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.