HPB
Elliott J. Yee, MD (he/him/his)
General Surgery Resident
University of Colorado - Anschutz, CO
Denver, Colorado, United States
Elliott J. Yee, MD (he/him/his)
General Surgery Resident
University of Colorado - Anschutz, CO
Denver, Colorado, United States
Elliott J. Yee, MD (he/him/his)
General Surgery Resident
University of Colorado - Anschutz, CO
Denver, Colorado, United States
Isaac Vigil, BS
Professional Research Assistant
University of Colorado - Anschutz, CO, United States
Yi Sun, MD
Associate research professor
University of Colorado - Anschutz, CO, United States
Carlton Barnett, MD
Professor
University of Colorado - Anschutz, CO, United States
Richard D. Schulick, MD, MBA
Chair of Surgery and Cancer Center Director
University of Colorado, Department of Surgery, United States
Yuwen Zhu, PhD
Associate Professor
University of Colorado - Anschutz, CO, Colorado, United States
Liver metastases are a substantial cause of morbidity and mortality in gastrointestinal malignancies. Current therapies against liver metastases are nonspecific and limited by significant toxicity. We demonstrate in the preclinical setting that blocking cell-surface glycoprotein CD93 expressed on liver sinusoidal endothelial cells (LSECs) offers a promising, liver-specific therapy that dismantles the early steps of hepatic metastatic dissemination thereby reducing metastatic burden in the liver.
Methods:
CD93 expression on LSECs was investigated in healthy/wildtype and liver specimens harboring pancreatic ductal adenocarcinoma (PDAC) and colorectal (CRC) metastases in both human and murine tissue via immunofluorescence (IF) staining. In vivo CD93 blockade was achieved by intraperitoneal administration of a blocking monoclonal antibody (mAb) against CD93. In vivo murine liver metastasis model was performed by hemispleen procedure. Liver specimens were harvested at varying timepoints after hemispleen injection to assess micrometastatic and gross hepatic tumor burden.
Results:
We confirmed low baseline expression of CD93 at the protein level on normal human and murine LSECs via IF. CD93 was significantly upregulated on both human and murine liver tissues harboring PDAC and CRC metastases (p< 0.001; Fig. 1a-d). Anti-CD93 mAb bound to LSEC-expressed CD93 and when administered therapeutically, significantly attenuated the hepatic tumor burden compared to control mice (p< 0.001; Fig. 1e). Administration of anti-CD93 mAb in the prophylactic setting demonstrated significantly decreased number of single tumor cells within the liver parenchyma compared to controls (p< 0.001; Fig. 1f-g). We found that ICAM-1, a known cell-surface promoter of cell adhesion and tumor cell intravasation into the liver, was upregulated on murine LSECs from non-treated livers whereas ICAM-1 expression of anti-CD93 treated livers were similar to healthy controls (data not shown).
Conclusions:
Our preliminary studies demonstrate a potential role of CD93 in altering the development of liver metastases. Targeting CD93 with a mAb leads to mitigation of murine micrometastatic and decreased gross tumor burden in both a prophylactic and therapeutic setting. Upregulation of tumor-promoting adhesion molecules such as ICAM-1 on LSECs appears to be a potential downstream effector of CD93 signaling. Further investigation into the role of CD93 mediating liver-specific metastases is warranted.