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Elevated cutaneous Smad activation associates with enhanced skin tumor susceptibility in organ transplant recipients.

ABSTRACT: Nonmelanoma skin cancer incidence is enhanced >50-fold in patients taking antirejection drugs (ARD) following organ transplantation. Preclinical studies suggest that ARD treatment increases transforming growth factor-beta1 (TGF-beta1) levels, which contribute to enhanced tumor susceptibility independent of the immunosuppressive effects of ARDs. This study investigates whether TGF-beta signaling is elevated in transplant patients.Immunohistochemical tissue microarray analysis was used to determine the levels of TGF-beta1, TGF-beta2, TGF-beta3, TbetaRII, and activated P-Smad2/3 and P-Smad1/5/8, which are phosphorylated directly by distinct TGF-beta/BMP receptor complexes. We analyzed >200 cutaneous lesions and adjacent nonlesional skin samples from 87 organ transplant recipients, and 184 cutaneous lesions and adjacent skin samples from 184 individuals who had never received ARDs.We found significantly higher levels of P-Smad2 in both nonlesional and lesional tissue from transplant recipients compared with those not exposed to ARDs (P < or = 0.001). In contrast, P-Smad1/5/8, a marker of activation of the bone morphogenetic protein signaling pathway, was generally not expressed at higher levels in patients taking ARDs, including analysis of nonlesional skin, actinic keratoses, carcinoma in situ, or squamous cell carcinoma but was differentially expressed between keratoacanthoma from transplant recipients compared with those from non-transplant recipients (P < or = 0.005).Observation of elevated P-Smad2 levels in transplant recipients is consistent with the notion that elevated TGF-beta signaling may contribute to malignancy in organ transplant recipients. Disparate P-Smad1/5/8 expression levels between keratoacanthoma from the two patient groups might reflect the distinct BMP-responsive cell of origin for this hair follicle-derived lesion.

SUBMITTER: Harradine KA

PROVIDER: S-EPMC2812428 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Elevated cutaneous Smad activation associates with enhanced skin tumor susceptibility in organ transplant recipients.

Harradine Kelly A KA Ridd Katie K Saunier Elise F EF Clermont Frederic F FF Perez-Losada Jesus J Moore Dan H DH Epstein Ervin H EH Bastian Boris C BC Akhurst Rosemary J RJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20090811 16

<h4>Purpose</h4>Nonmelanoma skin cancer incidence is enhanced >50-fold in patients taking antirejection drugs (ARD) following organ transplantation. Preclinical studies suggest that ARD treatment increases transforming growth factor-beta1 (TGF-beta1) levels, which contribute to enhanced tumor susceptibility independent of the immunosuppressive effects of ARDs. This study investigates whether TGF-beta signaling is elevated in transplant patients.<h4>Experimental design</h4>Immunohistochemical tis ...[more]

PMID: 19671862

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Project description:Importance:Solid organ transplant recipients (SOTRs) have a 100-fold increased risk of squamous cell carcinoma (SCC), and they may develop more aggressive SCCs compared with immunocompetent individuals. Objective:To compare outcomes associated with aggressive behavior of SCC in SOTRs and high-risk immunocompetent patients. Design, Setting, and Participants:A retrospective cohort study of 58 SOTRs and 40 immunocompetent patients evaluated at the Yale Transplant Dermatology Clinic in New Haven, Connecticut, who had at least 1 SCC confirmed histopathologically between January 1, 2008, and December 31, 2015. Cumulative follow-up time for this study was 369 patient-years. Exposure:Immunosuppressive medication regimen for SOTRs. Main Outcomes and Measures:The primary outcome measure was tumor depth of SCC. Secondary outcome measures that reflected tumor aggressiveness included perineural invasion, regional metastases, nodal metastases, disease-specific death, and overall death. Results:Of the 58 SOTR study participants, 14 were women and 44 were men; the mean (SD) age was 61.3 (8.4) years. Of the 40 immunocompetent study participants, 16 were women and 24 were men; the mean (SD) age was 69.8 (10.9) years, resulting in a statistically significant difference from the SOTR group. The mean (SD) number of years that SOTRs were immunosuppressed was 14.6 (9.2) years (range, 2-37 years). The SOTR and immunocompetent groups were statistically comparable regarding race and sex, patient care, follow-up time, numbers of skin lesions, and field cancerization and chemopreventive therapies. The SOTR group had a significantly higher annual frequency of visits (mean [SD], 4 [2] vs 3 [2] office visits per patient per year, P?=?.02) and annual biopsy rates (mean [SD], 6 [4] vs 5 [3] biopsies per patient per year, P?=?.04). The SOTRs developed SCCs that did not appear to be significantly more aggressive than those found in the immunocompetent control group. These SOTRs also did not develop significantly thicker tumors than the immunocompetent control group (median [IQR] tumor depth, 1.30 [0.90-1.60] mm in 35 SOTRs vs 1.22 [1.10-1.60] mm in 20 immunocompetent patients). Conclusions and Relevance:The increased risk and the potential for aggressive behavior of SCCs in SOTRs may be successfully managed at a level comparable to that in high-risk immunocompetent individuals through close adherence to current dermatologic surveillance recommendations and a marginally lower threshold for biopsy of suspicious lesions for SOTRs.

Project description:BackgroundThe risk of developing cutaneous squamous cell carcinoma (SCC) is markedly increased in organ transplant recipients (OTRs) compared to the normal population. Next to sun exposure, the immunosuppressive regimen is an important risk factor for the development of SCC in OTRs. Various gene mutations (e.g. TP53) and genetic alterations (e.g. loss of CDKN2A, amplification of RAS) have been found in SCCs. The aim of this genome-wide study was to identify pathways and genomic alterations that are consistently involved in the formation of SCCs and their precursor lesions, actinic keratoses (AKs).MethodsTo perform the analysis in an isogenic background, RNA and DNA were isolated from SCC, AK and normal (unexposed) epidermis (NS) from each of 13 OTRs. Samples were subjected to genome-wide expression analysis and genome SNP analysis using Illumina's HumanWG-6 BeadChips and Infinium II HumanHap550 Genotyping BeadChips, respectively. mRNA expression results were verified by quantitative PCR.ResultsHierarchical cluster analysis of mRNA expression profiles showed SCC, AK and NS samples to separate into three distinct groups. Several thousand genes were differentially expressed between epidermis, AK and SCC; most upregulated in SCCs were hyperproliferation related genes and stress markers, such as keratin 6 (KRT6), KRT16 and KRT17. Matching to oncogenic pathways revealed activation of downstream targets of RAS and cMYC in SCCs and of NFκB and TNF already in AKs. In contrast to what has been reported previously, genome-wide SNP analysis showed very few copy number variations in AKs and SCCs, and these variations had no apparent relationship with observed changes in mRNA expression profiles.ConclusionVast differences in gene expression profiles exist between SCC, AK and NS from immunosuppressed OTRs. Moreover, several pathways activated in SCCs were already activated in AKs, confirming the assumption that AKs are the precursor lesions of SCCs. Since the drastic changes in gene expression appeared unlinked to specific genomic gains or losses, the causal events driving SCC development require further investigation. Other molecular mechanisms, such as DNA methylation or miRNA alterations, may affect gene expression in SCCs of OTRs. Further study is required to identify the mechanisms of early activation of NFκB and TNF, and to establish whether these pathways offer a feasible target for preventive intervention among OTRs.

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Elevated cutaneous Smad activation associates with enhanced skin tumor susceptibility in organ transplant recipients.

Publications

Elevated cutaneous Smad activation associates with enhanced skin tumor susceptibility in organ transplant recipients.

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