Expression of C4.4A in precursor lesions of pulmonary adenocarcinoma and squamous cell carcinoma

Abstract

The protein C4.4A, a structural homologue of the urokinase-type plasminogen activator receptor, is a potential new biomarker in non-small cell lung cancer, with high levels of expression recently shown to correlate to poor survival of adenocarcinoma patients. In this study, C4.4A immunoreactivity in precursor lesions of lung squamous cell carcinoma and adenocarcinoma was investigated by stainings with a specific anti-C4.4A antibody. In the transformation from normal bronchial epithelium to squamous cell carcinoma, C4.4A was weakly expressed in basal cell hyperplasia but dramatically increased in squamous metaplasia. This was confined to the cell membrane and sustained in dysplasia, carcinoma in situ, and the invasive carcinoma. The induction of C4.4A already at the stage of hyperplasia could indicate that it is a marker of very early squamous differentiation, which aligns well with our earlier finding that C4.4A expression levels do not provide prognostic information on the survival of squamous cell carcinoma patients. In the progression from normal alveolar epithelium to peripheral adenocarcinoma, we observed an unexpected, distinct cytoplasmic staining for C4.4A in a fraction of atypical adenomatous hyperplasias, while most bronchioloalveolar carcinomas were negative. Likewise, only a fraction of the invasive adenocarcinomas was positive for C4.4A. With a view to the prognostic impact of C4.4A in adenocarcinoma patients, this finding might suggest that C4.4A could be an early biomarker for a possibly more malignant subtype of this disease.Despite intense research efforts, survival rates in non-small cell lung cancer (NSCLC) have not improved significantly over the last decades and remain at only 15% after 5 years.

Ly6/uPAR-Related Protein C4.4A as a Marker of Solid Growth Pattern and Poor Prognosis in Lung Adenocarcinoma

“…11,12 When investigating premalignant stages of pulmonary adenocarcinomas and squamous cell carcinomas (SCCs) in terms of C4.4A expression, we have recently demonstrated that C4.4A appears in atypical adenomatous hyperplasia (AAH) and basal cell hyperplasia/ squamous metaplasia, which are considered to precede the development of the two respective histologic subtypes. 13 In an immunohistochemical retrospective study of NSCLC patients, we have furthermore shown that high expression of C4.4A in adenocarcinomas correlates with a very poor patient survival. 7 The gene encoding C4.4A, designated LYPD3, was recently shown to be up-regulated in esophageal cancer cell lines with a concomitant loss of the tumor suppressor LKB1, and LYPD3 knockdown reduced the migratory and invasive potential of these cells.…”

The Urokinase Receptor Homolog Haldisin Is a Novel Differentiation Marker of Stratum Granulosum in Squamous Epithelia

“…The normal lung epithelium is devoid of C4.4A, but early, non-neoplastic changes in the bronchial epithelium (e.g., basal cell hyperplasia and metaplasia) are generally associated with the emergence of C4.4A (Jacobsen et al 2012). In this histological subtype, the levels of C4.4A are of no prognostic significance as it merely reflects the non-malignant transformation into squamous epithelia Jacobsen et al 2013).…”

Crystal Structures of Human C4.4A Reveal the Unique Association of Ly6/uPAR/α-neurotoxin Domain

“…Nonetheless, expression of C4.4A is strictly regulated under normal homeostatic conditions as it represents a robust biomarker for the presence of stratum spinosum in stratified squamous epithelia of the skin and for squamous differentiation of epithelia in other organs such as esophagus, vagina, oral cavity, and rectum [27,42,47]. Along the same lines, squamous metaplasia of bronchial epithelia (not yet a malignant lesion) is strictly correlated with the emergence of C4.4A expression [48]. Consequently, high expression levels of C4.4A predicts poor prognosis for patients with pulmonary adenocarcinoma but not for those with squamous cell carcinoma [20,49,50].…”