PDGFRα governs multiple cellular signals and plays a protective role in tumor progression

Extensive research has been done on the molecular mechanisms of tumor development and growth. However, multiple aspects remain elusive. We examined cellular signaling mechanisms involving platelet-derived growth factor (PDGF) and its receptor (PDGFR), using adult PDGFRα conditional knockout (α-KO) mice implanted with Lewis lung carcinoma (LLC) cells, which express PDGFRα. Unexpectedly, α-KO mice exhibited larger tumors and extensive lung metastasis compared to control mice. Mechanistically, under the activation of PDGF-BB-PDGFRα signal axis in LLC cells, transforming growth factor-α (TGF-α) induced accelerated tumor growth via epidermal growth factor receptor (EGFR) signal. Insufficient vascular development with lower pericyte coverage was also noted, leading to hypoxia and increased expression of transforming growth factor-β (TGF-β), which induced as a critical signaling molecule determining lung metastatic changes with the AKT1 activity. Our findings suggested that PDGFRα in interstitial cells may serve a protective role against tumor progression and selective inhibition of PDGFRα in tumor cells could offer a more targeted therapeutic approach for cancer patients. Statement of significance: PDGFRα in interstitial cells in tumors governs multiple cellular signals such as PDGF-BB, TGF-α, and TGF-β and plays a protective role in tumor progression.

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Publication Details

Journal
Neoplasia
Published
2025-11-03
DOI
https://doi.org/10.1016/j.neo.2025.101248
Primary Topic
Fibroblast Growth Factor Research
Type
article
Field-Weighted Citation Impact
0.00
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PDGFRα governs multiple cellular signals and plays a protective role in tumor progression

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Fibroblast Growth Factor Research
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PDGFRα governs multiple cellular signals and plays a protective role in tumor progression

Fumiko Itoh, Toshihiko Fujimori, Katsuyoshi Takata, Tadamichi Shimizu, Noriko Okuno, Tran Ngọc Dung, Takeharu Minamitani, A. Ejiri, Takayuki Kunisawa, Masakiyo Sasahara, Liem Q. Trang, Masao Hayashi, Dang Thanh Chung, Pham Văn Thinh, Hisashi Mori, Takeru Hamashima, Tsutomu Yanagibashi, Dang Son Tung, Miwa Fujikawa, Masashi Muramatsu, Teruhiko Makino, Yasuharu Watanabe, Yutaka Kato, Seiji Yamamoto, Rieko Kojima, Ayaka Inami
article en

Abstract

Extensive research has been done on the molecular mechanisms of tumor development and growth. However, multiple aspects remain elusive. We examined cellular signaling mechanisms involving platelet-derived growth factor (PDGF) and its receptor (PDGFR), using adult PDGFRα conditional knockout (α-KO) mice implanted with Lewis lung carcinoma (LLC) cells, which express PDGFRα. Unexpectedly, α-KO mice exhibited larger tumors and extensive lung metastasis compared to control mice. Mechanistically, under the activation of PDGF-BB-PDGFRα signal axis in LLC cells, transforming growth factor-α (TGF-α) induced accelerated tumor growth via epidermal growth factor receptor (EGFR) signal. Insufficient vascular development with lower pericyte coverage was also noted, leading to hypoxia and increased expression of transforming growth factor-β (TGF-β), which induced as a critical signaling molecule determining lung metastatic changes with the AKT1 activity. Our findings suggested that PDGFRα in interstitial cells may serve a protective role against tumor progression and selective inhibition of PDGFRα in tumor cells could offer a more targeted therapeutic approach for cancer patients. Statement of significance: PDGFRα in interstitial cells in tumors governs multiple cellular signals such as PDGF-BB, TGF-α, and TGF-β and plays a protective role in tumor progression.

NeoplasiaVol. 71
National Institute for Basic Biology (JP), Tokyo University of Pharmacy and Life Sciences (JP), Tsumura Research Institute (Japan) (JP), Toyama Prefectural Institute for Pharmaceutical Research (JP), Vietnam Military Medical University (VN), Toyama University Hospital (JP), University of Toyama (JP)
Openalex Percentile: Top 71%
Fibroblast Growth Factor Research
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