Role of telomerase in the tumour microenvironment

Abstract

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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“…TERT encodes telomerase reverse transcriptase and is essential for telomere maintenance, but it also appears to function as a transcriptional co-activator 35 and impacts on the tumor microenvironment via diverse pathways, including inflammation. It is possible therefore that chronic inflammation provides a link between genetic and environmental predisposition to CH.…”

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“…In light of new observations indicating that maintaining genome stability CSCs might be on account of activation of DDR pathways. Activation of telomerase is one of the critical DDR pathways in GSCs ( 54 ). Guanine-rich repeated sequences are attached to the chromosomal terminals using the RNA template by telomerase which recompense the loss of DNA replication.…”

“…Irrespective of telomerase function, the TERC subunit is expressed in most cell types and the TERT subunit is heavily regulated through cell differentiation. The expression of TERT and TERC in normal cells is small, but the expression of TERT and TERC in tumor cells is indeed very substantial ( 54 , 57 ). Telomerase is a reverse transcriptase enzyme that has a canonical and non-canonical function in cancer cells.…”

“…Of note, the investigations have revealed that TERT has direct interaction with β-catenin and presumably enhance transcriptional outputs of it. Besides, activated-TERT- β-catenin axis mayhap stimulate epithelial-mesenchymal transformation (EMT) in CSCs ( 54 , 86 , 88 ). CSCs and TERT could be linked together by Wnt/β-catenin pathway ( 85 , 89 ).…”

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“…In that study, it was demonstrated that sulforaphane reduces the expression of both miR-21 and telomerase reverse transcriptase (TERT) [ 30 ]. TERT is generally recognized to exhibit multiple oncogenic activities, contributing to the regulation of angiogenesis, stemness, EMT, and metastasis [ 159 ]. Downregulation of TERT levels can be due to the ability of sulforaphane to turn off the transcription of TERT by recruiting methyl-CpG binding protein 2 (MECP2) to the TERT promoter [ 160 ].…”