Ovarian cancer is considered to be the most lethal gynecologic malignancy, and despite the development of conventional therapies and new therapeutic approaches, the patient's survival time remains short because of tumor recurrence and metastasis. Therefore, effective methods to control tumor progression are urgently needed. The oncofetal tumor‐associated antigen 5T4 (trophoblast glycoprotein, TPBG) represents an appealing target for adoptive T‐cell immunotherapy as it is highly expressed on the surface of various tumor cells, has very limited expression in normal tissues, and spreads widely in malignant tumors throughout their development. In this study, we generated second‐generation human chimeric antigen receptor (CAR) T cells with redirected specificity to 5T4 (5T4 CAR‐T) and demonstrated that these CAR‐T cells can elicit lytic cytotoxicity in targeted tumor cells, in addition to the secretion of cytotoxic cytokines, including IFN‐γ, IL‐2, and GM‐CSF. Furthermore, adoptive transfer of 5T4 CAR‐T cells significantly delayed tumor formation in xenografts of peritoneal and subcutaneous animal models. These results demonstrate the potential efficacy and feasibility of 5T4 CAR‐T cell immunotherapy and provide a theoretical basis for the clinical study of future immunotherapies targeting 5T4 for ovarian cancer.
The ‘angiogenic switch’ is critical for tumor progression. However, the pathological details and molecular mechanisms remain incompletely characterized. In this study, we established mammal xenografts in zebrafish to visually investigate the first vessel growth (angiogenic switch) in real-time, by inoculating tumor cells into the perivitelline space of live optically transparent Transgenic (flk1:EGFP) zebrafish larvae. Using this model, we found that hypoxia and hypoxia-inducible factor (HIF) signaling were unnecessary for the angiogenic switch, whereas vascular endothelial growth factor A gene (Vegfa) played a crucial role. Mechanistically, transcriptome analysis showed that the angiogenic switch was characterized by inhibition of translation, but not hypoxia. Phosphorylation of eukaryotic translation initiation factor 2 alpha (Eif2α) and the expression of Vegfa were increased in the angiogenic switch microtumors, and 3D tumor spheroids, and puromycin-treated tumor cells. Vegfa overexpression promoted early onset of the angiogenic switch, whereas Vegfa knockout prevented the first tumor vessel from sprouting. Pretreatment of tumor cells with puromycin promoted the angiogenic switch in vivo similarly to Vegfa overexpression, whereas Vegfa knockdown suppressed the increase. This study provides direc and dynamic in vivo evidences that inhibition of translation, but not hypoxia or HIF signaling promotes the angiogenic switch in tumor by increasing Vegfa transcription.
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