The radiation therapy in keloids treatment: a comprehensive review of pathomechanism, damage mechanisms and cellular response

Abstract

Keloid management has always been frustrating and challenging. The combination therapy of surgical excision and radiation therapy was deemed as the last resort for decades. The authors performed a thorough and comprehensive review over the mechanisms on how radiation therapy damages the keloid cells. The keloid cells’ cellular response towards damage induced by irradiation was also studied based on original and current literatures. Mechanisms of damage generated by radiation therapy on keloid cells remained partially understood. However, direct damage was identified playing dominant role, in contrast to damage involved cancer cell apoptosis. Moreover, the p53 pathway and some inflammatory factors like interleukin-6 were believed to function in cellular response to irradiation. However, the transforming growth factor beta, which was the major dysregulated pathway involved in pathogenesis of keloid formation showed no apparent correlation with cellular response to irradiation damage. These pathways could partially explain radiation resistance in some refractory keloid lesions. The scientific basis and experimental proof in this field was still inadequate, which drove us to find more evidence to identify the key regulator response to damage engendered by radiation therapy. Further pathway identification may benefit the drug development to prevent keloid recurrence.

Keywords

Radiation therapy / keloids / combination therapy

References

[1] Bennett KG,Hayman JA.Treatment of keloids with excision and adjuvant radiation: a single center experience and review of the literature..Ann Plast Surg2017;78:157-61

[2] Ogawa R.Mechanobiological dysregulation of the epidermis and dermis in skin disorders and in degeneration..J Cell Mol Med2013;17:817-22 PMCID:PMC3822886

[3] Ha JM,Cho EB,Park EJ,Kim LS.Comparison of the effectiveness of nonablative fractional laser versus pulsed-dye laser in thyroidectomy scar prevention..Ann Dermatol2014;26:615-20 PMCID:PMC4198590

[4] Rabello FB,Farina Junior JA.Update on hypertrophic scar treatment..Clinics (Sao Paulo).2014;69:565-73

[5] Supp DM,McFarland KL.Inhibition of hyaluronan synthase 2 reduces the abnormal migration rate of keloid keratinocytes..J Burn Care Res2014;35:84-92

[6] Ogawa R.Keloid and hypertrophic scars are the result of chronic inflammation in the reticular dermis..Int J Mol Sci2017;18:E606 PMCID:PMC5372622

[7] Andrews JP,Macarak E,Uitto J.Keloids: the paradigm of skin fibrosis - pathomechanisms and treatment..Matrix Biol2016;51:37-46 PMCID:PMC4842154

[8] van den Broek LJ,Niessen FB.Human hypertrophic and keloid scar models: principles, limitations and future challenges from a tissue engineering perspective..Exp Dermatol2014;23:382-6 PMCID:PMC4369123

[9] Zonari A,Paula AC,Novikoff S,Correlo VM,Goes AM.Polyhydroxybutyrate-co-hydroxyvalerate structures loaded with adipose stem cells promote skin healing with reduced scarring..Acta Biomater2015;17:170-81

[10] Hahn JM,McFarland KL,Boyce ST.Keloid-derived keratinocytes exhibit an abnormal gene expression profile consistent with a distinct causal role in keloid pathology..Wound Repair Regen2013;21:530-44

[11] Ma X,Xu B,Qin H,Wang X.Keloid-derived keratinocytes acquire a fibroblast-like appearance and an enhanced invasive capacity in a hypoxic microenvironment in vitro..Int J Mol Med2015;35:1246-56 PMCID:PMC4380122

[12] Douaiher J,Lancerotto L,Orgill DP,Krilis SA.Development of mast cells and importance of their tryptase and chymase serine proteases in inflammation and wound healing..Adv Immunol2014;122:211-52 PMCID:PMC4115062

[13] Har-Shai Y,Gil T,Gal-Or N,Lavi I,Brizgalin L,Har-Shai L.Intralesional cryosurgery for the treatment of basal cell carcinoma of the lower extremities in elderly subjects: a feasibility study..Int J Dermatol2016;55:342-50

