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


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Harradine
Kelly A
KA
UCSF Helen Diller Family Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California, USA.
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
D000367:Age Factors; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000378:metabolism*; D004198:Disease Susceptibility / Q000209:etiology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism*; D046888:Tissue Array Analysis; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D019737:Transplants; D015854:Up-Regulation / Q000187:drug effects
D019485:Bone Morphogenetic Proteins; D007166:Immunosuppressive Agents; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II