Induction of p53 Expression in Skin by Radiotherapy and UV Radiation: a Randomized Study

Pontén, Fredrik; Lindman, Henrik; Boström, Åsa; Berne, Berit; Bergh, Jonas

doi:10.1093/jnci/93.2.128

Cited by 42 publications

(28 citation statements)

References 30 publications

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“…HE staining revealed an increased in the number of apoptotic cells with condensed nuclei surrounded by a bright halo. These morphological changes were similar to what has been described in Ponten F. 14 The keratinocytes were enlarged with cytologic atypia.…”

Section: Discussionsupporting

confidence: 87%

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Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure

Wong

Chor

Moorthy

et al. 2013

Int J Cancer Ther Oncol

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Purpose: Knowledge of the pathophysiology of the irradiated skin is important to understand the tolerance and cosmetic response of the human skin to radiation. There are limited studies on the effect of radiotherapy dosage and fraction size in inducing apoptotic cell death in human skin. The expression of apoptotic biomarkers within a controlled population in different fractionation schemes has also never been studied. This study aims to investigate radiation induced apoptotic cell death in human skin cells after fractionated radiation exposure and the expression of unique biomarkers that reflect cell death or biology using multiplexed immunoassays. Methods: Breast skin biopsies were obtained from a single individual and divided into small pieces. Each piece was irradiated under different radiotherapy treatment fractionation schedules to a total dose of 50Gy. The irradiated skin tissues were analysed using Tunnel, immunohistochemistry and Western blot assays for expression of apoptotic keratinocytes and biomarkers (p53, p21, and PCNA). Haematoxylin and eosin (H&E) immunostaining was performed to study the morphological changes in the skin cells. Results: Radiation is mostly absorbed by the epidermal layers and observed to damage the epidermal keratinocytes leading to the activation of apoptotic proteins. Apoptotic proteins (p53, p21 and PCNA) were confirmed to be up-regulated in radiation exposed skin cells as compared to normal skin cells with no radiation. There is strong correlation of apoptotic protein expressions with increased radiation dosage and dose fractionation. Statistical analysis with ANOVA revealed a significant increase of PCNA and p21 expression with increased radiation dosage and dose fractionation (p < 0.05). Immunohistochemically, 14 % (range 10.71% to 17.29%) of the keratinocytes were positive for PCNA and 22.5% (range 18.28% to 27.2%) for p21 after 2Gy of irradiation. The most widespread, intense and uniform staining for PCNA and p21 was observed in skin that had received 50Gy of irradiation. The maximum expression of p53 (range 37.09% to 50.91%) was reached at 10Gy. Conclusion: Findings from this study will assist clinicians in predicting radiation induced skin toxicity with the current changes in radiation fractionation protocols.Keywords: Apoptosis; Fractionated radiation therapy; Immunohistochemistry; Skin IntroductionRadiation therapy (RT) is a commonly utilized modality for the treatment of breast cancer. It is routinely employed in breast conservation therapy. Its role as adjuvant therapy in selected patients undergoing mastectomy for stages I and II disease is currently evolving, and has become an essential component of the combined modality approach for stage III disease. Postmastectomy Radiotherapy (PMRT) to the chest wall and to the regional lymphatics has shown to decrease locoregional recurrence and increase survival for women with large tumors and/or node-positive disease. 1-2 However, the risk of toxicity to skin and cosmesis must be weighed against local and regional...