[14] Pakyari M,Maharlooei MK.Critical role of transforming growth factor beta in different phases of wound healing..Adv Wound Care (New Rochelle).2013;2:215-24 PMCID:PMC3857353

[15] Wang YW,Cherng JH,Ma KH,Liu JC.siRNA-targeting transforming growth factor-beta type I receptor reduces wound scarring and extracellular matrix deposition of scar tissue..J Invest Dermatol2014;134:2016-25

[16] Shi JH,Shi S,Bai XZ,Fang XB,Tao K,Tang CW.Protection against TGF-beta 1-induced fibrosis effects of IL-10 on dermal fibroblasts and its potential therapeutics for the reduction of skin scarring..Arch Dermatol Res2013;305:341-52

[17] Walmsley GG,Wong VW,Hu MS,Wearda T,McArdle A,Atashroo DA,Lorenz HP,Longaker MT.Scarless wound healing: chasing the holy grail..Plast Reconstr Surg2015;135:907-17

[18] Ud-Din S,Derbyshire B,Bayat A.Identification of steroid sensitive responders versus non-responders in the treatment of keloid disease..Arch Dermatol Res2013;305:423-32

[19] Jumper N,Arscott G,Paus R.The Aldo-Keto Reductase AKR1B10 is up-regulated in keloid epidermis, implicating retinoic acid pathway dysregulation in the pathogenesis of keloid disease..J Invest Dermatol2016;136:1500-12

[20] Li ZJ.The application of the starfish hatching enzyme for the improvement of scar and keloid based on the fibroblast-populated collagen lattice..Appl Biochem Biotechnol2014;173:989-1002

[21] Lee WJ,Lee JH,Yun CO.A novel three-dimensional model system for keloid study: organotypic multicellular scar model..Wound Repair Regen2013;21:155-65

[22] Arno AI,Barret JP.Up-to-date approach to manage keloids and hypertrophic scars: a useful guide..Burns2014;40:1255-66 PMCID:PMC4186912

[23] Shaarawy E,Abdel Hay RM.Intralesional botulinum toxin type A equally effective and better tolerated than intralesional steroid in the treatment of keloids: a randomized controlled trial..J Cosmet Dermatol2015;14:161-6

[24] Brewin MP.Prevention or treatment of hypertrophic burn scarring: a review of when and how to treat with the pulsed dye laser..Burns2014;40:797-804

[25] Zhu Z,Tredget EE.The molecular basis of hypertrophic scars..Burns Trauma2016;4:2 PMCID:PMC4963951

[26] Seo BF,Jung SN.Models of abnormal scarring..Biomed Res Int2013;2013:423147 PMCID:PMC3775400

[27] Hwang SH.Outcomes of surgical excision with pressure therapy using magnets and identification of risk factors for recurrent keloids..Plast Reconstr Surg2013;132:e666-7

[28] Enwerem-Bromson N.Expanding global access to radiotherapy: the IAEA perspective..Lancet Oncol2015;16:1151-2

[29] Arno AI,Barret JP.Up-to-date approach to manage keloids and hypertrophic scars: a useful guide..Burns2014;40:1255-66 PMCID:PMC4186912

[30] Shen J,Sun Y,Hu K,Sun S,Yu L,Li W,Guan Q,Zhang F.Hypofractionated electron-beam radiation therapy for keloids: retrospective study of 568 cases with 834 lesions..J Radiat Res2015;56:811-7 PMCID:PMC4577000

[31] Basan M,Hannezo E,Levine H.Alignment of cellular motility forces with tissue flow as a mechanism for efficient wound healing..Proc Natl Acad Sci U S A2013;110:2452-9 PMCID:PMC3574962

[32] Shah VV,Mlacker S,Samarkandy S.5-fluorouracil in the treatment of keloids and hypertrophic scars: a comprehensive review of the literature..Dermatol Ther (Heidelb).2016;6:169-83 PMCID:PMC4906112

