Chromosomal Instability in Tumor Initiation and Development

Bach, Duc Hiep; Zhang, Wei; Sood, Anil K.

doi:10.1158/0008-5472.can-18-3235

Cited by 72 publications

(51 citation statements)

References 115 publications

(117 reference statements)

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“…Therefore, various studies have attempted to elucidate the mechanisms of resistance to overcome or delay the resistance of NSCLC cells (22,23,25,(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45). In addition, recent comprehensive proteomic technologies display a great opportunity to investigate novel clinically relevant oncogenic pathways that may have been over-looked by cancer gene screens (46,47). AGR2, one of these recently discovered oncogenes related to p53, is directly involved in malignant transformation and is able to act as a survival factor through drug resistance (48).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

et al. 2020

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Background/Aim: The resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib or erlotinib, is considered a major challenge in the treatment of patients with non-small cell lung cancer (NSCLC). Herein, we identified the critical roles of anterior gradient 2 (AGR2) in gefitinib (Gef) resistance of mutant NSCLC cells. Materials and Methods: Using datasets from a pair of NSCLCsensitive and NSCLC-resistant cells, immunoblotting, immunofluorescence and immunohistochemistry, and cell viability assays were applied to identify the effects of AGR2. Results: AGR2 was found to be significantly over-expressed in Gef-resistant cells and was highly associated with drug resistance, proliferation, migration, and invasion of cancer cells. Moreover, AGR2 and ADAMTS6 formed a negative feedback loop in drug-resistant cells. Conclusion: Modulation of overexpression of AGR2 in mutant NSCLC cells may be an attractive therapeutic strategy for the treatment of EGFR-TKI-resistant NSCLC. Non-small cell lung cancer (NSCLC) is one of the major causes of cancer-related death worldwide, and comprises 85% of all lung cancer cases (1). Acquired drug resistance in tumor cells is a major obstacle in the field of anti-cancer chemotherapies. Likewise, NSCLC patients who initially show a good response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib (Gef), acquire resistance to treatment (2). However, studies on the mechanisms through which overexpression of specific genes is involved in EGFR-TKI resistanse of NSCLC cells are scarce and its role remains to be elucidated. Therefore, novel approaches are required to elucidate their role in drug resistanse of cancer cells. The anterior gradient-2 (AGR2) has been identified in Xenopus laevis and plays a critical role in cemet gland differentiation (3). Recent studies have suggested that elevated expression of AGR2 is correlated with cell proliferation, metastasis, and drug resistance in various human cancer cell lines, such as prostate (4), breast (5), and pancreatic cancer (6). Moreover, overexpression of AGR2 has been notably correlated with a poor outcome of estrogen receptor-negative breast cancer patients (7). AGR2 is also a pro-oncogenic protein that has been shown to stimulate the epidermal growth factor receptor (EGFR) ligand amphiregulin, regulate p53 signaling, and interact with the AAA+ protein Reptin (8), suggesting its modulatory roles in gene expression. High expression of AGR2 has also been shown to be predictive of poor survival in lung cancer (9). However, there is still a lack of insightful understanding of the role of AGR2 in EGFR-TKI-resistant NSCLC cells. There are 19 members of zinc-dependent metalloproteases in the family of a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) (10). Recent reports suggest the critical roles of ADAMTSs in angiogenesis and cancer (11). They also play an important role in the modulation of extracellular matrix. For instance, ADAMTS-1 metallopro...

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Section: Discussionmentioning

confidence: 99%

Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

et al. 2020

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“…The cross‐talk between the cancer cells and their environment involves numerous oncogenic transcription factors. These factors are aberrantly reactivated and trigger a series of cellular events such as genome instability, reprogrammed metabolism, infinite proliferation, angiogenesis, invasion and metastasis, immune cell infiltration, and enhanced inflammation, all of which have been widely recognized as the characteristics of cancer …”

