p53 Mutation in Nonmelanoma Skin Cancers Occurring in Psoralen Ultraviolet A-Treated Patients: Evidence for Heterogeneity and Field Cancerization

Stern, Robert S.; Bolshakov, Svetlana; Nataraj, Arun J.; Ananthaswamy, Honnavara N.

doi:10.1046/j.1523-1747.2002.01814.x

Cited by 72 publications

(60 citation statements)

References 39 publications

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“…We posed the question of whether the presence of telomerase activation was conditioned by lymphocytic infiltration in the tumor margin or in control tissues and whether there was a higher telomerase expression, indicating field cancerization, in the region surrounding the tumor (28)(29)(30)(31). Telomerase activity was identified in activated lymphocytes (60,(84)(85)(86) and in an attendant lymphocytic infiltration (87,88) described in BCC tumor margin (38,87).…”

Section: Comparison Of Htert Results In Basal Cell Carcinomas and Squmentioning

confidence: 99%

“…BCCs are characterized by a high rate of loco-regional recurrence and secondary tumors. An important cause of this is field cancerization (28) in the area around the BCC (29)(30)(31)(32). Studies are in progress to find the best suited molecular or immunohistochemical markers for characterizing tumor-free margin tissue (8,12,13,24,(33)(34)(35)(36).…”

Section: Introductionmentioning

confidence: 99%

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Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Fabricius

Kruse-Boitschenko²,

Khoury³

et al. 2009

Int J Oncol

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Abstract.In previous studies we demonstrated telomerase activity in frozen tissues from BCC and their tumor-free margins by the PCR ELISA. In this study we examined in the same frozen sections immunohistochemical presence of hTERT in the nucleus. After fixation in acetone and methanol followed by steaming we used for visualization the antigenantibody reactions by APAAP. This was the best method of preparation of the frozen sections in our preliminary hTERT-study with squamous cell carcinomas. This study was supplemented with antibodies against Ki-67, nucleolin, common leucocyte antigen CD45 and mutated p53. The immunoreactive scores were determined and included the comparison with telomerase activity. The investigation of hTERT expression was performed in the tissues of 41 patients with BCC and control tissues of 14 patients without tumor. Eleven commercial antibodies were used for a nuclear staining of hTERT expression. With the anti-hTERT antibodies we looked for both satisfactory distribution and intensity of immunohistochemical labeling in the carcinomas and in the squamous epithelia of the tumor centers, of the tumor-free margins and of the control tissues. The hTERT expression in the BCC was distributed heterogeneously. The score values established by the anti-hTERT antibodies used were variably or significantly increased. In the stroma they tended to be negative, so we disregarded stroma hTERT. Proof of hTERT did not differ uniformly from telomerase activity. We compared the high with the lower median hTERT values in the Kaplan-Meier curve. Patients with lower hTERT scores in the center or tumor margin as shown by some of the antibodies suffered relapse earlier. Finally, we compared the hTERT expression in BCC tissues with the hTERT scores in HNSCC tissues from our previous study. Only one anti-hTERT antibody (our Ab 7) yielded significantly higher scores in BCC than in HNSCC.

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Section: Comparison Of Htert Results In Basal Cell Carcinomas and Squmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Fabricius

Kruse-Boitschenko²,

Khoury³

et al. 2009

Int J Oncol

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“…Therefore it seems highly desirable to investigate how the agents described here affect PUVA's therapeutic efficacy using newly available animal models of psoriasis [47][48][49][50][51] and eczema. 52 A better understanding of PUVA's mechanisms may not only offer the opportunity to dissect the beneficial (ie, therapeutic) effects from the detrimental (ie, carcinogenic) side effects 53,54 but also lead to the development of new drugs (eg, using the PAF pathway) acting like PUVA but having less side effects.…”

Section: Discussionmentioning

confidence: 99%

Platelet-Activating Factor Is Crucial in Psoralen and Ultraviolet A-Induced Immune Suppression, Inflammation, and Apoptosis

