The Balance of Stromal BMP Signaling Mediated by GREM1 and ISLR Drives Colorectal Carcinogenesis.

Adult Aged Aged, 80 and over Animals Bone Morphogenetic Proteins / metabolism Cancer-Associated Fibroblasts / metabolism Carcinogenesis / pathology Cell Differentiation Cell Line, Tumor Colorectal Neoplasms / mortality Disease Progression Female Hepatocytes / metabolism Humans Immunoglobulins / genetics Intercellular Signaling Peptides and Proteins / metabolism Kaplan-Meier Estimate Liver Neoplasms / secondary Male Mice Middle Aged Prognosis Signal Transduction Tumor Microenvironment Up-Regulation Xenograft Model Antitumor Assays
Bone Morphogenetic Protein Cancer-Associated Fibroblasts Colorectal Cancer Tumor Microenvironment

Journal

Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630

Informations de publication

Date de publication:
03 2021
Historique:
received: 23 06 2020
revised: 16 10 2020
accepted: 09 11 2020
pubmed: 17 11 2020
medline: 6 8 2021
entrez: 16 11 2020
Statut: ppublish

Résumé

Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored. Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC. We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor β and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5 Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.

Sections du résumé

BACKGROUND & AIMS
Cancer-associated fibroblasts (CAFs), key constituents of the tumor microenvironment, either promote or restrain tumor growth. Attempts to therapeutically target CAFs have been hampered by our incomplete understanding of these functionally heterogeneous cells. Key growth factors in the intestinal epithelial niche, bone morphogenetic proteins (BMPs), also play a critical role in colorectal cancer (CRC) progression. However, the crucial proteins regulating stromal BMP balance and the potential application of BMP signaling to manage CRC remain largely unexplored.
METHODS
Using human CRC RNA expression data, we identified CAF-specific factors involved in BMP signaling, then verified and characterized their expression in the CRC stroma by in situ hybridization. CRC tumoroids and a mouse model of CRC hepatic metastasis were used to test approaches to modify BMP signaling and treat CRC.
RESULTS
We identified Grem1 and Islr as CAF-specific genes involved in BMP signaling. Functionally, GREM1 and ISLR acted to inhibit and promote BMP signaling, respectively. Grem1 and Islr marked distinct fibroblast subpopulations and were differentially regulated by transforming growth factor β and FOXL1, providing an underlying mechanism to explain fibroblast biological dichotomy. In patients with CRC, high GREM1 and ISLR expression levels were associated with poor and favorable survival, respectively. A GREM1-neutralizing antibody or fibroblast Islr overexpression reduced CRC tumoroid growth and promoted Lgr5
CONCLUSIONS
Stromal BMP signaling predicts and modifies CRC progression and survival, and it can be therapeutically targeted by novel AAV-directed gene delivery to the liver.

Identifiants

DOI: 10.1053/j.gastro.2020.11.011 PMID: 33197448
pubmed: 33197448
pii: S0016-5085(20)35400-7
doi: 10.1053/j.gastro.2020.11.011
pii:
doi:

Substances chimiques

Bone Morphogenetic Proteins 0
GREM1 protein, human 0
ISLR protein, human 0
Immunoglobulins 0
Intercellular Signaling Peptides and Proteins 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1224-1239.e30

Subventions

Organisme : Wellcome Trust
ID : 206314/Z/17/Z
Pays : United Kingdom

Commentaires et corrections

Type : ErratumIn

Informations de copyright

Copyright © 2021 AGA Institute. All rights reserved.

Auteurs

Hiroki Kobayashi (H)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia; Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Krystyna A Gieniec (KA)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.

Josephine A Wright (JA)

South Australian Health and Medical Research Institute, Adelaide, Australia.

Tongtong Wang (T)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.

Naoya Asai (N)

Department of Molecular Pathology, Graduate School of Medicine, Fujita Health University, Toyoake, Japan.

Yasuyuki Mizutani (Y)

Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Tadashi Lida (T)

Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Ryota Ando (R)

Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Nobumi Suzuki (N)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Tamsin R M Lannagan (TRM)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.

Jia Q Ng (JQ)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.

Akitoshi Hara (A)

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Yukihiro Shiraki (Y)

Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Shinji Mii (S)

Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Mari Ichinose (M)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.

Laura Vrbanac (L)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.

Matthew J Lawrence (MJ)

Colorectal Unit, Department of Surgery, Royal Adelaide Hospital, Adelaide, Australia.

Tarik Sammour (T)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia; Colorectal Unit, Department of Surgery, Royal Adelaide Hospital, Adelaide, Australia.

Kay Uehara (K)

Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Gareth Davies (G)

UCB Pharma, Slough, Berkshire, United Kingdom.

Leszek Lisowski (L)

Translational Vectorology Research Unit, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Vector and Genome Engineering Facility, Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Westmead, Australia; Military Institute of Hygiene and Epidemiology, The Biological Threats Identification and Countermeasure Centre, Puławy, Poland.

Ian E Alexander (IE)

Gene Therapy Research Unit, Sydney Children's Hospitals Network and Children's Medical Research Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Australia.

Yoku Hayakawa (Y)

Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Lisa M Butler (LM)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.

Andrew C W Zannettino (ACW)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia.

M Omar Din (MO)

GenCirq, Inc, San Diego, California.

Jeff Hasty (J)

Department of Bioengineering, University of California, San Diego, La Jolla, California.

Alastair D Burt (AD)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; Precision and Molecular Pathology, Newcastle University, Newcastle Upon Tyne, United Kingdom.

Simon J Leedham (SJ)

Intestinal Stem Cell Biology Lab, Wellcome Trust Centre Human Genetics, University of Oxford, Oxford, United Kingdom.

Anil K Rustgi (AK)

Herbert Irving Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, New York, New York.

Siddhartha Mukherjee (S)

Department of Medicine and Irving Cancer Research Center, Columbia University, New York, New York.

Timothy C Wang (TC)

Department of Medicine and Irving Cancer Research Center, Columbia University, New York, New York.

Atsushi Enomoto (A)

Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: enomoto@iar.nagoya-u.ac.jp.

Masahide Takahashi (M)

Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan; International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan. Electronic address: mtakaha@med.nagoya-u.ac.jp.

Daniel L Worthley (DL)

South Australian Health and Medical Research Institute, Adelaide, Australia. Electronic address: Dan.Worthley@sahmri.com.

Susan L Woods (SL)

Adelaide Medical School, University of Adelaide, Adelaide, Australia; South Australian Health and Medical Research Institute, Adelaide, Australia. Electronic address: susan.woods@adelaide.edu.au.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Sujet âgé de 80 ans ou plus › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Eucaryotes › Animaux › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines de la superfamille du TGF bêta › Protéines morphogénétiques osseuses › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Cellules › Cellules du tissu conjonctif › Fibroblastes › Fibroblastes associés au cancer › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Carcinogenèse › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies gastro-intestinales › Maladies intestinales › Maladies du rectum › Tumeurs colorectales › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Évolution de la maladie › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Cellules › Cellules épithéliales › Hépatocytes › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de survie › Estimation de Kaplan-Meier › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Diagnostic › Pronostic › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Microenvironnement cellulaire › Microenvironnement tumoral › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation positive › The Balance of Stromal BMP Signaling Mediated...
questionsmedicales.fr › Techniques d'investigation › Transplantation tumorale › Tests d'activité antitumorale sur modèle de xénogreffe › The Balance of Stromal BMP Signaling Mediated...