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TIMP1缺陷的衰老重编程促进前列腺癌转移
作者:小柯机器人 发布时间:2020/11/15 0:53:37

瑞士南部的肿瘤研究所(IOSI) Andrea Alimonti研究组取得最新进展。他们发现TIMP1缺陷的衰老重编程促进前列腺癌转移。相关论文于2020年11月12日发表于国际顶尖学术期刊《癌细胞》杂志上。

他们鉴定了金属蛋白酶抑制剂TIMP1为决定前列腺癌衰老效应的分子开关。PTEN缺乏或化疗驱动的衰老限制了小鼠前列腺癌的进展。TIMP1敲除产生衰老并促进转移,而具有衰老作用的BCL-2抑制剂消除衰老细胞会减弱转移。

从机制上讲,TIMP1丢失通过激活基质金属蛋白酶(MMP)来重编程衰老肿瘤细胞的衰老相关分泌表型(SASP)。在辅助治疗中,前列腺癌中PTEN和TIMP1的丢失很常见,并且与多西紫杉醇的耐药性和最差的临床预后相关。

总而言之,这些发现提供了对肿瘤相关衰老的双重作用的见解,并可能影响前列腺癌的治疗。

据悉,转移是导致大多数与癌症相关死亡的原因,但对转移扩散的潜在机制仍知之甚少。最近的证据表明,衰老细胞虽然最初限制肿瘤发生,但可以诱导肿瘤进展。

附:英文原文

Title: Senescence Reprogramming by TIMP1 Deficiency Promotes Prostate Cancer Metastasis

Author: Ilaria Guccini, Ajinkya Revandkar, Mariantonietta DAmbrosio, Manuel Colucci, Emiliano Pasquini, Simone Mosole, Martina Troiani, Daniela Brina, Raheleh Sheibani-Tezerji, Angela Rita Elia, Andrea Rinaldi, Nicolò Pernigoni, Jan Hendrik Rüschoff, Susanne Dettwiler, Angelo M. De Marzo, Emmanuel S. Antonarakis, Costanza Borrelli, Andreas E. Moor, Ramon Garcia-Escudero, Abdullah Alajati, Giuseppe Attanasio, Marco Losa, Holger Moch, Peter Wild, Gerda Egger, Andrea Alimonti

Issue&Volume: 2020-11-12

Abstract: Metastases account for most cancer-related deaths, yet the mechanisms underlying metastaticspread remain poorly understood. Recent evidence demonstrates that senescent cells,while initially restricting tumorigenesis, can induce tumor progression. Here, weidentify 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 cellswith a senolytic BCL-2 inhibitor impairs metastasis. Mechanistically, TIMP1 loss reprograms the senescence-associated secretory phenotype (SASP) of senescenttumor cells through activation of matrix metalloproteinases (MMPs). Loss of PTEN and TIMP1 in prostate cancer is frequent and correlates with resistance to docetaxel and worstclinical outcomes in patients treated in an adjuvant setting. Altogether, these findingsprovide insights into the dual roles of tumor-associated senescence and can potentiallyimpact the treatment of prostate cancer.

DOI: 10.1016/j.ccell.2020.10.012

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30543-2

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx