Bone Morphogenetic Protein Signaling in Cancer; Some Topics in the Recent 10 Years

Ehata, Shogo; Miyazono, Kohei

doi:10.3389/fcell.2022.883523

Cited by 36 publications

(38 citation statements)

References 159 publications

(215 reference statements)

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“…Whether BMP is a tumor suppressor or promoter in CRC is controversial [5][6][7][8] . Such complexities in BMP signaling have been described in various cancers 9,10 . As CRC organoids exhibited varying responses to BMP inhibition in our study, one possible explanation for the controversy regarding the role of BMP in CRC is the heterogeneous nature of the disease.…”

Section: Discussionmentioning

confidence: 95%

“…More recently, Yokoyama et al reported that autocrine BMP4 signaling is a therapeutic target in CRC cell lines 8 . In addition to the context dependencies of the BMP effect that have been discussed in various cancers 9,10 , these controversies might represent inter-tumor heterogeneity among the CRC population. One possible explanation for the latter is that the mutation status of SMAD4 and TP53 is suggested to determine cell fate by BMP 11 .…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the BMP pathway suppresses tumor growth via downregulation of EGFR in MEK/ERK-dependent colorectal cancer

Sasaki

Kondo

Onuma

et al. 2022

Preprint

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The bone morphogenetic protein (BMP) pathway promotes differentiation and induces apoptosis in normal colorectal epithelial cells. However, the effect of the BMP pathway in colorectal cancer (CRC) is controversial; it can either be tumor promoting or tumor suppressing, depending on the study. In this study, we found that CRC cells reside in a BMP-rich environment based on RNA-sequencing database analysis. Suppression of BMP using a specific BMP inhibitor, LDN193189, suppresses the growth of organoids in some CRC cases. CRC organoids treated with LDN193189 exhibited a decrease in epidermal growth factor receptor, which was, at least in part, mediated by protein degradation induced by leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1). Among CRC organoid panels from 18 different patients, suppression of organoid growth by BMP inhibition correlated with the induction of LRIG1 gene expression. Notably, knockdown of LRIG1 in organoids diminished the growth-suppressive effect of LDN193189. Furthermore, simultaneous treatment with LDN192189 and trametinib, an FDA-approved MEK inhibitor, resulted in a combination effect in both in vivo and in vitro xenograft tumor treatment in CRC organoids, which are susceptible to growth suppression by LDN193189. Taken together, the simultaneous inhibition of BMP and MEK can be a novel treatment option in CRC cases, and evaluating in vitro growth suppression and LRIG1 induction by BMP inhibition using patient-derived organoids could offer functional biomarkers for predicting potential responders.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Inhibition of the BMP pathway suppresses tumor growth via downregulation of EGFR in MEK/ERK-dependent colorectal cancer

Sasaki

Kondo

Onuma

et al. 2022

Preprint

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“…BMP4 also contribute to neural development. BMPs interact with K-RAS and are upregulated in NSCLC [232]. The BMPs are also involved in adult tissue homeostasis.…”

Section: Role In Proliferation Differentiation and In Tumorigenesismentioning

confidence: 99%

The benign nature and rare occurrence of cardiac myxoma as a possible consequence of the limited cardiac proliferative/ regenerative potential: a systematic review

Shafi

Siddiqui

Jaffry

2022

Preprint

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Background: Cardiac Myxoma (CM) is a primary tumor of heart. Its origins, why the occurrence of primary cardiac tumors is extremely rare and how it may be related to limited cardiac regenerative potential, these aspects are not yet entirely known. This study investigates the key cardiac genes/TFs and signaling pathways to advance our understanding of these important questions. Methods: Databases including PubMed, MEDLINE, and Google Scholar were searched for published articles without any date restrictions, involving cardiac myxoma, cardiac genes/TFs/signaling pathways and their roles in cardiogenesis, proliferation, differentiation, key interactions and tumorigenesis, with focus on cardiomyocytes. Results: The cardiac genetic landscape is governed by a very tight control between proliferation and differentiation-related genes/TFs/pathways. Cardiac myxoma originates possibly as a consequence of dysregulations in the gene expression of differentiation regulators including Tbx5, GATA4, HAND1/2, MYOCD, HOPX, BMPs. Such dysregulations switch the expression of cardiomyocytes into progenitor-like state in cardiac myxoma development by dysregulating Isl1, Baf60 complex, Wnt, FGF, Notch, Mef2c and others. The Nkx2-5 and MSX2 contribute to both proliferation and differentiation of Cardiac Progenitor Cells (CPCs) may possibly serve roles based on the microenvironment and the direction of cell circuitry in cardiac tumorigenesis. The Nkx2-5 in cardiac myxoma may serve to limit progression of tumorigenesis as it has massive control over the proliferation of CPCs. The cardiac cell type-specific genetic programming plays governing role in controlling the tumorigenesis and regenerative potential. Conclusion: The cardiomyocytes have very limited proliferative and regenerative potential. They survive for long periods of time and tightly maintain the gene expression of differentiation genes such as Tbx5, GATA4 that interact with tumor suppressors (TS) and exert TS like effect. The total effect such gene expression exerts is responsible for the rare occurrence and benign nature of primary cardiac tumors. This prevents the progression of tumorigenesis. But this also limits the regenerative and proliferative potential of cardiomyocytes. Cardiac Myxoma (CM) develops as a consequence of dysregulations in these key genes which revert the cells towards progenitor-like state, hallmark of CM. The CM development in carney complex also signifies the role of TS in cardiac cells.

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“…DIPG is a result of genetic mutations (K27M) on the ACVRI/ALK2 gene locus encoding the serine/threonine kinase ALK2 resulting in single amino acid substitution -lysine to methionine (55,73). Interestingly, these somatic ACVR1 mutations in DIPG are identical to germline mutations found in FOP (55,74,75). Many DIPG tumors are exploiting Cordin-like-1 (CHRDL1) capacity to hijack BMP ligands.…”

Section: Bmps In Cancermentioning

confidence: 99%

State-of-the-art of the Bone Morphogenetic Protein research field: 13th International BMP Conference, Dubrovnik 2022

Štoković¹,

Ivanjko²,

Jelić³

et al. 2022

Rad Hrvatske akademije znanosti i umjetnosti

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who got an insight into the latest achievements in basic, translational, and clinical research of BMP molecules through 75 lectures categorized into several scienti c sections. is review paper provides the most important novel ndings on the structure, function, and signaling of BMPs, the role of BMPs in patterning and organoids as well as the role of BMP in metabolism. Moreover, we discussed the role of BMPs in various diseases including cancer pathogenesis, pulmonary arterial hypertension, and brodysplasia ossi cans progressiva (FOP). Finally, we provided an overview of the new BMP-based therapies in regenerative medicine that are currently in di erent stages of preclinical and clinical trials.

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Bone Morphogenetic Protein Signaling in Cancer; Some Topics in the Recent 10 Years

Cited by 36 publications

References 159 publications

Inhibition of the BMP pathway suppresses tumor growth via downregulation of EGFR in MEK/ERK-dependent colorectal cancer

Inhibition of the BMP pathway suppresses tumor growth via downregulation of EGFR in MEK/ERK-dependent colorectal cancer

The benign nature and rare occurrence of cardiac myxoma as a possible consequence of the limited cardiac proliferative/ regenerative potential: a systematic review

State-of-the-art of the Bone Morphogenetic Protein research field: 13th International BMP Conference, Dubrovnik 2022

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