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Elevated expression of podoplanin and its clinicopathological, prognostic, and therapeutic values in squamous non-small cell lung cancer

Authors Xie L, Lin C, Zhang Q, Piao H, Bigner DD, Zhang Z, Bao X

Received 23 January 2018

Accepted for publication 20 March 2018

Published 24 May 2018 Volume 2018:10 Pages 1329—1340

DOI https://doi.org/10.2147/CMAR.S163510

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Professor Nakshatri


Liyi Xie,1–3 Chen Lin,4 Qingfu Zhang,5 Hailan Piao,6 Darell D Bigner,3,7 Zhen Zhang,1,2 Xuhui Bao8

1Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; 3Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA; 4Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China; 5Department of Pathology, the First Affiliated Hospital and College of Basic Medical Sciences, China Medical University, Shenyang, Liaoning, China; 6Department of Medicine, Duke University Medical Center, Durham, NC, USA; 7Department of Pathology, Duke University Medical Center, Durham, NC, USA; 8Department of Surgery, Duke University Medical Center, Durham, NC, USA

Background: Squamous non-small cell lung cancer (SqNSCLC), as a leading cause of cancer-related deaths worldwide, has limited treatment options and poor prognosis. Thus, novel targeted therapies are desperately needed.
Materials and methods: SqNSCLC cases from derivation and validation cohorts were analyzed for podoplanin (PDPN) expression, and its clinicopathological correlation and prognostic prediction. The Human Proteome Map database was used to compare the expression of different lung cancer targets in normal human tissues. Two human lung cancer cell lines, H226 (a SqNSCLC line) and A549 (a non-SqNSCLC line), were examined for PDPN expression. The in vitro cytotoxicity of an anti-PDPN therapy (NZ-1-immunotoxin [NZ-1-IT]) was tested against both lines. The in vivo therapeutic effect of NZ-1-IT was examined in subcutaneous non-small cell lung cancer (NSCLC) xenograft mouse models.
Results: In the derivation cohort, 40% (28/70) were PDPN positive. There was significantly increasing pleural invasion (46.4% vs 9.5%, p=0.001), lymphovascular invasion (25.0% vs 9.5%, p=0.08), and lymph node involvement (53.6% vs 33.3%, p=0.09) in PDPN-positive vs PDPN-negative patients, along with poorer progression-free survival in PDPN-positive patients (p=0.07). The validation cohort with 224 randomly matched cases from The Cancer Genome Atlas data set also displayed significantly shorter overall survival in the group with elevated PDPN mRNA (p=0.05). However, PDPN showed limited expression in normal tissues. PDPN was highly and specifically expressed on the surface of H226 cells instead of A549 cells. Subsequently, PDPN-positive H226 cells were around 800 times more sensitive to anti-PDPN NZ-1-IT therapy than PDPN-negative A549 cells in vitro. Furthermore, NZ-1-IT significantly delayed tumorigenesis only in the H226 subcutaneous mouse model (p<0.05).
Conclusion: Our results demonstrate a distinctively elevated expression of PDPN in SqNSCLC, which is significantly associated with worse clinicopathological features and poorer prognosis. With promising preclinical therapeutic results, anti-PDPN targeted therapy can thus be a robust potential strategy for future SqNSCLC treatment.

Keywords: podoplanin, squamous non-small cell lung cancer, pleural invasion, prognosis, molecular targeted therapy, immunotoxins

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