Department of Developmental Biology and Cancer Research, Institute for Medical Research - Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Department of Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Gut. 2022 Feb;71(2):345-355. doi: 10.1136/gutjnl-2020-321112. Epub 2021 Mar 1.
Cellular senescence limits tumourigenesis by blocking the proliferation of premalignant cells. Additionally, however, senescent cells can exert paracrine effects influencing tumour growth. Senescent cells are present in premalignant pancreatic intraepithelial neoplasia (PanIN) lesions, yet their effects on the disease are poorly characterised. It is currently unknown whether senolytic drugs, aimed at eliminating senescent cells from lesions, could be beneficial in blocking tumour development.
To uncover the functions of senescent cells and their potential contribution to early pancreatic tumourigenesis, we isolated and characterised senescent cells from PanINs formed in a Kras-driven mouse model, and tested the consequences of their targeted elimination through senolytic treatment.
We found that senescent PanIN cells exert a tumour-promoting effect through expression of a proinflammatory signature that includes high Cox2 levels. Senolytic treatment with the Bcl2-family inhibitor ABT-737 eliminated Cox2-expressing senescent cells, and an intermittent short-duration treatment course dramatically reduced PanIN development and progression to pancreatic ductal adenocarcinoma.
These findings reveal that senescent PanIN cells support tumour growth and progression, and provide a first indication that elimination of senescent cells may be effective as preventive therapy for the progression of precancerous lesions.
细胞衰老通过阻止癌前细胞的增殖来限制肿瘤发生。然而，衰老细胞还可以发挥旁分泌作用，影响肿瘤生长。衰老细胞存在于癌前胰腺上皮内瘤变（PanIN）病变中，但它们对疾病的影响尚未得到充分描述。目前尚不清楚针对病变中衰老细胞的衰老细胞清除药物是否有益于阻断肿瘤的发展。
为了揭示衰老细胞的功能及其对早期胰腺肿瘤发生的潜在贡献，我们从 Kras 驱动的小鼠模型中形成的 PanIN 中分离和鉴定了衰老细胞，并通过衰老细胞清除的靶向治疗来测试它们的消除后果。
我们发现衰老的 PanIN 细胞通过表达包括高 Cox2 水平在内的促炎特征表达发挥促肿瘤作用。用 Bcl2 家族抑制剂 ABT-737 进行衰老细胞清除治疗消除了 Cox2 表达的衰老细胞，并且间歇性的短时间治疗过程显著减少了 PanIN 的发展和向胰腺导管腺癌的进展。
这些发现表明衰老的 PanIN 细胞支持肿瘤生长和进展，并首次表明清除衰老细胞可能是预防癌前病变进展的有效治疗方法。
