NDLI: Antifibrotic therapy to normalize the tumor microenvironment

Content Provider	Springer Nature : BioMed Central
Author	Hauge, Anette Rofstad, Einar K.
Abstract	Most tumors develop abnormal fibrotic regions consisting of fibroblasts, immune cells, and a dense extracellular matrix (ECM) immersed in a viscous interstitial fluid, and an abundant fibrotic tumor microenvironment (TME) is associated with poor outcome of treatment. It has been hypothesized that the treatment of cancer may be improved by interventions aiming to normalize this TME. The approaches used in attempts to normalize the fibrotic TME can be categorized into three strategies of targeted antifibrotic therapy: targeting of components of the ECM, targeting of the producers of the ECM components—the activated cancer-associated fibroblasts (CAFs), and targeting of the signaling pathways activating CAFs. To target the ECM, enzymes against components of the ECM have been used, including collagenase, relaxin, hyaluronidase, and lyxyl oxidase. Targeting of CAFs have been investigated by using agents aiming to eliminate or reprogram CAFs. CAFs are activated primarily by transforming growth factor-β (TGF-β), hedgehog, or focal adhesion kinase signaling, and several agents have been used to target these signaling pathways, including angiotensin II receptor I blockers (e.g., losartan) to inhibit the TGF-β pathway. Taken together, these studies have revealed that antifibrotic therapy is a two-edged sword: while some studies suggest enhanced response to treatment after antifibrotic therapy, others suggest that antifibrotic therapy may lead to increased tumor growth, metastasis, and impaired outcome of treatment. There are several possible explanations of these conflicting observations. Most importantly, tumors contain different subpopulations of CAFs, and while some subpopulations may promote tumor growth and metastasis, others may inhibit malignant progression. Furthermore, the outcome of antifibrotic therapy may depend on stage of disease, duration of treatment, treatment-induced activation of alternative profibrotic signaling pathways, and treatment-induced recruitment of tumor-supporting immune cells. Nevertheless, losartan-induced suppression of TGF-β signaling appears to be a particularly promising strategy. Losartan is a widely prescribed antihypertensive drug and highly advantageous therapeutic effects have been observed after losartan treatment of pancreatic cancer. However, improved understanding of the mechanisms governing the development of fibrosis in tumors is needed before safe antifibrotic treatments can be established.
Related Links	https://translational-medicine.biomedcentral.com/counter/pdf/10.1186/s12967-020-02376-y.pdf
Ending Page	11
Page Count	11
Starting Page	1
File Format	HTM / HTML
ISSN	14795876
DOI	10.1186/s12967-020-02376-y
Journal	Journal of Translational Medicine
Issue Number	1
Volume Number	18
Language	English
Publisher	BioMed Central
Publisher Date	2020-05-20
Access Restriction	Open
Subject Keyword	Biomedicine Medicine Public Health Antifibrotic therapy Cancer-associated fibroblasts Extracellular matrix Tumor microenvironment Profibrotic signaling pathways Targeted treatments Microenvironment normalization Losartan Medicine/Public Health
Content Type	Text
Resource Type	Review
Subject	Biochemistry, Genetics and Molecular Biology Medicine
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	6.3/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
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9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

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