Stress-induced TRAILR2 expression overcomes TRAIL resistance in cancer cell spheroids

Stöhr, Daniela; Schmid, Jens O.; Beigl, Tobias B.; Mack, Alexandra; Maichl, Daniela Simone; Cao, Kai; Budai, Beate; Fullstone, Gavin; Kontermann, Roland E.; Mürdter, Thomas E.; Tait, Stephen W.G.; Hagenlocher, Cathrin; Pollak, Nadine; Scheurich, Peter; Rehm, Markus

doi:10.1038/s41418-020-0559-3

Cited by 18 publications

(20 citation statements)

References 55 publications

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“…Analysis of sub-cellular entities such as the nucleus under individual stress conditions reveals that deprivation of glucose and protein for 72 h is not enough to inhibit cell division and induce cell death which contradict the previous reports from the monolayer culture [59,60]. The minimal occurrence of apoptotic cells can be explained by the anti-apoptotic nature of the three-dimensional structures of spheroids [61] and the availability of a TRAIL-resistant population [62]. Additional sporadic observations such as multi-nucleation and cell-in-cell phenomena can be explained by the mitotic stress [63] and entosis [64,65].…”

Section: Discussionmentioning

confidence: 77%

Macro- and micro-nutrient–based multiplex stress conditions modulate in vitro tumorigenesis and aggressive behavior of breast cancer spheroids

et al. 2021

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PurposeThe aggressive nature of a tumor is presumably its inherent one, but different environmental cues can manipulate it in many ways. In this context, the influence of metabolic stresses on tumor behavior needs to be analyzed to understand their far-reaching implications on tumor aggression and dormancy. This work investigates different facets of the tumor, such as tumorigenic capacity, tumor phenotype, and migration, under multiple metabolic stress conditions. Methods Non-invasive and invasive multicellular spheroids (MTS) were created and subjected to multiple stress conditions, namely glucose, amino acid, and oxygen deprivation. Altered behavior of the MTS has been evaluated in the context of in vitro tumorigenesis, spheroid formation capacity, phenotype, mRNA profile, migration, and recruitment of mesenchymal stem cells. ResultsThe metabolic stress conditions were observed to negatively impact the in vitro tumorigenesis and spheroid formation process of invasive and non-invasive breast cancer cells. While the stress seemingly influences the growth and phenotype of spheroids, it does not alter the organization of sub-cellular entities significantly. Metabolic stress conditions impact the transcriptomic landscape of hypoxic, angiogenic, ECM deformation, glycolysis shift, and protein starvation-related gene clusters. MTSs do not adhere or migrate under stress, but they exhibit different modalities of migration when rescued. Invasive spheroids, after the rescue, exhibit increased aggressiveness. Furthermore, stressed spheroid was observed to control the migration and recruitment of mesenchymal stem cells. Conclusion Multiplex metabolic stresses could control the tumorigenesis while influencing the physiology of invasive and non-invasive breast cancer spheroids along with their migration pattern and tumor-stromal crosstalk.

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Section: Discussionmentioning

confidence: 77%

Macro- and micro-nutrient–based multiplex stress conditions modulate in vitro tumorigenesis and aggressive behavior of breast cancer spheroids

et al. 2021

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“…Human tumor necrosis factor (TNF)-related apoptosis ligand (TRAIL) is suggested to be involved in triggering apoptosis in tumor cells [ 271 ]. However, experiments have shown capacity of tumor cells in obtaining resistance to TRAIL-mediated apoptosis [ 272 , 273 , 274 , 275 ]. Furthermore, TRAIL can surprisingly enhance progression of cancer cells via inducing NF-κB signaling [ 276 , 277 ].…”

Section: Dietary Agents and Cancer Stem Cellsmentioning

confidence: 99%

Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strategy against Human Malignancies

Paskeh

Asadi²,

Zabolian

et al. 2021

IJMS

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As a multifactorial disease, treatment of cancer depends on understanding unique mechanisms involved in its progression. The cancer stem cells (CSCs) are responsible for tumor stemness and by enhancing colony formation, proliferation as well as metastasis, and these cells can also mediate resistance to therapy. Furthermore, the presence of CSCs leads to cancer recurrence and therefore their complete eradication can have immense therapeutic benefits. The present review focuses on targeting CSCs by natural products in cancer therapy. The growth and colony formation capacities of CSCs have been reported can be attenuated by the dietary agents. These compounds can induce apoptosis in CSCs and reduce tumor migration and invasion via EMT inhibition. A variety of molecular pathways including STAT3, Wnt/β-catenin, Sonic Hedgehog, Gli1 and NF-κB undergo down-regulation by dietary agents in suppressing CSC features. Upon exposure to natural agents, a significant decrease occurs in levels of CSC markers including CD44, CD133, ALDH1, Oct4 and Nanog to impair cancer stemness. Furthermore, CSC suppression by dietary agents can enhance sensitivity of tumors to chemotherapy and radiotherapy. In addition to in vitro studies, as well as experiments on the different preclinical models have shown capacity of natural products in suppressing cancer stemness. Furthermore, use of nanostructures for improving therapeutic impact of dietary agents is recommended to rapidly translate preclinical findings for clinical use.

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“…Finally, miR-100 has been shown to target mTOR, a key regulator of motility by the PI3K/Akt pathway, which leads to the regulation of 4E-BP1 and p70S6K pathways. Interestingly, p70S6K is a cell cycle effector that directly regulates mRNA in cell cycle progression [ 100 ].…”

Section: Regulation Mechanismmentioning

confidence: 99%

Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL

Quiroz-Reyes,

Delgado-Gonzalez,

Islas

et al. 2021

Pharmaceutics

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Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. TRAIL has been widely studied as a novel strategy for tumor elimination, as cancer cells overexpress TRAIL death receptors, inducing apoptosis and inhibiting blood vessel formation. However, cancer stem cells (CSCs), which are the main culprits responsible for therapy resistance and cancer remission, can easily develop evasion mechanisms for TRAIL apoptosis. By further modifying their properties, they take advantage of this molecule to improve survival and angiogenesis. The molecular mechanisms that CSCs use for TRAIL resistance and angiogenesis development are not well elucidated. Recent research has shown that proteins and transcription factors from the cell cycle, survival, and invasion pathways are involved. This review summarizes the main mechanism of cell adaption by TRAIL to promote response angiogenic or pro-angiogenic intermediates that facilitate TRAIL resistance regulation and cancer progression by CSCs and novel strategies to induce apoptosis.

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Stress-induced TRAILR2 expression overcomes TRAIL resistance in cancer cell spheroids

Cited by 18 publications

References 55 publications

Macro- and micro-nutrient–based multiplex stress conditions modulate in vitro tumorigenesis and aggressive behavior of breast cancer spheroids

Macro- and micro-nutrient–based multiplex stress conditions modulate in vitro tumorigenesis and aggressive behavior of breast cancer spheroids

Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strategy against Human Malignancies

Behind the Adaptive and Resistance Mechanisms of Cancer Stem Cells to TRAIL

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