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Xu et al. Radiation therapy in keloids treatment

downregulation of Dickkopf-3 (DKK3) in keloids could potentially enhance damage towards lesion
fibroblasts disinhibited cell proliferation in TGF-β1- vasculature and obviously decrease inflammation. [65]
induced keloid fibroblasts transfected with pcDNA3 However, we believe that mTOR pathway is central to
through downregulated Bax and caspase-3 expression some solid tumor formation, which is not the case in
and increase expression of Bcl-2. [52] Additionally, keloid formation. Besides, inflammation is initial phase
dramatic overproduction of collagen proteins and of wound healing process and also keloid formation
mRNAs was also contributed to DKK3 overexpression, process, IL-6 is one of key cytokines mediating
which made DKK3 a potential mediator functioning inflammation. Overexpression of IL-6 first reported in
in TGF-β/SMAD signaling pathway. Overexpression 1990s, both in keloid fibroblasts culture and collagen
of TGF-β can explain overproduction of collagen and synthesis. [66] IL-6 is not only accumulated in collagen,
extracellular matrix, [53] outweighing other postulated but also related to JAK/STAT3 and ERK/MAP kinase. In
pathways explaining the pathogenesis. [54] Immune an epidemiological study in China, a marked increase
system including T-cell function and keloid fibroblasts in serum IL-6 levels in KS patients with GG genotypes
proliferation were included in this process. [55] Radiation when compared to keloids patients harboring the CC
therapy can induce and enhance TGF-β signaling in genotype indicating IL-6 polymorphisms is partially
radiation oncology, which means this process was related to keloid susceptibility. [67] Recently, a case
much less important in keloid treatment. [56] Several report demonstrated a Castleman’s disease (a rare
literatures reported that radiation could potentially lymphoproliferative disorder) patient developed
induce persistent TGF-β overproduction in animal bilateral auricular keloids, which is believed due
models. [57-59] In radiation induced fibrosis, high doses of to overproduction of IL-6 in Castleman’s disease
radiation can be delivered to the skin and the underlying patients. [68] Moreover, antibody towards IL-6 resulted
subcutaneous tissues, and severe skin burns can be in reduced collagen accumulation which made IL-6
observed, resulting in extensive fibronecrotic tissues. [60] a target for pharmacologic intervention. However,
TGF-β1 was observed sustainably overexpressed no post-radiation therapy can potentially support this
in all phases of skin fibrosis, especially in late phase assumption. From genetics to epigenetics is another
of fibrosis at a level of 10 folds more than underlying very important issue in the past few years. The fact that
tissue. In human patients, similar long-term activation of the proportion of apoptotic cells in keloid fibroblasts
TGF-β expression pattern was found in mammary skin can be modulated by methylation inhibitors indicated
biopsies from breast cancer patients who had received that methylation also plays an important role in
radiation therapy up to 10 years before. Considering keloid formation. [69] DNMT1, DNA methyltransferase
the parallel relation between keloid scarring and skin 1, a well-known DNA methyltransferase, expressed
fibrosis, TGF-β pathway is less likely to be target of 100% in keloid tissue compared to 8% in normal skin
radiation therapy in treating keloid lesions. However, tissue. [70] In one study working on relevance between
TGF-β overexpression could potentially provide methylation levels and radiation therapy, clear
plausible explanation of some radiation-refractory difference induced by radiation therapy is observed. [71]
patients, explaining their higher rates of recurrence. Moreover, histonedeacetylase 2 (HDAC2) upregulated
Therefore, direct and indirect DNA damage and p53- in keloid tissue in vivo, was also observed in scar tissue
induced apoptosis possibly outweigh TGF-β signaling mice model of wound repair. [72] Notably, the capacity of
activation in keloid radiation therapy treatment. the HDAC inhibitor suberoylanilide hydroxamic acid to
modulate radiation response in human tumor cell lines
Other potential responses is verified in another study, demonstrating a dose-
TNF receptor superfamily not only coordinates with dependent inhibition effect. The radiation-induced
p53 in canonical extrinsic apoptotic pathway, but apoptosis was significantly enhanced. [73] Acetylation
also induces necrosis by TNF (alpha)-PARP-jnk- level of histone is also altered after radiation therapy
Caspases pathway. [61] The signaling cascade ULK-1 in lymphoblastoid cell lines. [74] Therefore, even though
initiated the process of autophagy, upregulating Hif1a valid evidence is absent, we can still predict that the
and blocking Bcl-2 and, finally releasing Beclin1. [62] methylation and histone post-translational modification
Beclin1 was deemed as the initiator of autophagy. Anti- levels will change in response to radiation therapy.
inflammation effect was considered playing the minor Besides, a recent new perspective of keloid and
role in treating keloids and other proliferative benign hypertrophic scars renders these two disorders as
disease. [63] Moreover, PI3K/Akt/mTOR pathway can vascular disease. [75] All so-called effective treatments
potentially enhance the tissue sensitivity towards of keloids including radiotherapy, compression therapy,
the radiation damage through inducing apoptosis, steroid administration, and long-pulsed Nd:YAG
reducing autophagy, suppressing NHEJ and HR laser therapy all directly or indirectly damage blood
repair pathways. [64] Inhibition of mTOR pathway vessels or suppress new blood vessel growth. The
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