title: Expression of Fhit, cell adhesion molecules and matrix metalloproteinases in atypical adenomatous hyperplasia and pulmonary adenocarcinoma.
abstract: Invasive parenchymal-type lung adenocarcinoma develops from atypical adenomatous hyperplasia (AAH), through an intermediate in situ stage of bronchioloalveolar carcinoma (BAC). We examined the expression of the putative tumour suppressor gene product Fhit, cell adhesion molecules CD44v6, E-cadherin and beta-catenin, and matrix metalloproteinase 2 and its inhibitor, TIMP-2, in a range of AAH lesions, BACs and invasive adenocarcinomas, to determine the changes in molecular expression associated with this form of neoplastic progression. Sections of formalin-fixed wax-embedded archival tissue were stained by standard Immunohistochemical techniques and scored semi-quantitatively, resulting in a grading of negative/low- or high-level staining. Fhit protein was retained at high levels in over 90% of AAH and 83% of BAC, but was found in only 6% of stromally invasive tumours (p < 0.0001). CD44v6 staining was high-level in 64% of AAH but fell to 26% in stromally invasive tumour (p = 0.007). E-cadherin and beta-catenin showed the opposite, with more high-level staining as adenocarcinoma developed (p < 0.001). High-level MMP-2 and TIMP-2 expression was relatively infrequent in AAH (32% and 40% respectively), rose in BAC (89% each) but fell in stromally invasive tumour (31% and 17% respectively) (p < 0.01). Unlike in central bronchial carcinogenesis, loss of Fhit expression is a relatively late event in this putative progression of lung adenocarcinogenesis, and has potential as a surrogate marker of invasion, which could be of value in screening patients for lung cancer. Loss of CD44v6 expression follows the convention of falling adhesion molecule expression as malignancy develops. Increased expression of E-cadherin and beta-catenin may reflect increased cell-cell contact as tissue architecture changes in the transition from AAH to adenocarcinoma. Loss of MMP-2 and TIMP-2 in stromally invasive tumour may reflect a particular role for MMP-2 at the BAC stage, with later down-regulation of this particular enzyme.
authors.affiliation: Department of Pathology, Aberdeen University Medical School, Aberdeen, UK. k.kerr@abdn.ac.uk
authors.forename: Keith M
authors.initials: KM
authors.lastname: Kerr
authors.forename: Suzi J
authors.initials: SJ
authors.lastname: MacKenzie
authors.forename: Sharmini
authors.initials: S
authors.lastname: Ramasami
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Murray
authors.forename: Nicky
authors.initials: N
authors.lastname: Fyfe
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Chapman
authors.forename: Marianne C
authors.initials: MC
authors.lastname: Nicolson
authors.forename: George
authors.initials: G
authors.lastname: King
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000032:analysis*; D000230:Adenocarcinoma / Q000737:chemistry*; D002282:Adenocarcinoma, Bronchiolo-Alveolar / Q000737:chemistry*; D014408:Biomarkers, Tumor / Q000032:analysis*; D015820:Cadherins / Q000032:analysis; D015815:Cell Adhesion Molecules / Q000032:analysis*; D003598:Cytoskeletal Proteins / Q000032:analysis; D004848:Epithelium / Q000737:chemistry; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D006965:Hyperplasia; D008168:Lung / Q000737:chemistry / Q000473:pathology*; D008175:Lung Neoplasms / Q000737:chemistry*; D020778:Matrix Metalloproteinase 2 / Q000032:analysis*; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis*; D011230:Precancerous Conditions / Q000737:chemistry; D011650:Pulmonary Alveoli / Q000737:chemistry / Q000473:pathology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis; D015534:Trans-Activators / Q000032:analysis; D051176:beta Catenin; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D014408:Biomarkers, Tumor; D015820:Cadherins; D015815:Cell Adhesion Molecules; D003598:Cytoskeletal Proteins; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D020778:Matrix Metalloproteinase 2; D009363:Neoplasm Proteins; D019716:Tissue Inhibitor of Metalloproteinase-2; D015534:Trans-Activators; D051176:beta Catenin; D000099170:Bis(5'-adenosyl)triphosphatase; C112697:CD44v6 antigen; C495270:CTNNB1 protein, human