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.

Overexpression of Dicer in Precursor Lesions of Lung Adenocarcinoma

“…Similar Dicer and PACT expression is expected because it has been shown earlier that PACT may contribute to the stabilization of Dicer protein (14). The Fragile Histidine Triad, a tumor suppressor, is another protein with a similar expression pattern along the AAH-BAC-adenocarcinoma sequence (15).…”

RhoB Determines Tumor Aggressiveness in a Murine EGFRL858R-Induced Adenocarcinoma Model and Is a Potential Prognostic Biomarker for Lepidic Lung Cancer

“…This subtype of carcinoma is associated with good survival when it is diagnosed at an early stage, but it can rapidly become invasive, spreading along the bronchial tree, invading through the basal membrane, and eventually leading to a very aggressive phenotype with a poor outcome (38)(39)(40)(41). The crucial event in the progression of this type of cancer is the switch from a "horizontal" spread toward "vertical" invasion of the basal membrane.…”

Lung Cancer Susceptibility in Fhit-Deficient Mice Is Increased by Vhl Haploinsufficiency

“…Some studies have focused specifically on the relationship between loss of Fhit and tumor progression in lung cancer. Association of aberrant Fhit expression with a high rate of tumor cell proliferation was found in lung carcinomas (24) and loss of Fhit was more frequent in invasive lung adenocarcinomas than in earlier stages of the disease (25). Based on the histologic diversity of lung cancers, molecular information has been summarized and stepwise malignant progression models of adenocarcinoma, squamous cell carcinoma, and small cell carcinoma constructed (26).…”