Significance of host heparanase in promoting tumor growth and metastasis.
Significance of host heparanase in promoting tumor growth and metastasis.
复制标题
宿主乙酰肝素酶在促进肿瘤生长和转移中的意义
DOI：
10.1016/j.matbio.2020.06.001
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Vlodavsky I
中科院分区：
文献类型：
--
作者：
Zhang GL;Gutter-Kapon L;Ilan N;Batool T;Singh K;Digre A;Luo Z;Sandler S;Shaked Y;Sanderson RD;Wang XM;Li JP;Vlodavsky I
乙酰肝素酶是唯一的硫酸乙酰肝素内切糖苷酶，具有多种生物学活性，可促进肿瘤生长、血管生成和转移。乙酰肝素酶对肿瘤进展的大部分影响与其在介导肿瘤-宿主串扰、启动肿瘤微环境以更好地支持肿瘤生长和转移中的功能有关。我们利用小鼠过表达（Hpa-tg）乙酰肝素酶，揭示宿主乙酰肝素酶在肿瘤发生，生长和转移中的作用。虽然在野生型小鼠中，响应于DMBA致癌作用的肿瘤发展仅限于乳腺，但Hpa-tg小鼠也在其肺和肝中发展肿瘤，这与荷瘤小鼠的存活率降低有关。一致地，与野生型小鼠相比，移植到Hpa-tg小鼠中的异种移植肿瘤（淋巴瘤、黑素瘤、肺癌、胰腺癌）表现出加速的肿瘤生长和较短的荷瘤小鼠存活期。Hpa-tg小鼠在静脉或皮下注射肿瘤细胞后也更容易发生转移。在一些模型中，生长优势与高乙酰肝素酶宿主细胞浸润到肿瘤中相关。然而，在其他模型中，在原发性肿瘤中未检测到乙酰肝素酶高的宿主细胞，这意味着Hpa-tg小鼠的生长优势是由于全身因素。事实上，我们发现来自Hpa-tg小鼠的血浆增强了肿瘤细胞的迁移和侵袭，这归因于促肿瘤发生因子（即，RANKL、RANKL、MIP-2）。此外，在移植有来自Hpa-tg的骨髓的野生型小鼠中证明了肿瘤侵袭性和短存活时间，但在野生型小鼠中没有。除其他因素外，这些结果归因于促肿瘤发生（即，IL 35+）和下调抗肿瘤（即，Hpa-tg与野生型小鼠的脾、淋巴结和血液中的（IFN-γ+）T细胞亚群及其向原发性肿瘤中的浸润增加。总的来说，我们的研究结果强调了宿主乙酰肝素酶在介导肿瘤细胞与宿主肿瘤微环境、免疫细胞和全身因素之间的促肿瘤发生和促转移相互作用中的重要性。
Heparanase, the sole heparan sulfate degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, angiogenesis and metastasis. Much of the impact of heparanase on tumor progression is related to its function in mediating tumor-host crosstalk, priming the tumor microenvironment to better support tumor growth and metastasis. We have utilized mice over-expressing (Hpa-tg) heparanase to reveal the role of host heparanase in tumor initiation, growth and metastasis. While in wild type mice tumor development in response to DMBA carcinogenesis was restricted to the mammary gland, Hpa-tg mice developed tumors also in their lungs and liver, associating with reduced survival of the tumor-bearing mice. Consistently, xenograft tumors (lymphoma, melanoma, lung carcinoma, pancreatic carcinoma) transplanted in Hpa-tg mice exhibited accelerated tumor growth and shorter survival of the tumor-bearing mice compared with wild type mice. Hpa-tg mice were also more prone to the development of metastases following intravenous or subcutaneous injection of tumor cells. In some models, the growth advantage was associated with infiltration of heparanase-high host cells into the tumors. However, in other models, heparanase-high host cells were not detected in the primary tumor, implying that the growth advantage in Hpa-tg mice is due to systemic factors. Indeed, we found that plasma from Hpa-tg mice enhanced tumor cell migration and invasion attributed to increased levels of pro-tumorigenic factors (i.e., RANKL, SPARC, MIP-2) in the plasma of Hpa-Tg vs. wild type mice. Furthermore, tumor aggressiveness and short survival time were demonstrated in wild type mice transplanted with bone marrow derived from Hpa-tg but not wild type mice. These results were attributed, among other factors, to upregulation of pro-tumorigenic (i.e., IL35+) and downregulation of anti-tumorigenic (i.e., IFN-γ+) T-cell subpopulations in the spleen, lymph nodes and blood of Hpa-tg vs. wild type mice and their increased infiltration into the primary tumor. Collectively, our results emphasize the significance of host heparanase in mediating the pro-tumorigenic and pro-metastatic interactions between the tumor cells and the host tumor microenvironment, immune cells and systemic factors.
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影响因子：
8.8
作者：
Dredge, K.;Hammond, E.;Handley, P.;Gonda, T. J.;Smith, M. T.;Vincent, C.;Brandt, R.;Ferro, V.;Bytheway, I.
通讯作者：
Bytheway, I.
影响因子：
10.3
作者：
Edovitsky, E;Elkin, M;Vlodavsky, I
通讯作者：
Vlodavsky, I
影响因子：
11.2
作者：
Gingis-Velitski, Svetlana;Loven, David;Shaked, Yuval
通讯作者：
Shaked, Yuval
影响因子：
10.3
作者：
Barash, Uri;Lapidot, Moshe;Vlodavsky, Israel
通讯作者：
Vlodavsky, Israel
影响因子：
4.8
作者：
de Mestre, AM;Khachigian, LM;Hulett, MD
通讯作者：
Hulett, MD