Platelet-Derived Growth Factor-AA Is an Essential and Autocrine Regulator of Vascular Endothelial Growth Factor Expression in Non–Small Cell Lung Carcinomas

Yasunori Shikada,Yoshihiko Maehara,Katsuo Sueishi,Shinji Okano,Kazunori Nakagawa,Mitsuho Onimaru,Takaomi Koga,Shihoko Sata,Ichiro Yoshino,Yoshikazu Yonemitsu,Toshiaki Nakano

doi:10.1158/0008-5472.can-04-4171

Abstract

It is widely accepted that angiogenesis is required for tumor progression. Vascular endothelial growth factor (VEGF) is a key molecule for tumor angiogenesis; however, its expressional regulation is not well understood during all stages of tumorigenesis. Using cell lines and surgical specimens of human non-small cell lung cancers (NSCLCs), we here show that platelet-derived growth factor-AA (PDGF-AA) is an essential autocrine regulator for VEGF expression. To directly assess the expression of PDGF-AA-dependent VEGF and its roles in tumorigenesis, we stably transfected established cell lines with their antisense genes. In addition, the levels of PDGF-AA and VEGF expression in surgical sections were measured and compared with clinicopathologic findings such as tumor size and patient prognosis. PDGF-AA tightly regulated VEGF expression and had a greater effect on tumor size and patient prognosis than did VEGF in both cell lines and surgical sections. PDGF-AA expression was not seen in the atypical adenomatous hyperplasia at all, whereas VEGF was occasionally seen. Furthermore, the frequency of VEGF expression was higher in advanced NSCLCs than in precancerous lesions, which was tightly correspondent to the results for PDGF-AA. These results indicate that PDGF-AA is an important regulator of the frequency and level of VEGF expression during the transition from a precancerous lesion to advanced cancer. The PDGF-AA/VEGF axis, therefore, may be a ubiquitous autocrine system for enhancing angiogenic signals, and PDGF-AA, and its related pathways could be a more efficient target of antiangiogenic therapy for cancers than VEGF and its pathways.

Highlights

Angiogenesis is required for tumor progression, as supported by a number of studies showing a reduction in tumor growth by antiangiogenic agents [1,2,3]
To obtain direct evidence that platelet-derived growth factor-AA (PDGF-AA) is an autocrine regulator for Vascular endothelial growth factor (VEGF) in human non–small cell lung cancers (NSCLCs), we first established independent cell lines [i.e., QG56 and A549] which were stably transfected with plasmid pcDNA3.1(+) expressing full-length antisense human PDGF-A cDNA (AS-PDGFA)
The key observations obtained in the present study were as follows: (a) similar to our earlier observations in noncancerous mesenchymal cells, PDGF-AA was found to be an autocrine regulator for VEGF in NSCLCs, indicating that the PDGF-AA/VEGF axis may be a ubiquitous autocrine system for enhancing angiogenic signals; (b) the expression level of PDGF-AA was more critical for experimental tumor growth than that of VEGF in vivo, and the expression of PDGF-AA was rarely seen in precancerous or early cancer lesions of surgical sections; and (c) PDGF-AA expression was a prognostic indicator for individuals with NSCLCs

Summary

Introduction

Angiogenesis is required for tumor progression, as supported by a number of studies showing a reduction in tumor growth by antiangiogenic agents [1,2,3]. This is not likely, because VEGF is abundantly expressed in cancers, precancerous lesions, and their originating tissue, VEGF is essential for tumor angiogenesis and its frequency of expression is higher in advanced malignancies than in noncancerous tissue [9, 10]. These theoretical considerations suggest the existence of upstream regulator(s) that mediate the expression of VEGF in tumors as molecular candidates for the angiogenic switch; the regulational mechanism of the expression of VEGF in each tumor has not been fully elucidated

Methods

Results

Conclusion