Role of myofibroblasts in tumour encapsulation of hepatocellular carcinoma in haemochromatosis.
OBJECTIVE
Hepatocellular carcinoma is a common malignancy and a major complication of untreated haemochromatosis. Encapsulation of liver tumours has been associated with a better prognosis and longer disease-free periods following resection. This study investigated the source of the tumour capsule in patients with haemochromatosis and coexisting hepatocellular carcinoma and examined potential factors influencing development.


METHODS
Five haemochromatosis patients with encapsulated hepatocellular carcinoma were studied. Myofibroblasts were identified using combined immunohistochemistry and in situ hybridisation for alpha-smooth muscle actin and procollagen alpha1(I) mRNA, respectively. Immunohistochemistry was also performed for transforming growth factor (TGF)-beta1, platelet-derived growth factor (PDGF)-beta receptor and malondialdehyde.


RESULTS
Procollagen alpha1(I) mRNA co-localised to alpha-smooth muscle actin positive myofibroblasts. The number of myofibroblasts was maximal within the capsule and decreased away from the tumour. TGF-beta1 protein was expressed in iron-loaded cells in non-tumour liver at the interface of tumour capsule. PDGF-beta receptor expression was observed in mesenchymal cells in the tumour capsule and in portal tracts. Malondialdehyde adducts were observed in the tumour, non-tumour tissue and in the capsule.


CONCLUSIONS
This study provides evidence that myofibroblasts are the cell type responsible for collagen production within the tumour capsule surrounding hepatocellular carcinoma in haemochromatosis. The production of TGF-beta1 by iron-loaded hepatic cells at the tumour capsule interface may perpetuate the myofibroblastic phenotype, resulting in the formation of the tumour capsule.
Bridle
K R
KR
The Hepatic Fibrosis Group, The Queensland Institute of Medical Research and The University of Queensland, Queensland, Australia.
Crawford
D H
DH
Powell
L W
LW
Ramm
G A
GA
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006432:Hemochromatosis / Q000150:complications* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008113:Liver Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008239:Lysine / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008875:Middle Aged; D009130:Muscle, Smooth / Q000378:metabolism / Q000473:pathology*; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D000199:Actins; D011347:Procollagen; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D008315:Malondialdehyde; D020797:Receptor, Platelet-Derived Growth Factor beta; D008239:Lysine