GDF11 Implications in Cancer Biology and Metabolism. Facts and Controversies

Simoni‐Nieves, Arturo; Gerardo-Ramírez, Monserrat; Pedraza-Vázquez, Gibrán; Chávez-Rodríguez, Lisette; Bucio, Leticia; Souza, Verónica; Miranda-Labra, Roxana U.; Gómez–Quiroz, Luis E.; Gutiérrez‐Ruiz, María Concepción

doi:10.3389/fonc.2019.01039

Cited by 24 publications

(28 citation statements)

References 84 publications

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“…This controversy suggests that the functional roles of GDF11 are complicated, and revealing the fundamental role of endogenous GDF11 could provide clear clues for clarification of the GDF11 function. Growth differentiation factor 11 has been shown widely expressed in proliferative cells and tissues ( Zhang et al, 2018 ; Simoni-Nieves et al, 2019 ; Tito et al, 2019 ; Dai et al, 2020 ; Rochette et al, 2020 ). However, it is still unknown whether GDF11 plays a causal role in replicative cellular senescence.…”

Section: Discussionmentioning

confidence: 99%

“…Growth differentiation factor 11 (GDF11, also known as bone morphogenetic protein 11, BMP11) is a member of transforming growth factor-beta (TGF-β) family. Accumulated evidence has shown that GDF11 is widely expressed in both the proliferative cells and tissues including the activated hepatic stellate cells of the liver ( Zhang et al, 2018 ; Dai et al, 2020 ; Rochette et al, 2020 ), keratinocytes and dermal fibroblasts of the skin ( Tito et al, 2019 ; Rochette et al, 2020 ), pancreas, skeletal muscle, kidney, retina, among others ( Simoni-Nieves et al, 2019 ), and postmitotic cells such as neurons of the central nervous system ( Hayashi et al, 2018 ). The expression of GDF11 in proliferative cells suggests its possible important functions in the proliferative cells ( Rochette et al, 2015 , 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity

Wang

Zhu

et al. 2021

Front. Physiol.

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Maintenance of telomere length is essential to delay replicative cellular senescence. It is controversial on whether growth differentiation factor 11 (GDF11) can reverse cellular senescence, and this work aims to establish the causality between GDF11 and the telomere maintenance unequivocally. Using CRISPR/Cas9 technique and a long-term in vitro culture model of cellular senescence, we show here that in vitro genetic deletion of GDF11 causes shortening of telomere length, downregulation of telomeric reverse transcriptase (TERT) and telomeric RNA component (TERC), the key enzyme and the RNA component for extension of the telomere, and reduction of telomerase activity. In contrast, both recombinant and overexpressed GDF11 restore the transcription of TERT in GDF11KO cells to the wild-type level. Furthermore, loss of GDF11-induced telomere shortening is likely caused by enhancing the nuclear entry of SMAD2 which inhibits the transcription of TERT and TERC. Our results provide the first proof-of-cause-and-effect evidence that endogenous GDF11 plays a causal role for proliferative cells to maintain telomere length, paving the way for potential rejuvenation of the proliferative cells, tissues, and organs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity

Wang

Zhu

et al. 2021

Front. Physiol.

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“…GDF11 has also previously been associated with aging in numerous studies; however, its exact pathophysiological role remains unclear [ 56 ]. Increased GDF11 has been associated with increased stemness [ 57 ], and CRC patients with increased expression of this genes have been shown to have reduced survival [ 58 ]. Silencing GDF11 in the CRC cell line Caco-2 has also implicated a role for this gene in proliferation [ 57 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

“…Increased GDF11 has been associated with increased stemness [ 57 ], and CRC patients with increased expression of this genes have been shown to have reduced survival [ 58 ]. Silencing GDF11 in the CRC cell line Caco-2 has also implicated a role for this gene in proliferation [ 57 , 59 ]. These findings add further weight to the potential role of known lifestyle factors in EOCRC.…”

Section: Discussionmentioning

confidence: 99%

Insights into Early Onset Colorectal Cancer through Analysis of Normal Colon Organoids of Familial Adenomatous Polyposis Patients

Devall

Eaton

Ali

et al. 2022

Cancers

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Early onset colorectal cancer (EOCRC) rates have increased in recent decades. While lowering the recommended age for routine colonoscopies to 45 may reduce this burden, such measures do not address those who develop CRC before that age. Additional measures are needed to identify individuals at-risk for CRC. To better define transcriptomic events that precede the development of CRC, we performed RNA-sequencing analysis in colon organoids derived from seven healthy and six familial adenomatous polyposis (FAP) patients. This led to the identification of 2635 significant differentially expressed genes (FDR < 0.05). Through secondary analysis of publicly available datasets, we found that these genes were enriched for significant genes also present in FAP CRC and non-hereditary CRC datasets, including a subset that were unique to EOCRC. By exposing FAP colon organoids to a three-day ethanol treatment, we found that two EOCRC-relevant genes were also targets of CRC related lifestyle factors. Our data provides unique insight into the potential, early mechanisms of CRC development in colon epithelial cells, which may provide biomarkers for patient monitoring. We also show how modifiable lifestyle factors may further alter genes relevant to EOCRC, adding weight to the hypothesis that such factors represent an important contributor to increased EOCRC incidence.

