Researchers have identified a way to treat cutaneous fibrosis in cancer patients

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Radiotherapy (RT) is the primary treatment for many cancers, and it can damage the healthy tissues in both short and long term.

The latest data show that >70% of patients with malignant tumors need RT. Radiation-induced skin reaction (RISR) is one of the main adverse effects.

Acute RISRs may have severe sequelae, affecting the quality of life and the progress of cancer treatment.

The main factors affecting patients’ quality of life include pain and discomfort caused by RISRs.1 

Therefore, it is crucial to alleviate or even eradicate the radiation-induced adverse events.2

RISRs are often assessed as acute and chronic and classified on a scale of 1–4 on the basis of the Common Terminology Criteria for Adverse Events v3.0. Grade 1 changes include dry desquamation with generalized erythema. Grade 2 changes include brisk erythema or patchy moist desquamation.

When the cumulative radiation dose reaches 40 Gy or higher, moist desquamation occurs at the folds of the skin.3 

Grade 3 changes include extensive moist desquamation outside of the skin folds.

Grade 4 changes include ulcers, bleeding, and skin necrosis.4 

The chronic radiation-induced reactions include chronic ulcerations and wounds, fibrosis, telangiectasias, secondary skin cancers, and radiation-induced keratoses.5 

Chronic RISRs are true late-stage reactions that take months to years to develop after exposure to ionizing radiation (IR).4 

These chronic effects are more dependent on the type, area, volume, fraction size, and schedule of radiation rather than total radiation dose.6

Many factors increasing the risk of acute RISRs have been identified. The severity of the reactions is related to both internal and external factors.

External factors include the total radiation dose, fractioned delivery schedules, volume of irradiated tissue, and the internal radiosensitivity of the involved tissue.7 

Genetics influences the development of acute RISRs, particularly conditions resulting from mutations in DNA repair mechanisms.

Ataxia telangiectasia is closely related to the mutation of ATM gene.8 

Patients with the disease are more likely to develop serious complications after RT because they cannot repair their DNA. Many clinical trials have attempted to study the relationship between radiosensitivity and radiation-associated complications.911

The mechanisms associated with RISRs include inflammatory response and oxidative stress (OS).

Inflammatory response and OS interact and promote each other.12,13 

After radiation-induced cell damage, cells die in various forms, especially mitotic death, leading to inflammation and chronic OS.

In chronic phases, inflammation and OS can lead to changes in various cytokines, cell cycle changes, and DNA damage, sustaining the cascade leading to late reactions.

Treatment is based on the severity of acute RISRs.

Treatments are incorporated into wound care management to maintain a moist environment to speed up recovery.

Permanence, gradualness, and irreversibility are a unique subset of the adverse effects of RT in chronic RISRs; fibrosis of the skin and soft tissue may progress from months to years after the treatment.14 

Chronic RISRs have a significant impact on the quality of life because of the irreversibility of the damage.15

In this review, we summarize the important mechanisms that cause RISRs as well as some standard treatments and advanced innovative treatments for acute and chronic RISRs.

Mechanism of RISRs

Inflammatory response

Inflammatory response has been shown to be generally associated with RISRs.12 In the initial period of RT, there is an immediate generation of an inflammatory response.

The early inflammatory response to radiation is mainly caused by pro-inflammatory cytokines (IL-1, IL-3, IL-5, IL-6, and tumor necrosis factor [TNF]-a), chemokines (eotaxin and IL-8), receptor tyrosine kinase, and adhesions molecules (intercellular adhesion molecule 1 [ICAM-1], E-selectin, and vascular cell adhesion protein).

These factors can create a local inflammatory response of eosinophils and neutrophils, leading to self-perpetuating tissue damage and loss of protective barriers16 (Figure 1). Janko et al ascertained that IL-1 had an important role in the development of RISRs.

They found that mice that lack either IL-1 or the IL-1 receptor developed less inflammation and less severe pathological changes in their skin, especially at later time points.

This study provided a potential therapeutic targeting of IL-1 for the remission of RISRs. The production of IL-1 in skin is mainly regulated by monocytes, macrophages, fibroblasts, keratinocytes, and many other immune mediators.17 

In the acute phase, all resident cells, including keratinocytes, fibroblasts, and endothelial cells, respond to IR by the activation of the early response genes and proteins, which include a lot of growth factors, chemokines, and cytokines.

These various growth factors then attract inflammatory cells that participate in the second phase of RISRs.

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Figure 1

Mechanisms associated with RISRs: inflammation and oxidative stress.

