Targeting PDGF-CC as a promising therapeutic strategy to inhibit cholangiocarcinoma progression

J Transl Med. 2024 Nov 14;22(1):1023. doi: 10.1186/s12967-024-05857-6.

Abstract

Background: Cholangiocarcinoma (CCA) is an aggressive malignancy with limited treatment options and poor prognosis. Platelet-Derived Growth Factor CC (PDGF-CC) has been implicated in the progression of various tumors, but its specific role in CCA is not well understood. This study aims to investigate the expression and function of PDGF-CC in CCA and evaluate its potential as a therapeutic target.

Methods: We conducted gene expression analysis using the GEPIA database to compare PDGF-CC mRNA levels in CCA tissues and normal tissues. Serum samples from CCA patients were analyzed for PDGF-CC protein levels, and immunohistochemistry was used to assess PDGF-CC expression in tissue samples. The impact of PDGF-CC on CCA cell behavior was examined by knocking out PDGF-CC in HuCCT1 and QBC939 cell lines, followed by assessments of cell proliferation, migration, invasion, and colony formation in vitro. Additionally, the effects of PDGF-CC knockout were evaluated in xenograft models. The therapeutic potential of PDGF-CC inhibition was further explored using pharmacological inhibitors and antibodies.

Results: PDGF-CC mRNA and protein levels were significantly elevated in CCA tissues and patient sera compared to normal controls. Immunohistochemical analysis confirmed increased PDGF-CC expression in CCA tissues. High PDGF-CC expression correlated with poor overall survival in CCA patients, as shown by Kaplan-Meier analysis. Functional assays revealed that PDGF-CC knockout significantly reduced proliferation, migration, invasion, and colony formation in HuCCT1 and QBC939 cells, the lines with the highest PDGF-CC levels. In vivo, PDGF-CC knockout markedly decreased tumor growth in xenograft models. Pharmacological inhibition of PDGF-CC mirrored the effects of genetic knockout, suggesting it as a viable therapeutic strategy.

Conclusions: This study underscores the critical role of PDGF-CC in CCA progression and supports the potential of PDGF-CC inhibitors as a therapeutic approach. Given the association between high PDGF-CC expression and poor prognosis, targeting PDGF-CC may improve outcomes for CCA patients. Further clinical investigations are warranted to develop PDGF-CC-targeted therapies for CCA.

Keywords: Cell proliferation; Cholangiocarcinoma; Invasion; Ki67; Migration; PDGF-CC; PDGFR inhibitor; Therapeutic target; Tumor growth; Xenograft model.

MeSH terms

  • Animals
  • Bile Duct Neoplasms* / drug therapy
  • Bile Duct Neoplasms* / genetics
  • Bile Duct Neoplasms* / metabolism
  • Bile Duct Neoplasms* / pathology
  • Cell Line, Tumor
  • Cell Movement* / drug effects
  • Cell Proliferation* / drug effects
  • Cholangiocarcinoma* / drug therapy
  • Cholangiocarcinoma* / genetics
  • Cholangiocarcinoma* / metabolism
  • Cholangiocarcinoma* / pathology
  • Disease Progression*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lymphokines* / genetics
  • Lymphokines* / metabolism
  • Male
  • Mice
  • Mice, Nude
  • Middle Aged
  • Molecular Targeted Therapy
  • Neoplasm Invasiveness
  • Platelet-Derived Growth Factor* / genetics
  • Platelet-Derived Growth Factor* / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Xenograft Model Antitumor Assays

Substances

  • Lymphokines
  • Platelet-Derived Growth Factor
  • platelet-derived growth factor C
  • RNA, Messenger