[33] Yamamori T,Bo T,Sakai Y,Yamamoto K,Yasui H.Inhibition of the mitochondrial fission protein dynamin-related protein 1 (Drp1) impairs mitochondrial fission and mitotic catastrophe after x-irradiation..Mol Biol Cell2015;26:4607-17 PMCID:PMC4678018

[34] Maier P,Wenz F.Cellular pathways in response to ionizing radiation and their targetability for tumor radiosensitization..Int J Mol Sci2016;17:E102 PMCID:PMC4730344

[35] Sun XJ,Guo B,Wang B.Identification of skin-related lncRNAs as potential biomarkers that involved in Wnt pathways in keloids..Oncotarget2017;8:34236-44

[36] Stamatakos G,Lunzer A,Kolokotroni E,Erdt M,Rüeping S,d'Onofrio A,Marias K,Tsiknakis M.The technologically integrated oncosimulator: combining multiscale cancer modeling with information technology in the in silico oncology context..IEEE J Biomed Health Inform2014;18:840-54

[37] Wick W,Bendszus M,Henriksson R,Nishikawa R,Kerloeguen Y.Evaluation of pseudoprogression rates and tumor progression patterns in a phase III trial of bevacizumab plus radiotherapy/temozolomide for newly diagnosed glioblastoma..Neuro Oncol2016;18:1434-41 PMCID:PMC5035525

[38] Chinot OL,Mason W,Saran F,Carpentier AF,Kavan P,Brandes AA,Abrey L.Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma..N Engl J Med2014;370:709-22

[39] Gadgeel SM,Riely GJ,West HL,Morcos PN,Garcia L,Boisserie F,Golding S,Yokoyama S,Ou SH.Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study..Lancet Oncol2014;15:1119-28

[40] Armstrong TS,Wu J,Vera-Bolanos E,Brown PD,Chung C.The relationship between corticosteroids and symptoms in patients with primary brain tumors: utility of the Dexamethasone Symptom Questionnaire-Chronic..Neuro Oncol2015;17:1114-20 PMCID:PMC4490874

[41] Grossman R,Hadelsberg U,Sitt R,Corn BW.Impact of resecting radiation necrosis and pseudoprogression on survival of patients with glioblastoma..World Neurosurg2016;89:37-41

[42] Das A,Dixon-Mah YN,Samant VN,Lindhorst SM,Varma AK,Banik NL,Raizer JJ,Patel SJ.RIP1 and RIP3 complex regulates radiation-induced programmed necrosis in glioblastoma..Tumour Biol2016;37:7525-34

[43] Ladin DA,Patel D,Olson JC,Fivenson DP.p53 and apoptosis alterations in keloids and keloid fibroblasts..Wound Repair Regen1998;6:28-37

[44] Son D.Overview of surgical scar prevention and management..J Korean Med Sci2014;29:751-7 PMCID:PMC4055805

[45] Unahabhokha T,Nimmannit U,Yongsanguanchai N.Molecular signalings in keloid disease and current therapeutic approaches from natural based compounds..Pharm Biol2015;53:457-63

[46] Filgueiras Mde C,Soares PM,Mermelstein C.Effects of 5-fluorouracil in nuclear and cellular morphology, proliferation, cell cycle, apoptosis, cytoskeletal and caveolar distribution in primary cultures of smooth muscle cells..PLoS One2013;8:e63177 PMCID:PMC3639966

[47] Huang C.Pharmacological treatment for keloids..Expert Opin Pharmacother2013;14:2087-100

[48] De Felice B,Mondola P,Seru R,Nacca M,Garbi C.Differential p63 and p53 expression in human keloid fibroblasts and hypertrophic scar fibroblasts..DNA Cell Biol2007;26:541-7

[49] Trace AP,Mantel A.Keloids and hypertrophic scars: a spectrum of clinical challenges..Am J Clin Dermatol2016;17:201-23

