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Targeting claudin-4 enhances chemosensitivity of pancreatic ductal carcinomas
Takamitsu Sasaki1, Rina Fujiwara-Tani1, Shingo Kishi1
1Department of Molecular Pathology, Nara Medical University, Kashihara, Nara, Japan.
Abstract:
Claudin (CLDN) family comprises of protein that form a tight junction, and is involved in regulating polarity and differentiation of cells. Here, we aimed to investigate the effects of inhibiting CLDN4 in pancreatic ductal carcinomas (PDC). We first examined 91 cases of human PDC by immunohistochemistry and found that CLDN4 expression was correlated with tumor invasion, nodal metastasis, and distant metastasis. Anti-CLDN4 extracellular domain antibody, previously established by us (4D3), inhibited the proliferation of MIA-PaCa-2 PDC cells and increased intracellular 5-fluorouracil (5-FU) concentration with lowering transepithelial electrical resistance. Concurrent treatment of 5-FU and 4D3 resulted in synergistic inhibition of growth of MIA-PaCa-2 cells in nude mice. In addition, MIA-PaCa-2 cell tumors treated with full-dose folfirinox (FFX) decreased tumor diameters to 50%; however, 60% of mice were dead from adverse effects. In contrast, half-dose FFX concomitant with 4D3 treatment decreased tumors equivalent to full-dose FFX, but without the adverse effects. These findings suggest that targeting CLDN4 might increase the effectiveness and safety of anticancer drug therapy in PDC.
Insights
Targeting Claudin 4 (CLDN4) shows promise in pancreatic cancer treatment. Inhibiting CLDN4 enhances chemotherapy effectiveness and reduces adverse effects, improving patient outcomes.
Area of Science:
- Oncology
- Cell Biology
- Molecular Medicine
Background:
- Claudin (CLDN) proteins form tight junctions, regulating cell polarity and differentiation.
- Claudin 4 (CLDN4) dysregulation is implicated in various cancers, including pancreatic ductal carcinomas (PDC).
Purpose of the Study:
- To investigate the role of CLDN4 in PDC progression.
- To evaluate the therapeutic potential of inhibiting CLDN4 in PDC models.
Main Methods:
- Immunohistochemical analysis of CLDN4 expression in 91 human PDC cases.
- In vitro studies using MIA-PaCa-2 PDC cells treated with anti-CLDN4 antibody (4D3) and 5-fluorouracil (5-FU).
- In vivo studies assessing tumor growth inhibition and survival in nude mice using combination therapies.
Main Results:
- CLDN4 expression correlated with increased tumor invasion, nodal, and distant metastasis in PDC.
- Anti-CLDN4 antibody (4D3) inhibited PDC cell proliferation, increased intracellular 5-FU, and reduced transepithelial electrical resistance.
- Concurrent 4D3 and 5-FU synergistically inhibited tumor growth in vivo.
- Combination of half-dose folfirinox (FFX) with 4D3 achieved tumor reduction comparable to full-dose FFX but with significantly reduced toxicity.
Conclusions:
- CLDN4 is a potential biomarker for PDC progression and metastasis.
- Targeting CLDN4 with antibody 4D3 enhances the efficacy of standard chemotherapies like 5-FU and FFX.
- CLDN4 inhibition offers a promising strategy to improve the safety and effectiveness of PDC treatment.
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