Section: Introductionmentioning

confidence: 99%

Role of telomerase in the tumour microenvironment

Liu

Guo

Liu

et al. 2019

Clin Exp Pharma Physio

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The tumour mass is an organ-like structure consisting of cancer cells and their directly associated microenvironment. The tumour microenvironment (TME) is the local environment where malignant cells strive and survive, and is composed of cancers cells and their surroundings such as blood vessels, extracellular matrix (ECM), infiltrating immune cells, fibroblasts, and signalling molecules. 1,2 In addition, cancer stem cells (CSCs) and endoplasmic reticulum (ER) stress influence the properties of the TME to benefit tumour cell growth. 3,4 The cross-talk between the cancer cells and their environment involves numerous oncogenic transcription factors. These factors are aberrantly reactivated and trigger a series of cellular events such as genome instability, reprogrammed metabolism, infinite proliferation, angiogenesis, invasion and metastasis, immune cell infiltration, and enhanced inflammation, all of which have been widely recognized as the characteristics of cancer. Telomeres consist of a non-coding DNA tandem repeat of sequence 5′-TTAGGG-3′, located at the ends of the linear eukaryotic chromosomes. 26,27 Due to "the end replication problem", the telomeres shorten with each round of DNA replication. Once their lengths shorten to a certain level, the cells may undergo replicative senescence. 26,28 Telomerase is an RNA-dependent DNA polymerase that synthesizes telomeric DNA sequences and maintains the telomere length, providing the immortal cells with the molecular basis for unlimited proliferation potential. Human telomerase essentially AbstractTelomeres are specialized genomic structures that protect chromosomal ends to maintain genomic stability. Telomeric length is primarily regulated by the telomerase complex, essentially consisting of an RNA template (TERC), an enzymatic subunit (telomerase reverse transcriptase, TERT). In humans, telomerase activity is repressed during embryonic differentiation and is absent in most somatic cells. However, it is upregulated or reactivated in 80%-90% of the primary tumours in humans. The human TERT (hTERT) plays a pivotal role in cellular immortality and tumourigenesis.However, the molecular mechanisms of telomerase functioning in cancer have not been fully understood beyond the telomere maintenance. Several research groups, including ours, have demonstrated that hTERT possesses vital functions independent of its telomere maintenance, including angiogenesis, inflammation, cancer cell stemness, and epithelial-mesenchymal transformation (EMT). All these telomereindependent activities of hTERT may contribute to the regulation of the dynamics and homeostasis of the tumour microenvironment (TME), thereby promoting tumour growth and development. Cancer progression and metastasis largely depend upon the interactions between cancer cells and their microenvironment. In this review, the involvement of TERT in the tumour microenvironment and the underlying implications in cancer therapeutics have been summarized. K E Y W O R D Sangiogenesis, inflammation, telomerase, TERT, tumour micro...

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“…Besides MSI, tumor cells can harbor another major type of instability that contributes to tumor heterogeneity called chromosomal instability, or CIN. CIN is generally associated with structural and numerical chromosomal changes (Bach et al, 2019 ) and is caused by errors in chromosome segregation due to abnormal alignments of chromosomes in mitotic metaphase. The high rate of chromosome segregation errors, characteristic for cancer, ultimately leads to aneuploidy in the resulting progeny of cancer cells (Sansregret and Swanton, 2017 ).…”

Section: Mismatch Repair System (Mmr) and Microsatellite Instability mentioning

confidence: 99%

Mismatch Repair Pathway, Genome Stability and Cancer

Pećina‐Šlaus

Kafka

Salamon

et al. 2020

Front. Mol. Biosci.

148

107

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The acquisition of genomic instability is one of the key characteristics of the cancer cell, and microsatellite instability (MSI) is an important segment of this phenomenon. This review aims to describe the mismatch DNA repair (MMR) system whose deficiency is responsible for MSI and discuss the cellular roles of MMR genes. Malfunctioning of the MMR repair pathway increases the mutational burden of specific cancers and is often involved in its etiology, sometimes as an influential bystander and sometimes as the main driving force. Detecting the presence of MSI has for a long time been an important part of clinical diagnostics, but has still not achieved its full potential. The MSI blueprints of specific tumors are useful for precize grading, evaluation of cancer chance and prognosis and to help us understand how and why therapy-resistant cancers arise. Furthermore, evidence indicates that MSI is an important predictive biomarker for the application of immunotherapy.

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Chromosomal Instability in Tumor Initiation and Development

Cited by 72 publications

References 115 publications

Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

Overexpression of AGR2 Is Associated With Drug Resistance in Mutant Non-small Cell Lung Cancers

Role of telomerase in the tumour microenvironment

Mismatch Repair Pathway, Genome Stability and Cancer

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