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<p>An elevated extracellular matrix (ECM) and interstitial fluid pressure (IFP) in gastric cancer limits the targeting of HER2-expressing cells when radioimmunotherapy (RIT) with <sup>64</sup>Cu-trastuzumab (<sup>64</sup>Cu-TRZ) is utilized. Here, we used Losartan (LOS) to downregulate ECM and IFP in gastric cancer mice model. In our study we treated the gastric cancer mice model with a dose of 40&#xa0;mg/kg of LOS. We found that the LOS treatment increases a twofold higher Alexa-647-TRZ accumulation which significantly enhanced <sup>64</sup>Cu-TRZ. We determined that the LOS-treated samples exhibited reduced mRNA and protein expression of SERPINE1, a gene associated with the ECM degradation. Additionally, LOS treatment resulted in the downregulated mRNA expression of the TGF-β1 and COL13A1, the genes involved in ECM deposition and an upregulated RNA expression of MMP2, a gene associated with the ECM degradation. There were no significant changes in metastatic markers of N-Cadherin and E-Cadherin. Moreover, our study demonstrates that silencing SERPINE1 increases the activity of the MMP2 and decreases COL13A1 with no effect on the N-cadherin and E-cadherin were observed. Our novel combinational therapy of using <sup>64</sup>Cu-TRZ with LOS is attributed to the downregulation of SERPINE1 targeting ECM and IFP is highly effective for treatment of gastric cancer.</p>

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Tumor microenvironment modulation by SERPINE1 increases radioimmunotherapy in murine model of gastric cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月12日

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  • Javeria Zaheer,
  • Joycie Shanmugiah,
  • Seungyoun Kim,
  • Hyeongi Kim,
  • Jin Su Kim

摘要

An elevated extracellular matrix (ECM) and interstitial fluid pressure (IFP) in gastric cancer limits the targeting of HER2-expressing cells when radioimmunotherapy (RIT) with 64Cu-trastuzumab (64Cu-TRZ) is utilized. Here, we used Losartan (LOS) to downregulate ECM and IFP in gastric cancer mice model. In our study we treated the gastric cancer mice model with a dose of 40 mg/kg of LOS. We found that the LOS treatment increases a twofold higher Alexa-647-TRZ accumulation which significantly enhanced 64Cu-TRZ. We determined that the LOS-treated samples exhibited reduced mRNA and protein expression of SERPINE1, a gene associated with the ECM degradation. Additionally, LOS treatment resulted in the downregulated mRNA expression of the TGF-β1 and COL13A1, the genes involved in ECM deposition and an upregulated RNA expression of MMP2, a gene associated with the ECM degradation. There were no significant changes in metastatic markers of N-Cadherin and E-Cadherin. Moreover, our study demonstrates that silencing SERPINE1 increases the activity of the MMP2 and decreases COL13A1 with no effect on the N-cadherin and E-cadherin were observed. Our novel combinational therapy of using 64Cu-TRZ with LOS is attributed to the downregulation of SERPINE1 targeting ECM and IFP is highly effective for treatment of gastric cancer.