Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Institute of Molecular Health Sciences, ETH Zurich, Zurich 8093, Switzerland.
Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland (IOSI), Bellinzona 6500, Switzerland; Università della Svizzera Italiana, Lugano 6900, Switzerland.
Cancer Cell. 2021 Jan 11;39(1):68-82.e9. doi: 10.1016/j.ccell.2020.10.012. Epub 2020 Nov 12.
Metastases account for most cancer-related deaths, yet the mechanisms underlying metastatic spread remain poorly understood. Recent evidence demonstrates that senescent cells, while initially restricting tumorigenesis, can induce tumor progression. Here, we identify the metalloproteinase inhibitor TIMP1 as a molecular switch that determines the effects of senescence in prostate cancer. Senescence driven either by PTEN deficiency or chemotherapy limits the progression of prostate cancer in mice. TIMP1 deletion allows senescence to promote metastasis, and elimination of senescent cells with a senolytic BCL-2 inhibitor impairs metastasis. Mechanistically, TIMP1 loss reprograms the senescence-associated secretory phenotype (SASP) of senescent tumor cells through activation of matrix metalloproteinases (MMPs). Loss of PTEN and TIMP1 in prostate cancer is frequent and correlates with resistance to docetaxel and worst clinical outcomes in patients treated in an adjuvant setting. Altogether, these findings provide insights into the dual roles of tumor-associated senescence and can potentially impact the treatment of prostate cancer.
转移是大多数癌症相关死亡的原因，但转移性扩散的机制仍知之甚少。最近的证据表明，衰老细胞虽然最初限制了肿瘤发生，但可以诱导肿瘤进展。在这里，我们确定金属蛋白酶抑制剂 TIMP1 是决定前列腺癌衰老效应的分子开关。由 PTEN 缺失或化疗引起的衰老在小鼠中限制了前列腺癌的进展。TIMP1 缺失允许衰老促进转移，用衰老细胞溶解剂 BCL-2 抑制剂消除衰老细胞会损害转移。从机制上讲，TIMP1 的缺失通过基质金属蛋白酶 (MMPs) 的激活重新编程衰老相关分泌表型 (SASP)。前列腺癌中 PTEN 和 TIMP1 的缺失很常见，与多西他赛耐药和辅助治疗患者的最差临床结局相关。总的来说，这些发现为肿瘤相关衰老的双重作用提供了深入的了解，并可能影响前列腺癌的治疗。
