Differential prognostic impact of platelet-derived growth factor receptor expression in NSCLC

Thomas Karsten Kilvaer,Arne Ostman,Turid Hellevik,Luigi De Petris,Lill-Tove Rasmussen Busund,Mehrdad Rakaee,Carina Strell,Tom Donnem,Jørg Vik,Inigo Martinez-Zubiaurre

doi:10.1038/s41598-019-46510-3

Abstract

Preclinical evidence suggests that stromal expression of platelet-derived growth factor receptors (PDGFRs) stimulates tumor development and diminishes intratumoral drug uptake. In non-small cell lung cancer (NSCLC), the clinical relevance of stromal PDGFR expression remains uncertain. Tumor specimens from 553 patients with primary operable stage I-IIIB NSCLC was obtained and tissue micro-arrays (TMA) were constructed (Norwegian cohort). Immunohistochemistry (IHC) was used to evaluate the expression of PDGFRα and -β in stromal cells and to explore their impact on patient survival. Results were validated in a non-related cohort consisting of TMAs of 367 stage I (A and B) NSCLC patients (Swedish cohort). High stromal PDGFRα expression was an independent predictor of increased survival in the overall populations and SCC (squamous cell carcinoma) subgroups of both investigated cohorts. PDGFRβ was an independent predictor of poor survival in the overall Norwegian cohort and an independent predictor of increased survival in the ADC (adenocarcinoma) subgroup of the Swedish cohort. Tumors displaying the combination PDGFRα-low/PDGFRβ-high exhibited inferior survival according to increasing stage in the Norwegian cohort. This study confirms that high stromal expression of PDGFRα is a predictor of increased survival in NSCLC. Further exploration of the prognostic impact of PDGFRβ and the relationship between PDGFRα and -β is warranted.

Highlights

In solid neoplasms, a dynamic relationship between the malignant component and the surrounding stroma is established early during tumorigenesis and is ever evolving during tumor progression
The Platelet-derived growth factors (PDGF) are a family of dimeric disulfide-bound growth factors, consisting of four proteins forming five possible dimers in vivo, namely PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD
PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC dimers bind with high affinity to the α-receptor whereas PDGF-BB and PDGF-DD has preference for the β-receptor[4,5]

Summary

Introduction

A dynamic relationship between the malignant component and the surrounding stroma is established early during tumorigenesis and is ever evolving during tumor progression. The PDGF/PDGFR axis is one of the best-described tumor-stroma interconnections. The PDGFs are a family of dimeric disulfide-bound growth factors, consisting of four proteins forming five possible dimers in vivo, namely PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD. Each of these isoforms exerts its biological effects by activating two structurally related α- and β-tyrosine kinase receptors. The net effect of PDGF dimers on cells will depend in the specific expression of each PDGF receptor isoform. Activation via the PDGF/PDGFR axis may directly impact important tumor biological features such as proliferation, vascular reorganization, endothelial cell activation, pericyte recruitment, regulation of the tumor interstitial fluid pressure and desmoplastic reactions[6]. Available pathological data (A) Norwegian cohort 553 307 239 7 1990–2010 67 (28–85) 2013-10-01 86 (34–267) Age, gender, smoking status, ECOG PS, weightloss before diagnosis, surgical procedure, adjuvant radiotherapy and/ or chemotherapy Histology, differentiation, pStage, tStage, nStage, resection margins, vascular invasion, perineural infiltration OS, DSS, PFS 0.6 mm Four – two primarily stromal and two primarily epithelial 4 μm

Methods

Results

Conclusion