Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer

Bryce, Adam; Dreyer, Stephan; Froeling, Fieke E. M.; Chang, David K.

doi:10.3390/cancers14215302

Cited by 8 publications

(7 citation statements)

References 164 publications

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“…The apCAFs express the proteins of the major histocompatibility complex class II (MHC II), but they are also able to stimulate the differentiation of immunosuppressive Tregs [ 53 ]. Recently, Bryce et al [ 54 ] proposed a putative classification for CAFs containing also the subtypes of metabolic CAFs (meCAF) and the complement-secreting CAFs (csCAF), in addition to the iCAF, myCAF, and apCAF subsets. The activation of iCAFs from tissue-resident quiescent fibroblasts in tumor microenvironments has a crucial role in the progression of tumor growth.…”

Section: Fibroblasts Act As Immune Regulatorsmentioning

confidence: 99%

The role of immunosuppressive myofibroblasts in the aging process and age-related diseases

Salminen

2023

J Mol Med

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Tissue-resident fibroblasts are mesenchymal cells which control the structural integrity of the extracellular matrix (ECM). Fibroblasts possess a remarkable plasticity to allow them to adapt to the changes in the microenvironment and thus maintain tissue homeostasis. Several stresses, also those associated with the aging process, convert quiescent fibroblasts into myofibroblasts which not only display fibrogenic properties but also act as immune regulators cooperating both with tissue-resident immune cells and those immune cells recruited into affected tissues. TGF-β cytokine and reactive oxygen species (ROS) are major inducers of myofibroblast differentiation in pathological conditions either from quiescent fibroblasts or via transdifferentiation from certain other cell types, e.g., macrophages, adipocytes, pericytes, and endothelial cells. Intriguingly, TGF-β and ROS are also important signaling mediators between immunosuppressive cells, such as MDSCs, Tregs, and M2 macrophages. It seems that in pathological states, myofibroblasts are able to interact with the immunosuppressive network. There is clear evidence that a low-grade chronic inflammatory state in aging tissues is counteracted by activation of compensatory immunosuppression. Interestingly, common enhancers of the aging process, such as oxidative stress, loss of DNA integrity, and inflammatory insults, are inducers of myofibroblasts, whereas anti-aging treatments with metformin and rapamycin suppress the differentiation of myofibroblasts and thus prevent age-related tissue fibrosis. I will examine the reciprocal interactions between myofibroblasts and immunosuppressive cells within aging tissues. It seems that the differentiation of myofibroblasts with age-related harmful stresses enhances the activity of the immunosuppressive network which promotes tissue fibrosis and degeneration in elderly individuals.

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Section: Fibroblasts Act As Immune Regulatorsmentioning

confidence: 99%

The role of immunosuppressive myofibroblasts in the aging process and age-related diseases

Salminen

2023

J Mol Med

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“…Thus, myofibroblasts secrete most of the components of the ECM, such as collagens, fibronectin, and elastin, as well as the proteolytic enzymes which can remodel the structures of the ECM. Fibroblasts display an impressive plasticity, i.e., they can modify their phenotypes in response to changes in the tissue microenvironment (LeBleu and Neilson 2020 ; Shaw and Rognoni 2020 ; Bryce et al 2022 ; Salminen 2023a ). For instance, it has been characterized many heterogeneous subgroups of fibroblasts, e.g., cancer-associated fibroblasts (CAF), fibrosis-associated fibroblasts (FAF), wound-associated fibroblasts (WAF), and aging-associated fibroblasts (AAF) (LeBleu and Neilson 2020 ).…”

Section: Myofibroblastsmentioning

confidence: 99%

“…Interestingly, fibroblasts/myofibroblast are able to display both pro- and anti-inflammatory responses involving the secretion of cytokines, chemokines, growth factors, and complement components as well as they can express ligands and receptors for immune checkpoint proteins (Powell et al 1999 ; Van Linthout et al 2014 ; Zhao et al 2023 ). Cancer associated fibroblasts (CAF) can display different immune phenotypes, such as the inflammatory CAFs (iCAF), the immunosuppressive myofibroblast population (myCAF), the antigen-presenting CAFs (apCAF), and the complement-secreting CAFs (csCAF) (Costa et al 2018 ; Mhaidly and Mechta-Grigoriou 2020 ; Bryce et al 2022 ; Ngwenyama et al 2022 ). For instance, during mouse myocardial infarction there occurred a transition of inflammatory fibroblasts to anti-inflammatory/immunosuppressive myofibroblast population with fibrogenic properties (Daseke et al 2020 ).…”