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Section: Discussionsupporting

confidence: 87%

“…This is in agreement with previous studies that shown that these cytokines are radiation-inducible cytokine. Fredrik Ponten et al 14 investigated levels of p53 and p21 in skin exposed to different types of radiation. Results show an early onset of increased p53 levels and a correlation between p53 and p21 was evident.…”

Section: Discussionmentioning

confidence: 99%

Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure

Wong

Chor

Moorthy

et al. 2013

Int J Cancer Ther Oncol

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“…The responses of normal human tissues to ionizing radiation in situ have been studied in skin biopsies from patients receiving radiotherapy for internal tumors such as breast and prostate (23)(24)(25), but other models of normal human tissue responses to radiation that preserve tissue architecture and cellular interactions with the stromal environment are currently lacking. The aim of this study was to develop a xenograft model of normal mammary tissues derived from women with breast cancer at the time of surgery (26,27) and apply the model to investigate the molecular pathways that are activated by ionizing radiation in human mammary tissues in vivo.…”

Section: Introductionmentioning

confidence: 99%

Differential Contextual Responses of Normal Human Breast Epithelium to Ionizing Radiation in a Mouse Xenograft Model

et al. 2010

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Radiotherapy is a key treatment option for breast cancer, yet the molecular responses of normal human breast epithelial cells to ionizing radiation are unclear. A murine subcutaneous xenograft model was developed in which nonneoplastic human breast tissue was maintained with the preservation of normal tissue architecture, allowing us to study for the first time the radiation response of normal human breast tissue in situ. Ionizing radiation induced dose-dependent p53 stabilization and p53 phosphorylation, together with the induction of p21(CDKN1A) and apoptosis of normal breast epithelium. Although p53 was stabilized in both luminal and basal cells, induction of Ser392-phosphorylated p53 and p21 was higher in basal cells and varied along the length of the ductal system. Basal breast epithelial cells expressed DNp63, which was unchanged on irradiation. Although stromal responses themselves were minimal, the response of normal breast epithelium to ionizing radiation differed according to the stromal setting. We also demonstrated a dose-dependent induction of g-H2AX foci in epithelial cells that was similarly dependent on the stromal environment and differed between basal and luminal epithelial cells. The intrinsic differences between human mammary cell types in response to in vivo irradiation are consistent with clinical observation that therapeutic ionizing radiation is associated with the development of basal-type breast carcinomas. Furthermore, there may be clinically important stromal-epithelial interactions that influence DNA damage responses in the normal breast. These findings demonstrate highly complex responses of normal human breast epithelium following ionizing radiation exposure and emphasize the importance of studying whole-tissue effects rather than single-cell systems. Cancer Res; 70(23); 9808-15. Ó2010 AACR.

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“…One of the most widely studied responses to UV-light is for DNA-damaged KCs to be eliminated via apoptosis ± a process referred to as a cellular proofreading Meek, 1998). The primary mediator responsible for removing DNA damaged keratinocytes in skin is believed to be p53, and this so-called`guardian of the tissue' role for p53 has dominated the ®eld of cutaneous carcinogenesis for the past several decades (Ananthaswamy et al, 1997;Burren et al, 1998;Cleaver, 1968;Gniadecki et al, 1997;Hall et al, 1993;Jonason et al, 1996;Levine, 1997;Li et al, 1996Li et al, , 1998Nakazawa et al, 1994;Ponten et al, 2001;Rees, 1995;Wolf et al, 1995;Ziegler et al, 1994). While many reports using rodent models are in line with a role for p53 in UV-induced apoptosis of KCs (ibid), the precise functional role for p53 in human skin remains to be clari®ed (Dazard et al, 2000;Kulms et al, 1999;Li et al, 1996;Spandau, 1994;Terui et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes

et al. 2002

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Induction of p53 Expression in Skin by Radiotherapy and UV Radiation: a Randomized Study

Abstract: Individual responses to radiation-induced DNA damage varied widely and may be independent of the type of radiation. The epidermal p53 response does not predict the degree of radiation dermatitis.

Cited by 42 publications

References 30 publications

Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure

Human epidermal keratinocytes death and expression of protein markers of apoptosis after ionizing radiation exposure

Differential Contextual Responses of Normal Human Breast Epithelium to Ionizing Radiation in a Mouse Xenograft Model

Regulation of apoptosis by p53 in UV-irradiated human epidermis, psoriatic plaques and senescent keratinocytes

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