Elsevier

Human Pathology

Volume 45, Issue 9, September 2014, Pages 1893-1899
Human Pathology

Original contribution
GP88 (progranulin): a novel tissue and circulating biomarker for non–small cell lung carcinoma,☆☆

https://doi.org/10.1016/j.humpath.2014.05.011Get rights and content

Summary

GP88 (progranulin) is a growth and survival factor implicated in tumorigenesis and drug resistance. Previous studies showed that GP88 was expressed in breast cancer tissue in inverse correlation with survival. This study evaluates GP88 tissue expression in localized/locally advanced lung cancer and GP88 serum levels in advanced disease. GP88 expression was determined by immunohistochemistry in tumor tissue from non–small cell lung carcinoma (NSCLC) patients, 85 with localized (stage I-II), and 40 with locally advanced disease (stage IIIa) and correlated with clinical outcome. Serum GP88 levels from stage IIIb/IV patients, quantified by enzyme immunoassay were compared with GP88 levels from patients with chronic obstructive pulmonary disease and healthy individuals. GP88 was expressed in more than 80% adenocarcinoma and squamous cell carcinoma in contrast to normal lung or small cell lung cancer. There was a statistically significant inverse association of GP88 expression (GP88 immunohistochemistry score, 3+ versus < 3+) with survival for patients with localized resected NSCLC with hazard ratio (HR) = 2.28 (P = .0076) for disease-free survival and HR = 2.17 (P = .014) for overall survival. A statistically significant decrease in progression-free survival (HR = 2.9; P = .022) for GP88 scores of 3+ versus less than 3+ was observed for stage IIIa after chemoradiotherapy. In addition, serum GP88 was significantly elevated in stage IIIb/IV NSCLC compared with control subjects (49.9 ng/mL versus 28.4 ng/mL; P < .0001). This is the first study demonstrating GP88 tissue and serum expression as a prognostic biomarker in localized and advanced disease. Future research will determine utility of monitoring GP88 and the potential of GP88 expression as a predictive marker for anti-GP88 therapeutics.

Introduction

Lung cancer is the leading cause of cancer-related deaths in the United States. One hundred fifty-nine thousand four hundred eighty deaths and 228 190 new cases of lung cancer were recorded in 2013 of which 85% were non–small cell lung carcinoma (NSCLC) [1]. In terms of therapeutic options, NSCLC is generally divided into 3 groups of patients: localized (stage I/II), locally advanced (stage III), and metastatic (stage IV). Outside radiographic testing, there are no validated diagnostic tools to distinguish patients with localized or locally advanced disease who are at high risk of relapse from those who are cured using current treatment modalities, nor are there nonimaging methods to detect recurrence or monitor response to therapy. The identification of biomarkers that have prognostic potential in lung cancer could provide a strategy to address these unmet needs.

The 88 000 kd, cysteine-rich glycoprotein GP88 (progranulin, PC cell-derived growth factor, granulin-epithelin precursor, or acrogranin) is the largest member of a unique family of growth factors called granulin/epithelin characterized by a unique double cysteine-rich motif [2], [3], [4]. Initially identified as being overexpressed in breast cancer, GP88 has since been reported by many investigators to be overexpressed in several human cancers, whereas normal tissues have been shown to express little or no GP88 [1], [5], [6].

In breast cancer, GP88 is associated with increased tumorigenesis and mediates, at least in part, cancer cell growth, survival, resistance to therapy (antiestrogen, herceptin, and doxorubicin) and many hallmarks of metastasis such as invasion, angiogenesis, and migration [6], [7], [8], [9], [10], [11], [12]. Immunohistochemistry (IHC) studies of formalin-fixed, paraffin-embedded (FFPE) tumor specimens demonstrated that GP88 expression is low or negative in normal tissues, whereas it is elevated in corresponding malignant tissues [5]. Analysis of GP88 tissue expression in 600 cases of estrogen receptor-positive, invasive ductal carcinoma in relation with clinical outcomes demonstrated that high GP88 expression was statistically associated with a 5.9-fold higher hazard of disease recurrence (P < .0001) and a 2.5-fold higher mortality hazard (P = .0002) compared with patients with no or low expression of tumor GP88 [13]. GP88 remained an independent risk predictor after considering age, ethnicity, nodal status, tumor size, tumor grade, disease stage, progesterone receptor expression, and treatments [13]. Because GP88 is a secreted protein, a prospective longitudinal clinical study to measure circulating level of GP88 with an enzyme immunoassay (EIA) developed in our laboratory demonstrated the performance of the serum GP88 EIA by establishing a basal range for GP88 in serum from healthy volunteers of 28 ng/mL and showing that serum GP88 levels in breast cancer patients was elevated to 40 ng/mL in early stage and more than 100 ng/mL in later stages of breast cancer [14].

Based on the above data and because GP88 can be measured both in tumor tissue and in biological fluids, we hypothesized that GP88 tissue expression might be a prognostic marker in localized and locally advanced NSCLC and that serum GP88 would be elevated in advanced disease. Specifically, we measured GP88 tissue expression in correlation with survival outcome in tumor biopsies from local and locally advanced patients. In addition, we examined GP88 serum level in patients with advanced disease when compared with control subjects.

Section snippets

GP88 expression in normal lung and lung cancer lesions

GP88 expression in normal and lung cancer tissues was examined by IHC using a tissue microarray (TMA) (US Biomax, Rockville, MD). The TMA consisted of 72 cases (normal tissue, adenocarcinoma, squamous cell carcinoma, and small cell carcinoma) from subjects with a median age of 59 (range, 30-77), of which 71% were male and 29% female. Tissue sections were 5 μm with a 1.5-mm core diameter.

GP88 expression in locally resected stage I and stage II NSCLC

A clinically annotated TMA of FFPE NSCLC was obtained from the University of Michigan. This TMA was

GP88 is expressed in NSCLC, whereas it is negative in normal lung tissues

A TMA that contained representative cases of adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and normal lung tissue was stained for GP88 by IHC and scored by board-certified pathologist as described above. As previously observed for breast carcinoma [13], GP88 staining pattern of lung cancer cases appeared cytoplasmic. As shown in Table 1, squamous cell carcinoma (70%) and adenocarcinoma (74%) stained positive for GP88 with 21% of squamous and 30% of adenocarcinoma showing a GP88

Discussion

GP88 (progranulin) has been shown to play a role in the pathogenesis of several cancers and has been demonstrated to be an autocrine growth and survival factor in cancer cells and also to stimulate angiogenesis, migration, and invasion [7], [10]. Increased GP88 expression is associated with increased tumorigenicity and drug resistance. We show here that GP88 is expressed in 70% of lung adenocarcinoma and squamous cell carcinoma, whereas it is negative in normal lung tissue and in small cell

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Competing interests: G Serrero, B Yue, and D Hicks are full-time employees of A&G Pharmaceutical (Columbia, MD). M Edelman, J Feliciano, P Bejarano, O Ioffe, D Reisman, D Hawkins, and Q Gai: No conflict of interest concerning the data contained in or preparation of this manuscript.

☆☆

Funding/Support: This work was supported by grant 1R43CA162629-01A1 from the National Cancer Institute, (Bethesda, MD).

1

Present address: Department for Clinical Research, University of New Mexico Cancer Center, Albuquerque, NM 87131.

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