Wolf

Nghiem

Walterscheid

et al. 2006

The American Journal of Pathology

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Psoralen plus UVA (PUVA) is used as a very effective treatment modality for various diseases, including psoriasis and cutaneous T-cell lymphoma. PUVA-induced immune suppression and/or apoptosis are thought to be responsible for the therapeutic action. However, the molecular mechanisms by which PUVA acts are not well understood. We have previously identified platelet-activating factor (PAF), a potent phospholipid mediator, as a crucial substance triggering ultraviolet B radiation-induced immune suppression. In this study, we used PAF receptor knockout mice, a selective PAF receptor antagonist, a COX-2 inhibitor (presumably blocking downstream effects of PAF), and PAF-like molecules to test the role of PAF receptor binding in PUVA treatment. We found that activation of the PAF pathway is crucial for PUVAinduced immune suppression (as measured by suppression of delayed type hypersensitivity to Candida albicans) and that it plays a role in skin inflammation and apoptosis. Psoralen and UVA (PUVA) photochemotherapy consists of the topical or oral application of a photosensitizing psoralen (ie, a furocoumarin compound), such as 8-methoxypsoralen, followed by exposure to photoactivating UVA light.

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“…Psoralen plus ultraviolet A (UVA) radiation is commonly used to treat a number of dermatologic conditions, but is associated with an increased risk of squamous cell carcinoma, and possibly malignant melanoma [2,3]. Psoralen photoadducts are mutagenic, though their role in cutaneous malignancy is still unclear [4][5][6]. Mechanistically, psoralen intercalates into DNA, and following ultraviolet A (UVA) radiation forms monoadducts with pyrimidine bases initially that with further UVA irradiation may form ICL predominantly at 5′ TpA 3′ sites [7].…”

Section: Introductionmentioning

confidence: 99%

γ-H2AX formation in response to interstrand crosslinks requires XPF in human cells

Mogi

2006

DNA Repair

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To further define the molecular mechanisms involved in processing interstrand crosslinks, we monitored the formation of phosphorylated histone H2AX (γ-H2AX), which is generated in chromatin near double strand break sites, following DNA damage in normal and repair-deficient human cells. Following treatment with a psoralen derivative and ultraviolet A radiation doses that produce significant numbers of crosslinks, γ-H2AX levels in nucleotide excision repair-deficient XP-A fibroblasts (XP12RO-SV) increased to levels that were twice those observed in normal control GM637 fibroblasts. A partial XPA revertant cell line (XP129) that is proficient in crosslink removal, exhibited reduced γ-H2AX levels that were intermediate between those of GM637 and XP-A cells. XP-F fibroblasts (XP2YO-SV and XP3YO) that are also repair-deficient exhibited γ-H2AX levels below even control fibroblasts following treatment with psoralen and ultraviolet A radiation. Similarly, another crosslinking agent, mitomycin C, did not induce γ-H2AX in XP-F cells, although it did induce equivalent levels of γ-H2AX in XPA and control GM637 cells. Ectopic expression of XPF in XP-F fibroblasts restored γ-H2AX induction following treatment with crosslinking agents. Angelicin, a furocoumarin which forms only monoadducts and not crosslinks following ultraviolet A radiation, as well as ultraviolet C radiation, resulted only in weak induction of γ-H2AX in all cells, suggesting that the double strand breaks observed with psoralen and ultraviolet A treatment result preferentially following crosslink formation. These results indicate that XPF is required to form γ-H2AX and likely double strand breaks in response to interstrand crosslinks in human cells. Furthermore, XPA may be important to allow psoralen interstrand crosslinks to be processed without forming a double strand break intermediate.

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p53 Mutation in Nonmelanoma Skin Cancers Occurring in Psoralen Ultraviolet A-Treated Patients: Evidence for Heterogeneity and Field Cancerization

Cited by 72 publications

References 39 publications

Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Localization of telomerase hTERT protein in frozen sections of basal cell carcinomas (BCC) and tumor margin tissues

Platelet-Activating Factor Is Crucial in Psoralen and Ultraviolet A-Induced Immune Suppression, Inflammation, and Apoptosis

γ-H2AX formation in response to interstrand crosslinks requires XPF in human cells

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