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ST6GAL1 OVEREXPRESSION DECREASES SURVIVAL IN AN ANIMAL MODEL OF RECTAL CANCER
Jeremie M. Lever
*1,2, Regina Irwin
2, Jacelyn E. Lever
1,2, Sameer Al Diffalha
1,2, Chandler McLeod
2, Karin M. Hardiman
1,2,31UAB Hospital, Birmingham, AL; 2The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL; 3Birmingham VA Medical Center, Birmingham, AL
Introduction: Rectal adenocarcinoma is a highly morbid and fatal disease with increasing incidence among young patients. Patients with neoadjuvant treatment resistance have increased risk of metastases and worse survival. ST6GAL1 is a sialyltransferase that our laboratory has shown causes treatment resistance in rectal cancer by decreasing radiation induced apoptosis. This enzyme has further been associated with increased invasiveness in breast and colon cancer. We created an immune competent mouse model of rectal cancer with increased ST6GAL1 and hypothesized that ST6GAL1 overexpression would lead to increased invasion and metastasis.
Methods: Adult female BALB/c mice underwent transanal orthotopic needle rectal injection of 5 x 10
4 CT26 cells with either constitutive overexpression (OE) or control levels (CV) of ST6GAL1 in 50% Matrigel. Mice underwent consecutive non contrasted CT scans, and tumor volume was measured over time. Lung and liver tissues were systematically evaluated by histopathology with H&E staining for metastases. Humane pre-defined endpoints were utilized, and survival was measured and compared via Kaplan-Meier analysis and the Log rank test. Time points reported in results are from day of cancer cell injection unless otherwise stated. Tumor volume compared with Mann Whitney test.
Results: Survival in mice injected with CT26 ST6GAL1 OE cells was significantly worse compared with ST6GAL1 CV (from date of tumor detection, median survival was 21 days in OE, n = 4, vs 36 days in CV, n = 3; p = 0.04). Tumor volume was increased at time 31 days in ST6GAL1 OE compared with CV (2207 ± 1395 mm
3 OE, n = 4, vs 1284 ± 915 mm
3 CV, n = 3; p = 0.4). We found lung metastases in both ST6GAL1 OE and CV injected animals, but metastases were detected earlier in OE (day 44 for OE and day 59 for CV). Large bowel obstruction leading to cachexia appeared to be the most common cause of death in this model.
Conclusions: ST6GAL1 overexpression led to worse survival in our mouse model of rectal cancer. ST6GAL1 OE animals had larger volume primary tumors. Earlier metastases detected in ST6GAL1 OE may suggest increased invasiveness, however, further studies are needed. ST6GAL1 represents an important target in rectal cancer because it causes treatment resistance and appears to augment primary tumor growth and invasiveness.
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