[50] Huang D,Huang Y,Shen K,Mou Y.Mechanical compression upregulates MMP9 through SMAD3 but not SMAD2 modulation in hypertrophic scar fibroblasts..Connect Tissue Res2014;55:391-6

[51] Zhang X,You T,Zhang H,Zhang W.Roles of TGF-beta/Smad signaling pathway in pathogenesis and development of gluteal muscle contracture..Connect Tissue Res2015;56:9-17 PMCID:PMC4438420

[52] Li Y,Liang Y,Ma X.DKK3 regulates cell proliferation, apoptosis and collagen synthesis in keloid fibroblasts via TGF-beta1/Smad signaling pathway..Biomed Pharmacother2017;91:174-80

[53] Lilja-Maula L,Laurila HP,Rönty M,Rajamäki MM.Comparative study of transforming growth factor-beta signalling and regulatory molecules in human and canine idiopathic pulmonary fibrosis..J Comp Pathol2014;150:399-407

[54] Lu J,Li M,Fu R,Duan Z,Yang Y,Jia L.Activation of AMPK by metformin inhibits TGF-beta-induced collagen production in mouse renal fibroblasts..Life Sci2015;127:59-65

[55] Jette ME,Thibeault SL.Characterization of human vocal fold fibroblasts derived from chronic scar..Laryngoscope2013;123:738-45 PMCID:PMC3584344

[56] Moding EJ,Kirsch DG.Strategies for optimizing the response of cancer and normal tissues to radiation..Nat Rev Drug Discov2013;12:526-42 PMCID:PMC3906736

[57] Wang M,Hada M,Pluth JM,Cucinotta FA.Novel Smad proteins localize to IR-induced double-strand breaks: interplay between TGFbeta and ATM pathways..Nucleic Acids Res2013;41:933-42 PMCID:PMC3553971

[58] Weigel C,Plass C.Epigenetics in radiation-induced fibrosis..Oncogene2015;34:2145-55

[59] Russell NS,van Werkhoven E,de Jong-Korlaar R,Stewart FA.Blood and lymphatic microvessel damage in irradiated human skin: the role of TGF-beta, endoglin and macrophages..Radiother Oncol2015;116:455-61

[60] Al-Omair A,Kiehl TR,Yu E,Keith J,Sahgal A.Radiation-induced vertebral compression fracture following spine stereotactic radiosurgery: clinicopathological correlation..J Neurosurg Spine2013;18:430-5

[61] Thibault I,Masucci GL,Lochray F,Cheng L,Yee A,Bjarnason GA.Spine stereotactic body radiotherapy for renal cell cancer spinal metastases: analysis of outcomes and risk of vertebral compression fracture..J Neurosurg Spine2014;21:711-8

[62] Honscheid P,Muders MH.Autophagy: detection, regulation and its role in cancer and therapy response..Int J Radiat Biol2014;90:628-35

[63] Canyilmaz E,Aynaci O,Serdar L,Aynaci O.Prospective randomized comparison of the effectiveness of radiation therapy and local steroid injection for the treatment of plantar fasciitis..Int J Radiat Oncol Biol Phys2015;92:659-66

[64] Chang L,Hao J,Bucci J,Kearsley JH.PI3K/Akt/mTOR pathway inhibitors enhance radiosensitivity in radioresistant prostate cancer cells through inducing apoptosis, reducing autophagy, suppressing NHEJ and HR repair pathways..Cell Death Dis2014;5:e1437 PMCID:PMC4237243

[65] Chinnaiyan P,Wen PY,Wendland M,Corn BW.RTOG 0913: a phase 1 study of daily everolimus (RAD001) in combination with radiation therapy and temozolomide in patients with newly diagnosed glioblastoma..Int J Radiat Oncol Biol Phys2013;86:880-4 PMCID:PMC3766839

[66] Van Linthout S,Tschöpe C.Crosstalk between fibroblasts and inflammatory cells..Cardiovasc Res2014;102:258-69

