Endothelin-axis antagonism enhances tumor perfusion in pancreatic cancer

Shailendra K. Gautam, Vipin Dalal, Balasrinivasa R. Sajja, Suprit Gupta, Mansi Gulati, Nidhi V. Dwivedi, Abhijit Aithal, Jesse L Cox, Satyanarayana Rachagani, Yutong Liu, Vincent Chung, Ravi Salgia, Surinder Kumar Batra, Maneesh Jain

Research output: Contribution to journalArticlepeer-review

Abstract

Delivery of therapeutic agents in pancreatic cancer (PC) is impaired due to its hypovascular and desmoplastic tumor microenvironment. The Endothelin (ET)-axis is the major regulator of vasomotor tone under physiological conditions and is highly upregulated in multiple cancers. We investigated the effect of dual endothelin receptor antagonist bosentan on perfusion and macromolecular transport in a PC cell-fibroblast co-implantation tumor model using Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI). Following bosentan treatment, the contrast enhancement ratio and wash-in rates in tumors were two- and nine times higher, respectively, compared to the controls, whereas the time to peak was significantly shorter (7.29 ± 1.29 min v/s 22.08 ± 5.88 min; p = 0.04). Importantly, these effects were tumor selective as the magnitudes of change for these parameters were much lower in muscles. Bosentan treatment also reduced desmoplasia and improved intratumoral distribution of high molecular weight FITC-dextran. Overall, these findings support that targeting the ET-axis can serve as a potential strategy to selectively enhance tumor perfusion and improve the delivery of therapeutic agents in pancreatic tumors.

Original languageEnglish (US)
Pages (from-to)215801
Number of pages1
JournalCancer Letters
Volume544
DOIs
StatePublished - Sep 28 2022

Keywords

  • Bosentan
  • Co-implantation
  • Endothelin axis
  • MRI
  • Pancreatic cancer
  • Perfusion
  • Tumor blood vessel
  • Tumor microenvironment (TME)
  • Vasodilation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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