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World J Clin Oncol. Oct 10, 2014; 5(4): 621-632
Published online Oct 10, 2014. doi: 10.5306/wjco.v5.i4.621
C4.4A as a biomarker in pulmonary adenocarcinoma and squamous cell carcinoma
Benedikte Jacobsen, Mette Camilla Kriegbaum, Eric Santoni-Rugiu, Michael Ploug
Benedikte Jacobsen, Mette Camilla Kriegbaum, Michael Ploug, The Finsen Laboratory, Rigshospitalet, Copenhagen Biocenter, 2200 Copenhagen, Denmark
Benedikte Jacobsen, Mette Camilla Kriegbaum, Michael Ploug, Biotech Research and Innovation Centre, University of Copenhagen, 2200 Copenhagen, Denmark
Eric Santoni-Rugiu, Department of Pathology, Diagnostic Center, Rigshospitalet, Copenhagen University Hospital, 2100 Copenhagen, Denmark
Michael Ploug, 2nd Danish-Chinese Centre for Proteases and Cancer (This is a virtual centre without a defined address)
Author contributions: All authors contributed equally to manuscript preparation.
Supported by Copenhagen University Hospital (Rigshospitalets Forskningspuljer), The Danish National Research Foundation (Danish-Chinese Centre for Proteases and Cancer), Harboefonden, Torben og Alice Frimodts Fond, Fabrikant Einar Willumsens Mindelegat, Holger Rabitz and hustrus Legat, The Lundbeck Foundation
Correspondence to: Michael Ploug, PhD, DSc, The Finsen Laboratory, Rigshospitalet, Copenhagen Biocenter, Ole Maaløes Vej 5, Room 3.3.31, 2200 Copenhagen, Denmark. m-ploug@finsenlab.dk
Telephone: +45-35456037 Fax: +45-35453797
Received: January 4, 2014
Revised: June 4, 2014
Accepted: June 14, 2014
Published online: October 10, 2014
Processing time: 209 Days and 15.1 Hours
Abstract

The high prevalence and mortality of lung cancer, together with a poor 5-year survival of only approximately 15%, emphasize the need for prognostic and predictive factors to improve patient treatment. C4.4A, a member of the Ly6/uPAR family of membrane proteins, qualifies as such a potential informative biomarker in non-small cell lung cancer. Under normal physiological conditions, it is primarily expressed in suprabasal layers of stratified squamous epithelia. Consequently, it is absent from healthy bronchial and alveolar tissue, but nevertheless appears at early stages in the progression to invasive carcinomas of the lung, i.e., in bronchial hyperplasia/metaplasia and atypical adenomatous hyperplasia. In the stages leading to pulmonary squamous cell carcinoma, expression is sustained in dysplasia, carcinoma in situ and invasive carcinomas, and this pertains to the normal presence of C4.4A in squamous epithelium. In pulmonary adenocarcinomas, a fraction of cases is positive for C4.4A, which is surprising, given the origin of these carcinomas from mucin-producing and not squamous epithelium. Interestingly, this correlates with a highly compromised patient survival and a predominant solid tumor growth pattern. Circumstantial evidence suggests an inverse relationship between C4.4A and the tumor suppressor LKB1. This might provide a link to the prognostic impact of C4.4A in patients with adenocarcinomas of the lung and could potentially be exploited for predicting the efficacy of treatment targeting components of the LKB1 pathway.

Keywords: LYPD3; Non-small cell lung cancer; Prognosis; Solid growth pattern; Liver kinase B1; Precursor lesions; Atypical adenomatous hyperplasia; Metaplasia; Squamous differentiation; Ly6/Urokinase-type plasminogen activator receptor

Core tip: C4.4A is a new biomarker with potential prognostic value in pulmonary adenocarcinoma. High levels of protein expression correlate with poor patient survival and a histological growth pattern of the solid type. Recent data suggest that C4.4A is negatively regulated by the tumor suppressor liver kinase B1 (LKB1), which is inactivated in a fraction of adenocarcinomas of the lung. Such an inverse association between C4.4A and LKB1 could possibly render C4.4A a candidate predictive biomarker for therapeutic intervention targeting components of the LKB1 pathway, such as mammalian target of rapamycin.