Section: Myofibroblastsmentioning

confidence: 99%

AMPK signaling inhibits the differentiation of myofibroblasts: impact on age-related tissue fibrosis and degeneration

Salminen

2023

Biogerontology

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Disruption of the extracellular matrix (ECM) and an accumulation of fibrotic lesions within tissues are two of the distinctive hallmarks of the aging process. Tissue fibroblasts are mesenchymal cells which display an impressive plasticity in the regulation of ECM integrity and thus on tissue homeostasis. Single-cell transcriptome studies have revealed that tissue fibroblasts exhibit a remarkable heterogeneity with aging and in age-related diseases. Excessive stress and inflammatory insults induce the differentiation of fibroblasts into myofibroblasts which are fusiform contractile cells and abundantly secrete the components of the ECM and proteolytic enzymes as well as many inflammatory mediators. Detrimental stresses can also induce the transdifferentiation of certain mesenchymal and myeloid cells into myofibroblasts. Interestingly, many age-related stresses, such as oxidative and endoplasmic reticulum stresses, ECM stiffness, inflammatory mediators, telomere shortening, and several alarmins from damaged cells are potent inducers of myofibroblast differentiation. Intriguingly, there is convincing evidence that the signaling pathways stimulated by the AMP-activated protein kinase (AMPK) are potent inhibitors of myofibroblast differentiation and accordingly AMPK signaling reduces fibrotic lesions within tissues, e.g., in age-related cardiac and pulmonary fibrosis. AMPK signaling is not only an important regulator of energy metabolism but it is also able to control cell fate determination and many functions of the immune system. It is known that AMPK signaling can delay the aging process via an integrated signaling network. AMPK signaling inhibits myofibroblast differentiation, e.g., by suppressing signaling through the TGF-β, NF-κB, STAT3, and YAP/TAZ pathways. It seems that AMPK signaling can alleviate age-related tissue fibrosis and degeneration by inhibiting the differentiation of myofibroblasts.

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“…CAFs also directly boost tumor cell proliferation and survival by secreting soluble mediators and promote angiogenesis ( 28 , 29 ). CAFs also exert negative immunomodulatory impacts and allow tumors to evade immune surveillance ( 30 ). Recent studies illustrate that CAFs can secrete exosomes to enhance the metastatic and invasive ability of cancer cells by creating a microenvironment suitable for tumor growth ( 31 , 32 ).…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between colorectal cancer cells and cancer-associated fibroblasts in the tumor microenvironment mediated by exosomal noncoding RNAs

Sun

Zhang

et al. 2023

Front. Immunol.

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Colorectal cancer (CRC) is a common malignant tumor of the digestive system, and its morbidity rates are increasing worldwide. Cancer-associated fibroblasts (CAFs), as part of the tumor microenvironment (TME), are not only closely linked to normal fibroblasts, but also can secrete a variety of substances (including exosomes) to participate in the regulation of the TME. Exosomes can play a key role in intercellular communication by delivering intracellular signaling substances (e.g., proteins, nucleic acids, non-coding RNAs), and an increasing number of studies have shown that non-coding RNAs of exosomal origin from CAFs are not only closely associated with the formation of the CRC microenvironment, but also increase the ability of CRC to grow in metastasis, mediate tumor immunosuppression, and are involved in the mechanism of drug resistance in CRC patients receiving. It is also involved in the mechanism of drug resistance after radiotherapy in CRC patients. In this paper, we review the current status and progress of research on CAFs-derived exosomal non-coding RNAs in CRC.

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Exploring the Biology of Cancer-Associated Fibroblasts in Pancreatic Cancer

Cited by 8 publications

References 164 publications

The role of immunosuppressive myofibroblasts in the aging process and age-related diseases

The role of immunosuppressive myofibroblasts in the aging process and age-related diseases

AMPK signaling inhibits the differentiation of myofibroblasts: impact on age-related tissue fibrosis and degeneration

Crosstalk between colorectal cancer cells and cancer-associated fibroblasts in the tumor microenvironment mediated by exosomal noncoding RNAs

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