Telomere DNA damage signaling regulates cancer stem cell evolution, epithelial mesenchymal transition, and metastasis

Lagunas, Angelica M.; Wu, Jianchun; Crowe, David L.

doi:10.18632/oncotarget.20960

Cited by 11 publications

(11 citation statements)

References 53 publications

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“…Aberrant TERT expression was shown to promote malignant transformation by influencing many processes such as cell signaling, proliferation, apoptosis and migration. Recently, TERT overexpression has been demonstrated to promote invasion in cancer cells through the acquisition of an invasive mesenchymal phenotype (epithelial-to-mesenchymal transition) and stem cell-like traits [56,57,58].…”

Section: Telomere Biology In Cancerogenesismentioning

confidence: 99%

Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma

Ventura

Pellegrini

Cardelli

et al. 2019

IJMS

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The role of telomere biology and telomerase activation in skin cancers has been investigated in melanoma and basal cell carcinoma but limited evidence is available for cutaneous squamous cell carcinoma (cSCC). We will review the current knowledge on the role of telomere and telomerase pathway in cSCC pathogenesis. At the somatic level, both long and short telomere lengths have been described in cSCC. This telomere dichotomy is probably related to two different mechanisms of tumour initiation which determines two tumour subtypes. Telomere shortening is observed during the invasive progression from in situ forms of cSCC, such as Bowen’s disease (BD) and actinic keratosis (AK), to invasive cSCC. At the germline level, controversial results have been reported on the association between constitutive telomere length and risk of cSCC. Approximately 75–85% of cSCC tumours are characterized by a high level of telomerase activity. Telomerase activation has been also reported in AKs and BD and in sun-damaged skin, thus supporting the hypothesis that UV modulates telomerase activity in the skin. Activating TERT promoter mutations have been identified in 32–70% of cSCCs, with the majority showing the UV-signature. No significant correlation was observed between TERT promoter mutations and cSCC clinico-pathological features. However, TERT promoter mutations have been recently suggested to be independent predictors of an adverse outcome. The attention on telomere biology and telomerase activity in cSCC is increasing for the potential implications in the development of effective tools for prognostic assessment and of therapeutic strategies in patients with cutaneous cSCC.

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Section: Telomere Biology In Cancerogenesismentioning

confidence: 99%

Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma

Ventura

Pellegrini

Cardelli

et al. 2019

IJMS

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“…DNA damage also activates metastasis-related gene through EPC1/E2F1 pathway [22]. Telomeric DNA damage signaling regulates cancer stem cell evolution, epithelial mesenchymal transition, and metastasis [23]. ATM activates JAK/STAT3 signaling in cisplatin-resistant lung cancer cells, while inhibition of ATM inhibits invasion and metastasis [24].…”

Section: Introductionmentioning

confidence: 99%

Topoisomerase inhibitors promote cancer cell motility via ROS-mediated activation of JAK2-STAT1-CXCL1 pathway

Liu

Meng

et al. 2019

J Exp Clin Cancer Res

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Background: Topoisomerase inhibitors (TI) can inhibit cell proliferation by preventing DNA replication, stimulating DNA damage and inducing cell cycle arrest. Although these agents have been commonly used in the chemotherapy for the anti-proliferative effect, their impacts on the metastasis of cancer cells remain obscure. Methods: We used the transwell chamber assay to test effects of Topoisomerase inhibitors Etoposide (VP-16), Adriamycin (ADM) and Irinotecan (CPT-11) on the migration and invasion of cancer cells. Conditioned medium (CM) from TI-treated cells was subjected to Mass spectrometry screening. Gene silencing, neutralizing antibody, and specific chemical inhibitors were used to validate the roles of signaling molecules. Results: Our studies disclosed that TI could promote the migration and invasion of a subset of cancer cells, which were dependent on chemokine (C-X-C motif) ligand 1 (CXCL1). Further studies disclosed that TI enhanced phosphorylation of Janus kinase 2 (JAK2) and Signal transducers and activators of transcription 1 (STAT1). Silencing or chemical inhibition of JAK2 or STAT1 abrogated TI-induced CXCL1 expression and cell motility. Moreover, TI increased cellular levels of reactive oxygen species (ROS) and promoted oxidation of Protein Tyrosine Phosphatase 1B (PTP1B), while reduced glutathione (GSH) reversed TI-induced JAK2-STAT1 activation, CXCL1 expression, and cell motility. Conclusions: Our study demonstrates that TI can promote the expression and secretion of CXCL1 by elevating ROS, inactivating PTP1B, and activating JAK2-STAT1 signaling pathway, thereby promoting the motility of cancer cells.

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“…As TGF-β, an essential factor in EMT development, and telomere protection factors, namely TRF2, both play an important role in age-related diseases such as cancer, a direct or indirect interaction may exist between the two. DNA damage signaling at the telomeres has been reported to regulate the progression and metastasis of cancer stem cells [ 110 ]. The schematic diagram, as shown in Figure 2 , suggests that Akt, a downstream factor in the TGF-β signaling pathway is directly inhibited by TRF1 [ 111 ].…”

Section: Is There Any Interconnection Between Emt and Telomeres?mentioning

confidence: 99%

Is There an Interconnection between Epithelial–Mesenchymal Transition (EMT) and Telomere Shortening in Aging?

Imran

Yazid

Idrus

et al. 2021

IJMS

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Epithelial–Mesenchymal Transition (EMT) was first discovered during the transition of cells from the primitive streak during embryogenesis in chicks. It was later discovered that EMT holds greater potential in areas other than the early development of cells and tissues since it also plays a vital role in wound healing and cancer development. EMT can be classified into three types based on physiological functions. EMT type 3, which involves neoplastic development and metastasis, has been the most thoroughly explored. As EMT is often found in cancer stem cells, most research has focused on its association with other factors involving cancer progression, including telomeres. However, as telomeres are also mainly involved in aging, any possible interaction between the two would be worth noting, especially as telomere dysfunction also contributes to cancer and other age-related diseases. Ascertaining the balance between degeneration and cancer development is crucial in cell biology, in which telomeres function as a key regulator between the two extremes. The essential roles that EMT and telomere protection have in aging reveal a potential mutual interaction that has not yet been explored, and which could be used in disease therapy. In this review, the known functions of EMT and telomeres in aging are discussed and their potential interaction in age-related diseases is highlighted.

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Telomere DNA damage signaling regulates cancer stem cell evolution, epithelial mesenchymal transition, and metastasis

Cited by 11 publications

References 53 publications

Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma

Telomeres and Telomerase in Cutaneous Squamous Cell Carcinoma

Topoisomerase inhibitors promote cancer cell motility via ROS-mediated activation of JAK2-STAT1-CXCL1 pathway

Is There an Interconnection between Epithelial–Mesenchymal Transition (EMT) and Telomere Shortening in Aging?

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