The Genes of Life and Death: A Potential Role for Placental‐Specific Genes in Cancer

Macaulay, Erin C.; Chatterjee, Aniruddha; Cheng, Xi; Baguley, Bruce C.; Eccles, Michael R.; Morison, Ian M.

doi:10.1002/bies.201700091

Cited by 13 publications

(11 citation statements)

References 122 publications

(168 reference statements)

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“…Trophoblast cells have many unique features that set them apart from all other cell types, including global hypomethylation, differential expression of microRNAs, unusual patterns of HLA molecule expression and expression of endogenous retroviral products (Macaulay et al, 2017;Sadovsky et al, 2015). Imprinted genes, preferentially expressed from one parental allele, are also important in placental development and, out of the 92 human imprinted genes, 75 are expressed in the placenta (Monk, 2015).…”

Section: Molecular Mechanisms Underpinning Human Placental Developmentmentioning

confidence: 99%

Development of the human placenta

2019

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The placenta is essential for normal in utero development in mammals. In humans, defective placental formation underpins common pregnancy disorders such as pre-eclampsia and fetal growth restriction. The great variation in placental types across mammals means that animal models have been of limited use in understanding human placental development. However, new tools for studying human placental development, including 3D organoids, stem cell culture systems and single cell RNA sequencing, have brought new insights into this field. Here, we review the morphological, molecular and functional aspects of human placental formation, with a focus on the defining cell of the placentathe trophoblast.

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Section: Molecular Mechanisms Underpinning Human Placental Developmentmentioning

confidence: 99%

Development of the human placenta

2019

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“…A number of placental-specific promoter elements in the human genome are derived from ERV sequences (50). In some cases, these are alternate promoters to the somatic promoter, giving rise to placental-specific transcripts (51). KCHN5 is a voltage-gated potassium channel, which has a diverse range of functions.…”

Section: Functional Tes In the Placentamentioning

confidence: 99%

Reawakening the Developmental Origins of Cancer Through Transposable Elements

et al. 2020

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Transposable elements (TEs) have an established role as important regulators of early human development, functioning as tissue-specific genes and regulatory elements. Functional TEs are highly active during early development, and interact with important developmental genes, some of which also function as oncogenes. Dedifferentiation is a hallmark of cancer, and is characterized by genetic and epigenetic changes that enable proliferation, self-renewal and a metabolism reminiscent of embryonic stem cells. There is also compelling evidence suggesting that the path to dedifferentiation in cancer can contribute to invasion and metastasis. TEs are frequently expressed in cancer, and recent work has identified a newly proposed mechanism involving extensive recruitment of TE-derived promoters to drive expression of oncogenes and subsequently promote oncogenesis-a process termed onco-exaptation. However, the mechanism by which this phenomenon occurs, and the extent to which it contributes to oncogenesis remains unknown. Initial hypotheses have proposed that onco-exaptation events are cancerspecific and arise randomly due to the dysregulated and hypomethylated state of cancer cells and abundance of TEs across the genome. However, we suspect that exaptationlike events may not just arise due to chance activation of novel regulatory relationships as proposed previously, but as a result of the reestablishment of early developmental regulatory relationships. Dedifferentiation in cancer is well-documented, along with expression of TEs. The known interactions between TEs and pluripotency factors such as NANOG and OCTt4 during early development, along with the expression of some placental-specific TE-derived transcripts in cancer support a possible link between TEs and dedifferentiation of tumor cells. Thus, we hypothesize that onco-exaptation events can be associated with the epigenetic reawakening of early developmental TEs to regulate expression of oncogenes and promote oncogenesis. We also suspect that activation of these early developmental regulatory TEs may promote dedifferentiation, although at this stage it is hard to predict whether TE activation is one of the initial drivers of dedifferentiation. We expect that developmental TE activation occurs as a result of the establishment of an epigenetic landscape in cancer that resembles that of early development and that developmental TE activation may also enable cancers to exploit early developmental pathways, repurposing them to promote malignancy.

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“…To some degree, this altered, or confused, developmental model has been applied to interpret the expression of meiotic genes in GC tumours. However, a range of cancers express distinct subsets of genes from various otherwise restricted programmes such as meiotic/germ line and placental/embryogenesis‐related to a varying degree (Jungbluth et al ., ; Macaulay et al ., ; McFarlane & Wakeman, ; Bruggeman et al ., ; Costanzo et al ., ). Hence, it could be speculated that cancer cells acquire their malignant characteristics by aberrant activation of a single gene or cluster of genes from one or more of these programmes, and this occurs as it confers a selective advantage on the cancer cell.…”

Section: Discussionmentioning

confidence: 99%

Meiotic gene activation in somatic and germ cell tumours

Feichtinger

McFarlane

2019

Andrology

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Background Germ cell tumours are uniquely associated with the gametogenic tissues of males and females. A feature of these cancers is that they can express genes that are normally tightly restricted to meiotic cells. This aberrant gene expression has been used as an indicator that these cancer cells are attempting a programmed germ line event, meiotic entry. However, work in non‐germ cell cancers has also indicated that meiotic genes can become aberrantly activated in a wide range of cancer types and indeed provide functions that serve as oncogenic drivers. Here, we review the activation of meiotic factors in cancers and explore commonalities between meiotic gene activation in germ cell and non‐germ cell cancers. Objectives The objectives of this review are to highlight key questions relating to meiotic gene activation in germ cell tumours and to offer possible interpretations as to the biological relevance in this unique cancer type. Materials and Methods PubMed and the GEPIA database were searched for papers in English and for cancer gene expression data, respectively. Results We provide a brief overview of meiotic progression, with a focus on the unique mechanisms of reductional chromosome segregation in meiosis I. We then offer detailed insight into the role of meiotic chromosome regulators in non‐germ cell cancers and extend this to provide an overview of how this might relate to germ cell tumours. Conclusions We propose that meiotic gene activation in germ cell tumours might not indicate an unscheduled attempt to enter a full meiotic programme. Rather, it might simply reflect either aberrant activation of a subset of meiotic genes, with little or no biological relevance, or aberrant activation of a subset of meiotic genes as positive tumour evolutionary/oncogenic drivers. These postulates provide the provocation for further studies in this emerging field.

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The Genes of Life and Death: A Potential Role for Placental‐Specific Genes in Cancer

Cited by 13 publications

References 122 publications

Development of the human placenta

Development of the human placenta

Reawakening the Developmental Origins of Cancer Through Transposable Elements

Meiotic gene activation in somatic and germ cell tumours

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