Glycocalyx mechanotransduction mechanisms are involved in renal cancer metastasis.
Glycocalyx mechanotransduction mechanisms are involved in renal cancer metastasis.
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DOI：
10.1016/j.mbplus.2021.100100
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发表时间：
2022-03
影响因子：
--
通讯作者：
Munn LL
中科院分区：
文献类型：
--
作者：
Moran H;Cancel LM;Huang P;Roberge S;Xu T;Tarbell JM;Munn LL
通过细胞表面GAG的机械转导是转移的潜在驱动因素。SAHA是一种组蛋白去乙酰化酶抑制剂，可减少肿瘤细胞NDST 1和HS。SAHA在小鼠模型中阻断高转移性肾癌细胞的转移。减少透明质酸抑制小鼠肾癌模型中的转移。包括癌细胞在内的哺乳动物细胞被表面层覆盖，该表面层含有细胞结合的蛋白聚糖、糖蛋白、相关的糖胺聚糖和结合的蛋白质，其通常被称为糖萼。实体瘤还具有动态流体微环境，具有升高的间质流。在目前的工作中，我们进一步调查的假设，即间质流是由肿瘤糖萼导致细胞运动和转移的激活。使用高转移性肾癌细胞系（SN 12 L1）和其低转移性对应物（SN 12 C），我们在体外证明了小分子琥珀酰苯胺异羟肟酸（SAHA）抑制硫酸乙酰肝素合成酶N-脱乙酰基酶-N-磺基转移酶-1，减少糖萼中的硫酸乙酰肝素并抑制SN 12 L1对间质流的运动性。移植到SCID小鼠肾包膜中的SN 12 L1细胞形成了大的原发性肿瘤并转移到远处器官，但当用SAHA治疗时未检测到转移。在另一组实验中，研究了透明质酸的作用。在SN 12 L1细胞中敲低透明质酸合成途径中的关键酶--透明质酸合成酶1，体外实验显示抑制间质流诱导的迁移。随后，将这些细胞植入小鼠肾脏中，未检测到远处转移。这些发现为肾癌转移的治疗提供了新的思路。
Mechanotransduction through cell surface GAGs is a potential driver of metastasis. SAHA, a histone deacetylase inhibitor, reduces tumor cell NDST1 and HS. SAHA blocked metastasis of highly metastatic renal carcinoma cells in a mouse model. Reduction of hyaluronic acid suppresses metastasis in a mouse kidney cancer model. Mammalian cells, including cancer cells, are covered by a surface layer containing cell bound proteoglycans, glycoproteins, associated glycosaminoglycans and bound proteins that is commonly referred to as the glycocalyx. Solid tumors also have a dynamic fluid microenvironment with elevated interstitial flow. In the present work we further investigate the hypothesis that interstitial flow is sensed by the tumor glycocalyx leading to activation of cell motility and metastasis. Using a highly metastatic renal carcinoma cell line (SN12L1) and its low metastatic counterpart (SN12C) we demonstrate in vitro that the small molecule Suberoylanilide Hydroxamic Acid (SAHA) inhibits the heparan sulfate synthesis enzyme N-deacetylase-N-sulfotransferase-1, reduces heparan sulfate in the glycocalyx and suppresses SN12L1 motility in response to interstitial flow. SN12L1 cells implanted in the kidney capsule of SCID mice formed large primary tumors and metastasized to distant organs, but when treated with SAHA metastases were not detected. In another set of experiments, the role of hyaluronic acid was investigated. Hyaluronan synthase 1, a critical enzyme in the synthetic pathway for hyaluronic acid, was knocked down in SN12L1 cells and in vitro experiments revealed inhibition of interstitial flow induced migration. Subsequently these cells were implanted in mouse kidneys and no distant metastases were detected. These findings suggest new therapeutic approaches to the treatment of kidney carcinoma metastasis.