Radiation-induced fibrosis: mechanisms and implications for therapy

Straub, Jeffrey; New, Jacob; Hamilton, Chase D.; Lominska, Chris; Shnayder, Yelizaveta; Thomas, Sufi M.

doi:10.1007/s00432-015-1974-6

Cited by 488 publications

(477 citation statements)

References 119 publications

(125 reference statements)

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“…However, effective mechanism-based options for the treatment of pulmonary fibrosis are still limited (229). Therefore, another important topic of current research is to develop effective therapeutic strategies to prevent or treat radiation-induced lung fibrosis (223, 230); experimental approaches mostly target radiation-induced formation of free radicals, cell death, or specific cytokines or growth factors, respectively.…”

Section: Therapeutic Approaches For Radiation-induced Pneumopathymentioning

confidence: 99%

The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

Wirsdörfer¹,

Jendrossek²

2016

Front. Immunol.

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Radiation-induced pneumonitis and fibrosis are dose-limiting side effects of thoracic irradiation. Thoracic irradiation triggers acute and chronic environmental lung changes that are shaped by the damage response of resident cells, by the resulting reaction of the immune system, and by repair processes. Although considerable progress has been made during the last decade in defining involved effector cells and soluble mediators, the network of pathophysiological events and the cellular cross talk linking acute tissue damage to chronic inflammation and fibrosis still require further definition. Infiltration of cells from the innate and adaptive immune systems is a common response of normal tissues to ionizing radiation. Herein, lymphocytes represent a versatile and wide-ranged group of cells of the immune system that can react under specific conditions in various ways and participate in modulating the lung environment by adopting pro-inflammatory, anti-inflammatory, or even pro- or anti-fibrotic phenotypes. The present review provides an overview on published data about the role of lymphocytes in radiation-induced lung disease and related damage-associated pulmonary diseases with a focus on T lymphocytes and B lymphocytes. We also discuss the suspected dual role of specific lymphocyte subsets during the pneumonitic phase and fibrotic phase that is shaped by the environmental conditions as well as the interaction and the intercellular cross talk between cells from the innate and adaptive immune systems and (damaged) resident epithelial cells and stromal cells (e.g., endothelial cells, mesenchymal stem cells, and fibroblasts). Finally, we highlight potential therapeutic targets suited to counteract pathological lymphocyte responses to prevent or treat radiation-induced lung disease.

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Section: Therapeutic Approaches For Radiation-induced Pneumopathymentioning

confidence: 99%

The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

Wirsdörfer¹,

Jendrossek²

2016

Front. Immunol.

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“…On the other hand, efforts to suppress tumor-associated stroma have generally been unsuccessful and have even resulted in increased tumor invasiveness in some models (12,(39)(40)(41). Although clearly many questions remain on the role played by connective tissue stiffness in cancer biology, it is a concern that conventional cancer treatments, including surgery and radiotherapy, can themselves contribute to fibrosis and matrix stiffening (42,43). Furthermore, a broader consideration of the connective tissue system throughout the host has been largely overlooked.…”

Section: Importance Of Connective Tissue In Cancer Biologymentioning

confidence: 99%

Connecting (T)issues: How Research in Fascia Biology Can Impact Integrative Oncology

et al. 2016

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Complementary and integrative treatments, such as massage, acupuncture, and yoga, are used by increasing numbers of cancer patients to manage symptoms and improve their quality of life. In addition, such treatments may have other important and currently overlooked benefits by reducing tissue stiffness and improving mobility. Recent advances in cancer biology are underscoring the importance of connective tissue in the local tumor environment. Inflammation and fibrosis are well-recognized contributors to cancer, and connective tissue stiffness is emerging as a driving factor in tumor growth. Physical-based therapies have been shown to reduce connective tissue inflammation and fibrosis and thus may have direct beneficial effects on cancer spreading and metastasis. Meanwhile, there is currently little knowledge on potential risks of applying mechanical forces in the vicinity of tumors. Thus, both basic and clinical research are needed to understand the full impact of integrative oncology on cancer biology as well as whole person health. Cancer Res; 76(21); 6159-62. Ó2016 AACR.

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“…The EMT program may account for enhanced resistance to further irradiation episodes or chemoresistance in case of combined radio- and chemotherapy regimens [32]. In the worst case, EMT induction eventually results in radiation-induced fibrosis [37] or even in the radiotherapy-associated formation of secondary malignancies. Given this important role of TGF-β/ALK5/Smad signaling in the DDR on the one hand and regulation of TGF-β/ALK5/Smads by PAR2 on the other hand, we would like to postulate a crucial role of PAR2 in DDR regulation by TGF-β.…”

Section: Possible Role Of Par2 In Tgf-β-induced Emt and Emt-associmentioning

confidence: 99%

Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer

Witte

Zeeh

Gädeken

et al. 2016

JCM

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TGF-β has a dual role in tumorigenesis, acting as a tumor suppressor in normal cells and in the early stages of tumor development while promoting carcinogenesis and metastasis in advanced tumor stages. The final outcome of the TGF-β response is determined by cell-autonomous mechanisms and genetic alterations such as genomic instability and somatic mutations, but also by a plethora of external signals derived from the tumor microenvironment, such as cell-to-cell interactions, growth factors and extracellular matrix proteins and proteolytic enzymes. Serine proteinases mediate their cellular effects via activation of proteinase-activated receptors (PARs), a subclass of G protein-coupled receptors that are activated by proteolytic cleavage. We have recently identified PAR2 as a factor required for TGF-β1-dependent cell motility in ductal pancreatic adenocarcinoma (PDAC) cells. In this article, we review what is known on the TGF-β-PAR2 signaling crosstalk and its relevance for tumor growth and metastasis. Since PAR2 is activated through various serine proteinases, it may couple TGF-β signaling to a diverse range of other physiological processes, such as local inflammation, systemic coagulation or pathogen infection. Moreover, since PAR2 controls expression of the TGF-β type I receptor ALK5, PAR2 may also impact signaling by other TGF-β superfamily members that signal through ALK5, such as myostatin and GDF15/MIC-1. If so, PAR2 could represent a molecular linker between PDAC development and cancer-related cachexia.

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Radiation-induced fibrosis: mechanisms and implications for therapy

Cited by 488 publications

References 119 publications

The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

Connecting (T)issues: How Research in Fascia Biology Can Impact Integrative Oncology

Proteinase-Activated Receptor 2 Is a Novel Regulator of TGF-β Signaling in Pancreatic Cancer

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