Article

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

UCSF Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
Clinical Cancer Research (impact factor: 7.74). 09/2009; 15(16):5101-7. DOI:10.1158/1078-0432.CCR-08-3286 pp.5101-7
Source: PubMed

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.

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Data provided are for informational purposes only. Although carefully collected, accuracy cannot be guaranteed. The impact factor represents a rough estimation of the journal's impact factor and does not reflect the actual current impact factor. Publisher conditions are provided by RoMEO. Differing provisions from the publisher's actual policy or licence agreement may be applicable.

Keywords

184 cutaneous lesions
 
184 individuals
 
87 organ transplant recipients
 
activated P-Smad2/3
 
adjacent nonlesional skin samples
 
ARD treatment increases
 
distinct BMP-responsive cell
 
distinct TGF-beta/BMP receptor complexes
 
elevated TGF-beta signaling
 
hair follicle-derived lesion
 
lesional tissue
 
non-transplant recipients
 
nonlesional skin
 
Nonmelanoma skin cancer incidence
 
organ transplant recipients
 
organ transplantation
 
Preclinical studies
 
squamous cell carcinoma
 
tumor susceptibility independent
 
two patient groups