Breast cancer cell adhesome and degradome interact to drive metastasis.
Breast cancer cell adhesome and degradome interact to drive metastasis.
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DOI：
10.1038/npjbcancer.2015.17
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发表时间：
2015
影响因子：
5.9
通讯作者：
Glunde K
中科院分区：
文献类型：
--
作者：
Rizwan A;Cheng M;Bhujwalla ZM;Krishnamachary B;Jiang L;Glunde K
虽然原发性乳腺肿瘤在大多数情况下都能早期发现，但由于微转移，许多患者仍有未来复发和死亡的风险。我们研究了降解组和驱动转移的粘附体之间的相互作用，并集中在降解组内的基质金属蛋白酶（MMPs）和粘附体内的整合素和E-钙粘蛋白。本研究的目的是确定乳腺癌转移中粘附分子和降解酶之间的相互作用网络。我们比较了非转移性（BT-474，T47 D，MCF 7）和转移性（MDA-MB-231，SUM 149，SUM 159）人乳腺癌细胞系和异种移植物，其中我们测量了体外和体内的生长速率，迁移，侵袭，集落形成，蛋白表达和酶活性。转移性乳腺癌细胞系和异种移植物显示出更高的MMP表达和活性水平，这也通过体内非侵入性成像证实。这些转移性乳腺癌模型还显示与非转移性模型相比，嗜异性细胞-细胞外基质（ECM）升高，嗜同性细胞-细胞粘附降低。这是由嗜异性细胞粘附分子整合素β1（ITGB 1）的表达增加和嗜同性细胞粘附分子E-钙粘蛋白的表达减少引起的。在转移性细胞中抑制MMP导致ITGB 1表达减少，而刺激ITGB 1导致转移性癌细胞中MMP活性升高，表明降解体和粘附体之间存在相互依赖性。E-cadherin（CDH 1）的重新表达导致ITGB 1的前体形式的表达增加。我们的研究结果指出，MMPs，ITGB 1和CDH 1的协调相互依赖性对乳腺癌转移至关重要。
Although primary breast tumors are detected early in most cases, it is inevitable that many patients remain at risk for future recurrence and death due to micrometastases. We investigated interactions between the degradome and the adhesome that drive metastasis, and have focused on matrix metalloproteases (MMPs) within the degradome and integrins and E-cadherin within the adhesome. The aim of this study is to identify interaction networks between adhesion molecules and degradative enzymes in breast cancer metastasis. We compared non-metastatic (BT-474, T47D, MCF7) and metastatic (MDA-MB-231, SUM149, SUM159) human breast cancer cell lines and xenografts, in which we measured growth rate, migration, invasion, colony formation, protein expression, and enzyme activity in vitro and in vivo. The metastatic breast cancer lines and xenografts displayed higher expression and activity levels of MMPs, which was also confirmed by noninvasive imaging in vivo. These metastatic breast cancer models also displayed elevated heterophilic cell-extracellular matrix (ECM) and lower homophilic cell–cell adhesion compared with those of non-metastatic models. This was conferred by an increased expression of the heterophilic cell adhesion molecule integrin β1 (ITGB1) and a decreased expression of the homophilic cell adhesion molecule E-cadherin. Inhibition of MMPs in metastatic cells led to a reduced expression of ITGB1, and stimulation of ITGB1 resulted in higher MMP activities in metastatic cancer cells, demonstrating reciprocal dependencies between degradome and adhesome. Re-expression of E-cadherin (CDH1) led to an increased expression of the precursor form of ITGB1. Our results point toward a concerted interdependence of MMPs, ITGB1, and CDH1 that is critical for breast cancer metastasis.