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“…We identified CXCL13 and GDF11 as potential cytokines that could explain the influence of the BMSC on leukaemia cell proliferation and migration. The cytoattractive properties on B-cells 47 and the role in the regulation of different tumours 75-77 of CXCL13 have been described, while GDF11 has been discussed to be involved in ageing and the development of various cancers 78 . GDF11 also plays a role in bone development and remodelling 79 .…”

Section: Cxcl13 Levels In the Bmm Are Age-dependentmentioning

confidence: 99%

Differential effects of young (growing) versus old (grown-up) bone marrow microenvironments on leukaemias by release of the cytokines CXCL13 and GDF11 from bone marrow stroma

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While B-cell acute lymphoblastic leukaemia (B-ALL) can be described as the leukaemia of childhood, chronic myeloid leukaemia (CML) mostly develops in elderly individuals. Understanding and utilising mechanisms involved in the development and persistence of these leukaemias as possible targets for treatment strategies has received particular interest. Processes that happen in the vicinity of the cancerous cells themselves could influence cancer growth and behaviour and hence can serve as novel targets, leading to the development of two-pronged therapies that act both on leukaemic cells directly as well as their niche. The niche in the case of leukaemia is the bone marrow microenvironment (BMM) where these cells are not only generated but also instructed and protected. As the BMM is situated inside bones that undergo drastic changes and growth processes during the ageing process, the BMM itself is also being altered throughout life. These alterations and the very process of expansion itself may therefore also provide distinct regulatory influences on the cells (healthy or malignant) that are generated inside this niche, leading to the question: Does the age of the bone marrow microenvironment differentially influence the development of (“childhood”) B-ALL versus (“adult”) CML by the release of cytokines? In previous studies by the host-laboratory the age distribution of B-ALL versus CML in a murine transduction/ transplantation model could be recapitulated; young mice which received the same number of leukaemia-initiating cells as their old counterparts died significantly earlier of B-ALL while showing a significantly delayed clinical course, when they were suffering from CML. The tumour load and other leukaemia-associated parameters also showed a clear disposition towards preferential induction of CML in elderly and B-ALL in younger mice. In this project we could support the hypothesis that the age of the BMM differentially influences the proliferation of leukaemic cells and thereby the development and persistence of different types of leukaemias by utilising different in vitro culture experiments. Specifically, we could show that young (compared to old) bone marrow 11 stroma cells (BMSC) support the growth of (BCR-ABL1+) B-ALL cells both in a direct, cell on cell co-culture setting, as well as in young BMSC-derived conditioned medium. This supports the hypothesis that varying factors are differentially released from a young versus an old BMM and influence the growth of the leukaemia cells. The opposite might be true for CML cells (BCR-ABL1+ 32D cells); BMSC obtained from old animals showed a tendency to support their growth more profoundly than cells acquired from young animals. Possible proteins responsible for the distinct regulation of myeloid versus lymphatic leukaemic cells by young versus old BMM have also been studied. We investigated C-X-C motif chemokine 13 (CXCL13) and growth differentiation factor 11 (GDF11) in their effect on leukaemia cells, as both proteins having previously been described to have tumour-modelling properties and age-dependent levels (see below). We identified an increased secretion of CXCL13, a B-cell chemotactic factor, into conditioned medium from young versus old BMSC. In accordance with this we found migration of B-ALL cells towards BMSC from young compared to old mice to be improved, while adhesion of both B-ALL and CML cells to young versus old BMSC did not show any differences. By blocking CXCL13 the proliferation-supporting effect of young BMSC on B-ALL cells could be diminished. Similar effects could be demonstrated by blocking GDF11. In the case of CML cells we could observe the opposite effect; blocking CXCL13 and GDF11 increased their proliferation in a co-culture with BMSC. This supported our hypothesis that both cytokines differentially regulate B-ALL and CML behaviour. After the completion of this thesis, another member of the host-laboratory convincingly demonstrated the role of BMM age in the regulation of B-ALL via CXCL13 signalling (see discussion).

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GDF11 Implications in Cancer Biology and Metabolism. Facts and Controversies

Cited by 24 publications

References 84 publications

Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity

Loss of Growth Differentiation Factor 11 Shortens Telomere Length by Downregulating Telomerase Activity

Insights into Early Onset Colorectal Cancer through Analysis of Normal Colon Organoids of Familial Adenomatous Polyposis Patients

Differential effects of young (growing) versus old (grown-up) bone marrow microenvironments on leukaemias by release of the cytokines CXCL13 and GDF11 from bone marrow stroma

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