Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype.
Chemotherapy induces expression and release of heparanase leading to changes associated with an aggressive tumor phenotype.
复制标题
DOI：
10.1016/j.matbio.2016.03.006
复制
发表时间：
2016-09
期刊：
影响因子：
6.9
通讯作者：
Sanderson, Ralph D.
中科院分区：
文献类型：
--
作者：
Ramani, Vishnu C.;Vlodaysky, Israel;Ng, Mary;Zhang, Yi;Barbieri, Paola;Noseda, Alessandro;Sanderson, Ralph D.
在许多类型的癌症中，高肝素酶表达与肿瘤生长、血管生成和转移增强有关。然而，驱动高肝素酶表达的机制尚不完全清楚。在本研究中，我们发现用于治疗骨髓瘤的药物可上调肝素酶的表达。前沿抗骨髓瘤药物硼替佐米和卡非佐米激活核因子κB （NF-κB）通路，触发肿瘤细胞中肝素酶的表达。阻断NF-κB通路可减少化疗诱导的肝素酶表达上调。活化的NF-κB信号也被发现在耐药骨髓瘤细胞系中驱动高肝素酶表达。化疗除了增强肝素酶的表达外，还引起肿瘤细胞向条件培养基中释放肝素酶。这种可溶性肝素酶被巨噬细胞吸收，并引发TNF-α产生的增加。肝素酶也被肿瘤细胞吸收，诱导HGF、VEGF和MMP-9的表达，激活ERK和Akt信号通路。这些由肝素酶诱导的变化已知与促进侵袭性肿瘤表型有关。重要的是，肝素酶抑制剂Roneparstat减少了可溶性肝素酶的摄取和下游效应。总之，这些发现揭示了化疗上调肝素酶（一种已知的骨髓瘤生长促进因子）的新机制，并表明在抗癌治疗中靶向肝素酶可能改善患者的预后。
High heparanase expression is associated with enhanced tumor growth, angiogenesis, and metastasis in many types of cancer. However, the mechanisms driving high heparanase expression are not fully understood. In the present study, we discovered that drugs used in the treatment of myeloma upregulate heparanase expression. Frontline anti-myeloma drugs, bortezomib and carfilzomib activate the nuclear factor-kappa B (NF-κB) pathway to trigger heparanase expression in tumor cells. Blocking the NF-κB pathway diminished this chemotherapy-induced upregulation of heparanase expression. Activated NF-κB signaling was also found to drive high heparanase expression in drug resistant myeloma cell lines. In addition to enhancing heparanase expression, chemotherapy also caused release of heparanase by tumor cells into the conditioned medium. This soluble heparanase was taken up by macrophages and triggered an increase in TNF-α production. Heparanase is also taken up by tumor cells where it induced expression of HGF, VEGF and MMP-9 and activated ERK and Akt signaling pathways. These changes induced by heparanase are known to be associated with the promotion of an aggressive tumor phenotype. Importantly, the heparanase inhibitor Roneparstat diminished the uptake and the downstream effects of soluble heparanase. Together, these discoveries reveal a novel mechanism whereby chemotherapy upregulates heparanase, a known promoter of myeloma growth, and suggest that therapeutic targeting of heparanase during anti-cancer therapy may improve patient outcome.
登录
查看更多内容
DOI：
10.1111/febs.12168
发表时间：
2013-05
期刊：
The FEBS journal
影响因子：
--
作者：
Ramani VC;Purushothaman A;Stewart MD;Thompson CA;Vlodavsky I;Au JL;Sanderson RD
通讯作者：
Sanderson RD
影响因子：
4.8
作者：
Dolcet, Xavier;Llobet, David;Matias-Guiu, Xavier
通讯作者：
Matias-Guiu, Xavier
肝素酶诱导的骨髓瘤和内皮细胞中Syndecan-1/CD138的脱落会激活VEGFR2和侵入性表型：新型合成蛋白预防。
影响因子：
6.2
作者：
Jung, O.;Trapp-Stamborski, V.;Purushothaman, A.;Jin, H.;Wang, H.;Sanderson, R. D.;Rapraeger, A. C.
通讯作者：
Rapraeger, A. C.
影响因子：
4.8
作者：
Gingis-Velitski, S;Zetser, A;Ilan, N
通讯作者：
Ilan, N
影响因子：
--
作者：
Demchenko YN;Kuehl WM
通讯作者：
Kuehl WM