Cellular polarity modulates drug resistance in primary colorectal cancers via orientation of the multidrug resistance protein ABCB1.
Cellular polarity modulates drug resistance in primary colorectal cancers via orientation of the multidrug resistance protein ABCB1.
复制标题
DOI：
10.1002/path.5179
复制
发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Bodmer WF
中科院分区：
文献类型：
--
作者：
Ashley N;Ouaret D;Bodmer WF
结肠上皮细胞高度极化，具有面向管腔的顶膜（称为刷状缘）和与下层细胞外基质（ECM）接触的基底膜。这种极性通常以肿瘤腺体的形式保持在癌组织中，并具有预后价值。我们比较了几种离体球形结肠癌培养物与其亲本肿瘤的细胞极性，发现那些生长为非附着集落的细胞在其外细胞膜上显示出顶端刷状缘蛋白。将这些培养物转移到ECM（如胶原蛋白）中，重新建立了体内观察到的中心化顶端极性。多药耐药蛋白ABCB 1也变得异常极化外菌落膜悬浮培养，不像培养在胶原蛋白，其中它被极化到中央管腔。这种极性转换取决于血清或选定血清成分的存在，包括表皮生长因子（EGF）、转化生长因子-β1（TGF-β1）和胰岛素样生长因子-1（IGF-1）。在胶原/血清中培养的原发性癌结肠培养物的顶端/基底方向由α2β1整联蛋白信号传导调节。集落中ABCB 1的极化显著改变了药物摄取和敏感性，因为悬浮集落中ABCB 1的向外极化比ECM生长的集落更有效地使底物流出，其中ABCB 1极化至中央管腔。因此，无血清悬浮集落比ECM生长的集落对各种抗癌药物更具抗性。总之，局部基质，或其缺乏，可以有深远的影响，对大肠癌的敏感性培养ABCB 1底物的药物。版权所有© 2018作者.病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
Colonic epithelial cells are highly polarised with a lumen‐facing apical membrane, termed the brush border, and a basal membrane in contact with the underlying extracellular matrix (ECM). This polarity is often maintained in cancer tissue in the form of neoplastic glands and has prognostic value. We compared the cellular polarity of several ex vivo spheroid colonic cancer cultures with their parental tumours and found that those grown as non‐attached colonies exhibited apical brush border proteins on their outer cellular membranes. Transfer of these cultures to an ECM, such as collagen, re‐established the centralised apical polarity observed in vivo. The multidrug resistance protein ABCB1 also became aberrantly polarised to outer colony membranes in suspension cultures, unlike cultures grown in collagen, where it was polarised to central lumens. This polarity switch was dependent on the presence of serum or selected serum components, including epidermal growth factor (EGF), transforming growth factor‐β1 (TGF‐β1) and insulin‐like growth factor‐1 (IGF‐1). The apical/basal orientation of primary cancer colon cultures cultured in collagen/serum was modulated by α2β1 integrin signalling. The polarisation of ABCB1 in colonies significantly altered drug uptake and sensitivity, as the outward polarisation of ABCB1 in suspension colonies effluxed substrates more effectively than ECM‐grown colonies with ABCB1 polarised to central lumens. Thus, serum‐free suspension colonies were more resistant to a variety of anti‐cancer drugs than ECM‐grown colonies. In conclusion, the local stroma, or absence thereof, can have profound effects on the sensitivity of colorectal cultures to drugs that are ABCB1 substrates. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
登录
查看更多内容
影响因子：
24.3
作者：
Correia, Ana Luisa;Bissell, Mina J.
通讯作者：
Bissell, Mina J.
DOI：
10.1186/s13058-014-0459-x
发表时间：
2014
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Nisticò P;Di Modugno F;Spada S;Bissell MJ
通讯作者：
Bissell MJ
影响因子：
8.3
作者：
Kappert, K;Schmidt, G;Graf, K
通讯作者：
Graf, K
影响因子：
6.4
作者：
KIRKLAND, SC;HENDERSON, K;PIGNATELLI, M
通讯作者：
PIGNATELLI, M
影响因子：
6.4
作者：
LIU, D;GAGLIARDI, G;PIGNATELLI, M
通讯作者：
PIGNATELLI, M