Notch-Jagged1 signaling and response to bevacizumab therapy in advanced colorectal cancer: A glance to radiomics or back to physiopathology?

Frontiers in Oncology

Oncology

Andrea Zavani¹  Ludovica Leo¹  Roberto Sala¹  Gianluca Di Rienzo¹  Giuseppe Pedrazzi¹  Francesca Negri²  Gian Luigi de’ Angelis³  Federica Gaiani³  Michele Maddalo⁴  Cecilia Bozzetti⁵  Lorena Bottarelli⁶  Cinzia Azzoni⁶  Nicoletta Campanini⁶  Enrico Maria Silini⁷  Letizia Gnetti⁸  Gianluca Milanese⁹  Nicola Sverzellati⁹  Michele Lecchini⁹ 

[1] Department of Medicine and Surgery, University of Parma, Parma, Italy;Gastroenterology and Endoscopy Unit, University Hospital of Parma, Parma, Italy;Gastroenterology and Endoscopy Unit, University Hospital of Parma, Parma, Italy;Department of Medicine and Surgery, University of Parma, Parma, Italy;Medical Physics Department, University Hospital of Parma, Parma, Italy;Oncology Unit, University Hospital of Parma, Parma, Italy;Pathology Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy;Pathology Unit, Department of Medicine and Surgery, University of Parma, Parma, Italy;Pathology Unit, University Hospital of Parma, Parma, Italy;Pathology Unit, University Hospital of Parma, Parma, Italy;Radiology, Department of Medicine and Surgery, University of Parma, Parma, Italy;

关键词: Notch signaling pathway;    bevacizumab;    colorectal cancer;    Jagged-1;    therapy resistance;   

DOI  :  10.3389/fonc.2023.1132564

 received in 2022-12-27, accepted in 2023-02-10,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionThe Notch intracellular domain (NICD) and its ligands Jagged-1(Jag1), Delta-like ligand (DLL-3) and DLL4 play an important role in neoangiogenesis. Previous studies suggest a correlation between the tissue levels of NICD and response to therapy with bevacizumab in colorectal cancer (CRC). Another marker that may predict outcome in CRC is radiomics of liver metastases. The aim of this study was to investigate the expression of NICD and its ligands and the role of radiomics in the selection of treatment-naive metastatic CRC patients receiving bevacizumab.MethodsImmunohistochemistry (IHC) for NICD, Jag1 and E-cadherin was performed on the tissue microarrays (TMAs) of 111 patients with metastatic CRC treated with bevacizumab and chemotherapy. Both the intensity and the percentage of stained cells were evaluated. The absolute number of CD4+ and CD8+ lymphocytes was counted in three different high-power fields and the mean values obtained were used to determine the CD4/CD8 ratio. The positivity of tumor cells to DLL3 and DLL4 was studied. The microvascular density (MVD) was assessed in fifteen cases by counting the microvessels at 20x magnification and expressed as MVD score. Abdominal CT scans were retrieved and imported into a dedicated workstation for radiomic analysis. Manually drawn regions of interest (ROI) allowed the extraction of radiomic features (RFs) from the tumor.ResultsA positive association was found between NICD and Jag1 expression (p < 0.001). Median PFS was significantly shorter in patients whose tumors expressed high NICD and Jag1 (6.43 months vs 11.53 months for negative cases; p = 0.001). Those with an MVD score ≥5 (CD31-high, NICD/Jag1 positive) experienced significantly poorer survival. The radiomic model developed to predict short and long-term survival and PFS yielded a ROC-AUC of 0.709; when integrated with clinical and histopathological data, the integrated model improved the predictive score (ROC-AUC of 0.823).DiscussionThese results show that high NICD and Jag1 expression are associated with progressive disease and early disease progression to anti VEGF-based therapy; the preliminary radiomic analyses show that the integration of quantitative information with clinical and histological data display the highest performance in predicting the outcome of CRC patients.

【 授权许可】

Unknown   
Copyright © 2023 Negri, Bottarelli, Pedrazzi, Maddalo, Leo, Milanese, Sala, Lecchini, Campanini, Bozzetti, Zavani, Di Rienzo, Azzoni, Silini, Sverzellati, Gaiani, de’ Angelis and Gnetti