[67] Zhu XJ,Li H,Liu J.Association of interleukin-6 gene polymorphisms and circulating levels with keloid scars in a Chinese Han population..Genet Mol Res2017;16:16029110

[68] Quong WL,Ogawa R.A case of keloids complicated by Castleman's disease: interleukin-6 as a keloid risk factor..Plast Reconstr Surg Glob Open2017;5:e1336 PMCID:PMC5459645

[69] Zou QP,Zhang HS.Effect of the methylation enzyme inhibitors of 5-aza-2-deoxycytidine on the TGF-beta/smad signal transduction pathway in human keloid fibroblasts..Zhonghua Zheng Xing Wai Ke Za Zhi2013;29:285-9(in Chinese)

[70] Yang E,Zhang H.The expression of DNMT1 in pathologic scar fibroblasts and the effect of 5-aza-2-deoxycytidine on cytokines of pathologic scar fibroblasts..Wounds2014;26:139-46

[71] Halvorsen AR,Fleischer T,Grenaker Alnaes GI,Syljuåsen RG,Busato F,Saetersdal AB,Kristensen V.Differential DNA methylation analysis of breast cancer reveals the impact of immune signaling in radiation therapy..Int J Cancer2014;135:2085-95 PMCID:PMC4298788

[72] Spallotta F,Straino S,Rosati J,Manni I,Piaggio G,Valente S,Capogrossi MC,Gaetano C.A nitric oxide-dependent cross-talk between class i and iii histone deacetylases accelerates skin repair..J Biol Chem2013;288:11004-12 PMCID:PMC3630901

[73] Chinnaiyan P,Armstrong E,Harari PM.Modulation of radiation response by histone deacetylase inhibition..Int J Radiat Oncol Biol Phys2005;62:223-9

[74] Maroschik B,Krämer A,Gomolka M,Mörtl S.Radiation-induced alterations of histone post-translational modification levels in lymphoblastoid cell lines..Radiat Oncol2014;9:15 PMCID:PMC3903440

[75] Ogawa R.Endothelial dysfunction may play a key role in keloid and hypertrophic scar pathogenesis - keloids and hypertrophic scars may be vascular disorders..Med Hypotheses2016;96:51-60

[76] Liang X,Long X.LncRNA expression profiles and validation in keloid and normal skin tissue..Int J Oncol2015;47:1829-38

[77] Kaboli PJ,Ismail P.MicroRNA-based therapy and breast cancer: a comprehensive review of novel therapeutic strategies from diagnosis to treatment..Pharmacol Res2015;97:104-21

[78] Liu Y,Xiao ZB.miRNA expression profiles in keloid tissue and corresponding normal skin tissue..Aesthet Plast Surg2012;36:193-201

[79] Rustad KC,Gurtner GC.The role of focal adhesion complexes in fibroblast mechanotransduction during scar formation..Differentiation2013;86:87-91

[80] Korpela E,Liu SK.MicroRNA in radiotherapy: miRage or miRador?.Br J Cancer2015;112:777-82 PMCID:PMC4453960

[81] Zhu H,Zhu S,Li Z,Yu X.Regulation of autophagy by systemic admission of microRNA-141 to target HMGB1 in L-arginine-induced acute pancreatitis in vivo..Pancreatology2016;16:337-46

[82] Shin VY,Cheuk I,Kwong A.Circulating cell-free miRNAs as biomarker for triple-negative breast cancer..Br J Cancer2015;112:1751-9 PMCID:PMC4647231

[83] Zhang PX,Zou S,Koff JL,Lee PJ,Egan ME.Pharmacological modulation of the AKT/microRNA-199a-5p/CAV1 pathway ameliorates cystic fibrosis lung hyper-inflammation..Nat Commun2015;6:6221 PMCID:PMC4324503

[84] Yi H,Jia J,Xu H,Ma S.Differential roles of miR-199a-5p in radiation-induced autophagy in breast cancer cells..FEBS Lett2013;587:436-43