Abbreviations: COX-2, cyclooxygenase 2; ICAM-1, intercellular adhesion molecule 1; iNOS, inducible nitric oxide synthase; NF-kB, nuclear factor kB; NLRP3, nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3; NO, nitric oxide; RISR, radiation-induced skin reaction; TNF, tumor necrosis factor; VCAM, vascular cell adhesion protein.

Nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflamma-some upregulation at the expression or activation level has been reported to play an important role in radiation damage including RISRs in recent years.1820 

NLRP3 inflammasome is a multi-protein complex that activates caspase-1, which leads to the maturation of the pro-inflammatory cytokines IL-1β and IL-18.21The study by Allam et al22 showed that radiation-induced mitochondrial apoptosis can lead to the release of oxidative mitochondrial DNA into the cytoplasm and bound it to NLRP3 inflammasome in the cytosol, which causes activation of the NLRP3 inflammasome (Figure 1).

The development of radiation-induced fibrosis is also mediated by inflammation, which begins immediately after RT and continues for months to years.14 TNF-a, IL-6, and IL-1 are involved in the inflammatory response, while TGF-β and platelet-derived growth factor regulate fibroblast activity and promote the production of extracellular matrix proteins.23 

Fibroblasts are the key cells in the development of late radiation-induced fibrotic changes.24 

Permanently atypical fibroblasts can cause skin atrophy, contraction, and fibrosis.25 

The TGF-β is a regulatory protein that controls wound healing, proliferation, and differentiation of multiple cell types and synthesis of extracellular matrix proteins in the normal tissue inflammatory response.26 

Its main function on connective tissues in vivo is to promote growth.

The proliferation of endothelial cell is also stimulated, but the growth of epithelial cell is inhibited.

Mice lacking a downstream mediator of TGF-β, Smad3, demonstrated reduced tissue damage and fibrosis after irradiation and accelerated healing.27 Although TGF-β is known as a central player in the fibrotic process, other cytokines and growth factors such as insulin-like growth factor 1 and connective tissue growth factors (CTGFs) are involved in this process in the skin24 (Figure 1).

Inhibition of pro-inflammatory cytokines such as MCP-1 and cyclooxygenase 2 (COX-2) can improve skin tolerance to RT.28 

Some studies have also reported COX-2 to be an important gene mediating the subsequent inflammation.29 

The study by Cheki et al30 showed that inhibition of COX-2 by celecoxib can reduce inflammation of the dermis, MCP-1 mRNA expression, and RISRs.

New study : Princess Margaret Cancer Centre, University Health Network

A clinical-scientific team specializing in head-and-neck cancer has identified a way to manipulate metabolism to potentially curb skin fibrosis—a common side effect of radiotherapy affecting quality of life of cancer survivors.

A clinical-scientific team specializing in head-and-neck cancer has identified a way to manipulate metabolism to potentially curb skin fibrosis—a common side effect of radiotherapy affecting quality of life of cancer survivors.

The study findings from the laboratory of principal investigator Dr. Fei-Fei Liu, Chief, Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, are published online today in Nature Metabolism. Dr. Liu is also Professor and Chair, Department of Radiation Oncology, University of Toronto and holds the Dr. Mariano Elia Chair in Head and Neck Oncology.

First author Dr. Xiao Zhao, a resident in head-and- neck surgery who completed Ph.D. studies with Dr. Liu, says the research team wanted to find a way to reduce radiation-induced fibrosis, a condition where normal tissue progressively thickens causing pain and dysfunction.

The underlying problem is the excess buildup of the extracellular matrix, a supporting structure for all tissues.

There is currently no effective treatment to reduce this accumulation.

The findings from human tissues with radiation-induced fibrosis and pre-clinical lab experiments steered the team to zero in on metabolic processes that trigger and perpetuate fibrosis.

Dr. Zhao says:

“We were surprised to see that metabolic abnormalities were predominant and consistently found in patients with skin fibrosis, even years after their original radiotherapy.

Our question was: ‘Can we manipulate metabolism to reduce fibrosis?'”

The team studied how regulating metabolism can shift cell behaviour and alter the buildup and degradation of the extracellular matrix.

Through uncovering this metabolic model of extracellular matrix regulation, the team also identified several metabolic drug compounds and potential cell therapy techniques which were successfully tested in pre-clinical models of fibrosis.

These therapeutic strategies centred on metabolism will be carried to the next stage of ongoing research.

“We’re highlighting fibrosis from this new perspective, thereby opening the door to metabolic regulation as a way to treat this side effect of radiation,” says Dr. Zhao.


More information: Xiao Zhao et al, Metabolic regulation of dermal fibroblasts contributes to skin extracellular matrix homeostasis and fibrosis, Nature Metabolism (2018). DOI: 10.1038/s42255-018-0008-5
Provided by University Health Network

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