips recreate cancer-modified ECM tracks, empowering studies into modes of confined motility. Intravasation and extravasation consist of complex cancer-endothelial interactions that modify an otherwise submicron-scale migration. Perfused microfluidic platforms facilitate the physiological culture of endothelial cells and thus enhance the translatability of basic research into metastatic transendothelial migration. These platforms also shed light on the poorly understood circulating tumor cell, which defies adherent cell norms by surviving the shear stress of blood flow and avoiding anoikis. Metastatic cancers possess the plasticity to adapt to new mechanical conditions, permitting their invasiveness, and ensuring their survival against anomalous stimuli. Here, we review the cellular mechanics of metastasis in the context of current in vitro approaches. Advances that further expose the mechanisms underpinning the phenotypic fluidity of metastatic cancers remain central to the development of novel interventions targeting cancer.

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Section: The Tumor Microenvironmentmentioning

confidence: 99%

The Cancer Microenvironment: Mechanical Challenges of the Metastatic Cascade

Amos

Choi

2021

Front. Bioeng. Biotechnol.

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“…genes involved in various cellular and physiological functions, triggers angiogenesis, and induces tumor cells escaping from the cytotoxic effect of chemotherapeutic agents, ultimately resulting in a more aggressive and lower chemotherapy-sensitive tumor phenotype. [16][17][18] It follows that a thorough elucidation of hypoxia-mediated tumorigenesis will provide a novel sight for NSCLC treatment. Previous studies have demonstrated that hypoxic cell-derived exos have a role in the development of human cancer.…”

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confidence: 99%

<p>Hypoxic Non-Small-Cell Lung Cancer Cell-Secreted Exosomal microRNA-582-3p Drives Cancer Cell Malignant Phenotypes by Targeting Secreted Frizzled-Related Protein 1</p>

Wang

Zhao

Zhu

et al. 2020

CMAR

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Background: Hypoxic environment and exosomes (exos)-mediated intercellular communication are crucial for cancer invasion and metastasis, but the mechanisms are not yet fully understood. In this study, we investigated the regulatory effect of hypoxic tumor cell-secreted exosomal miR-582-3p on non-small-cell lung cancer (NSCLC) cell malignant phenotypes. Methods: The concentration and diameters of exos were evaluated by nanosight particle tracking analysis. microRNA-582-3p (miR-582-3p) expression was detected by quantitative real-time PCR. The fluorescent dye PKH26 was used to label exos. The direct interaction between miR-582-3p and secreted frizzled-related protein 1 (SFRP1) was determined by dual-luciferase activity assay. NSCLC cell proliferation, migration, and invasion abilities were assessed by cell count kit-8 assay, wound healing assay, and transwell migration and invasion assay. Western blot analysis was performed to detect the protein expression level. Results: Hypoxic NSCLC cell-derived exos promoted the proliferation, migration, and invasion of normoxic NSCLC cells. miR-582-3p expression was upregulated in hypoxic NSCLC cells and hypoxic NSCLC cell-secreted exos. Hypoxic NSCLC cell-derived exos transmitted miR-582-3p to normoxic NSCLC cells. Hypoxic NSCLC cell-secreted exosomal miR-582-3p promoted the proliferation, migration, and invasion of normoxic NSCLC cells. miR-582-3p inhibited the expression of SFRP1 protein by binding to its 3ʹ-UTR. In addition, enforced expression of SFRP1 restrained malignant phenotypes of normoxic NSCLC cells, which was abrogated by hypoxic NSCLC cell-secreted exosomal miR-582-3p. Conclusion: Hypoxic NSCLC cell-secreted exosomal miR-582-3p drives cancer cell malignant phenotypes by targeting SFRP1, which provides a better understanding of cancer metastasis and may facilitate the development of therapeutics against human NSCLC.

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“…Tissue hypoxia is a key driver for angiogenic response and tumor progression [ 48 ]. The transcription factor HIF-1α regulates more than 100 genes involved in cancer cell proliferation, apoptosis and angiogenesis, and plays a key role in hypoxia-induced chemoresistance in ovarian cancers.…”

Section: Discussionmentioning

confidence: 99%

Theasaponin E1 Inhibits Platinum-Resistant Ovarian Cancer Cells through Activating Apoptosis and Suppressing Angiogenesis

Tong

Ren

et al. 2021

Molecules

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Novel therapeutic strategies for ovarian cancer treatment are in critical need due to the chemoresistance and adverse side effects of platinum-based chemotherapy. Theasaponin E1 (TSE1) is an oleanane-type saponin from Camellia sinensis seeds. Its apoptosis-inducing, cell cycle arresting and antiangiogenesis activities against platinum-resistant ovarian cancer cells were elucidated in vitro and using the chicken chorioallantoic membrane (CAM) assay. The results showed that TSE1 had more potent cell growth inhibitory effects on ovarian cancer OVCAR-3 and A2780/CP70 cells than cisplatin and was lower in cytotoxicity to normal ovarian IOSE-364 cells. TSE1 significantly induced OVCAR-3 cell apoptosis via the intrinsic and extrinsic apoptotic pathways, slightly arresting cell cycle at the G2/M phase, and obviously inhibited OVCAR-3 cell migration and angiogenesis with reducing the protein secretion and expression of vascular endothelial growth factor (VEGF). Western bolt assay showed that Serine/threonine Kinase (Akt) signaling related proteins including Ataxia telangiectasia mutated kinase (ATM), Phosphatase and tensin homolog (PTEN), Akt, Mammalian target of rapamycin (mTOR), Ribosome S6 protein kinase (p70S6K) and e IF4E-binding protein 1(4E-BP1) were regulated, and Hypoxia inducible factor-1α (HIF-1α) protein expression was decreased by TSE1 in OVCAR-3 cells. Moreover, TSE1 treatment potently downregulated protein expression of the Notch ligands including Delta-like protein 4 (Dll4) and Jagged1, and reduced the protein level of the intracellular domain (NICD) of Notch1. Combination treatment of TSE1 with the Notch1 signaling inhibitor tert-butyl (2S)-2-[[(2S)-2-[[2-(3,5-difluorophenyl)acetyl]amino]propanoyl]amino]-2-phenylacetate (DAPT), or the Akt signaling inhibitor wortmannin, showed a stronger inhibition toward HIF-1α activation compared with single compound treatment. Taken together, TSE1 might be a potential candidate compound for improving platinum-resistant ovarian cancer treatment via Dll4/Jagged1-Notch1-Akt-HIF-1α axis.

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Hypoxia as a signal for prison breakout in cancer

Cited by 8 publications

References 130 publications

The Cancer Microenvironment: Mechanical Challenges of the Metastatic Cascade

The Cancer Microenvironment: Mechanical Challenges of the Metastatic Cascade

<p>Hypoxic Non-Small-Cell Lung Cancer Cell-Secreted Exosomal microRNA-582-3p Drives Cancer Cell Malignant Phenotypes by Targeting Secreted Frizzled-Related Protein 1</p>

Theasaponin E1 Inhibits Platinum-Resistant Ovarian Cancer Cells through Activating Apoptosis and Suppressing Angiogenesis

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