[85] Wu ZY,Liang J,Zhang PH.Keloid microRNA expression analysis and the influence of miR-199a-5p on the proliferation of keloid fibroblasts..Genet Mol Res2014;13:2727-38

[86] Lin J,Gao F,Zhao L,Lei J.miR-200c enhances radiosensitivity of human breast cancer cells..J Cell Biochem2013;114:606-15

[87] Kurashige J,Sawada G,Eguchi H,Mori M,Yashiro M,Baba H.Epigenetic modulation and repression of miR-200b by cancer-associated fibroblasts contribute to cancer invasion and peritoneal dissemination in gastric cancer..Carcinogenesis2015;36:133-41

[88] Li P,Luo CQ.Overexpression of miR-200b inhibits the cell proliferation and promotes apoptosis of human hypertrophic scar fibroblasts in vitro..J Dermatol2014;41:903-11

[89] Feng J,Pang Q,Cui F.miR-141-3p inhibits fibroblast proliferation and migration by targeting GAB1 in keloids..Biochem Biophys Res Commun2017;490:302-8

[90] Chang L,Hao J,Cozzi PJ,Li Y.Emerging roles of radioresistance in prostate cancer metastasis and radiation therapy..Cancer Metastasis Rev2014;33:469-96

[91] Ji J,Zhu YQ,Ji SJ,Zhou XZ.Ionizing irradiation inhibits keloid fibroblast cell proliferation and induces premature cellular senescence..J Dermatol2015;42:56-63

[92] Igota S,Murakami M,Shimizu H,Ghazizadeh M.Identification and characterization of Wnt signaling pathway in keloid pathogenesis..Int J Med Sci2013;10:344-54 PMCID:PMC3590592

[93] Zhang Q,Kelly AP,Wang S,Wang L,Shi S.Tumor-like stem cells derived from human keloid are governed by the inflammatory niche driven by IL-17/IL-6 axis..PLoS One2009;4:e7798 PMCID:PMC2771422

[94] Meacham CE.Tumour heterogeneity and cancer cell plasticity..Nature2013;501:328-37 PMCID:PMC4521623

[95] Gao J,Liao N,Zeng W,Wang S.Relationship between p53 gene codon-72 polymorphisms and hypertrophic scar formation following caesarean section..Exp Ther Med2014;7:1243-6 PMCID:PMC3991505

[96] Nakano T,Ohno T,Suzuki M,Sato S,Tsujii H.Carbon beam therapy overcomes the radiation resistance of uterine cervical cancer originating from hypoxia..Clin Cancer Res2006;12:2185-90

[97] Abbasi AZ,Amini MA,Rauth AM,Wu XY.Hybrid manganese dioxide nanoparticles potentiate radiation therapy by modulating tumor hypoxia..Cancer Res2016;76:6643-56

[98] Huang WJ,Zhang X.Glioblastoma multiforme: effect of hypoxia and hypoxia inducible factors on therapeutic approaches..Oncol Lett2016;12:2283-8 PMCID:PMC5038353

[99] He Y,Alghamdi M,Fear MW.From genetics to epigenetics: new insights into keloid scarring..Cell Prolif2017;50:12326

[100] Polat M,Sahin A.A new approach in the treatment of keloids: UVA-1 laser..Photomed Laser Surg2016;34:130-3

[101] Commander SJ,Cox J,Lee EI.Update on postsurgical scar management..Semin Plast Surg2016;30:122-8 PMCID:PMC4961501

[102] Soltani AM,Motamed A,Hammoudeh JA,Reinisch JF.Hypertrophic scarring in cleft lip repair: a comparison of incidence among ethnic groups..Clin Epidemiol2012;4:187-91 PMCID:PMC3413167

[103] Kim S,Liu W,Suh JS.Update on scar management: guidelines for treating Asian patients..Plast Reconstr Surg2013;132:1580-9