Parallel Accumulation of Tumor Hyaluronan, Collagen, and Other Drivers of Tumor Progression.
Parallel Accumulation of Tumor Hyaluronan, Collagen, and Other Drivers of Tumor Progression.
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DOI：
10.1158/1078-0432.ccr-17-3284
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发表时间：
2018-10-01
期刊：
影响因子：
--
通讯作者：
Thompson CB
中科院分区：
文献类型：
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作者：
Li X;Shepard HM;Cowell JA;Zhao C;Osgood RJ;Rosengren S;Blouw B;Garrovillo SA;Pagel MD;Whatcott CJ;Han H;Von Hoff DD;Taverna DM;LaBarre MJ;Maneval DC;Thompson CB
肿瘤微环境(TME)的进化支持肿瘤的发展。更具侵袭性的恶性肿瘤的一个标志是透明质酸(HA)积聚。在这里，我们描述了与HA积聚(高HA)肿瘤相关的生物学和物理变化。我们采用免疫组织化学、肿瘤pH活体成像和微透析等方法对HA-High肿瘤的TME进行了表征，包括肿瘤血管结构、肿瘤缺氧、肿瘤阿霉素灌注、pH、胶原含量等。和平滑肌肌动蛋白(α-SMA)。建立了一种实时检测肿瘤相关的可溶性细胞因子和生长因子的新方法。我们还评估了小鼠和胰腺癌患者的活检组织，以调查HA和胶原含量，这是导致耐药性的重要因素。在免疫缺陷和免疫功能正常的小鼠中，肿瘤HA含量的增加伴随着胶原含量的增加、血管崩溃、缺氧和转移潜能的增加，α-SMA的增加反映了这一点。用聚乙二醇化的重组人透明质酸酶(PEGPH20)在体内治疗高HA肿瘤，显著逆转了这些变化并耗尽了血管内皮生长因子-A165的储存，这表明PEGPH20也可能降低TME的血管生成潜力。最后，我们在异种移植和胰腺癌患者中观察到HA和胶原蛋白肿瘤含量的协同增加。HA在肿瘤中的积聚与肿瘤尖端过高、血管塌陷、缺氧和耐药有关。这些发现可能部分解释了为什么在HA-高表型中观察到更具侵袭性的恶性肿瘤。我们已经证明，PEGPH20对HA的降解可以部分逆转这一表型，并导致肿瘤相关血管内皮生长因子-A165的缺失。这些结果鼓励对PEGPH20进行进一步的临床研究。
The tumor microenvironment (TME) evolves to support tumor progression. One marker of more aggressive malignancy is hyaluronan (HA) accumulation. Here, we characterize biological and physical changes associated with HA-accumulating (HA-high) tumors. We used immunohistochemistry, in vivo imaging of tumor pH, and microdialysis to characterize the TME of HA-high tumors, including tumor vascular structure, hypoxia, tumor perfusion by doxorubicin, pH, content of collagen. and smooth muscle actin (α-SMA). A novel method was developed to measure real-time tumor-associated soluble cytokines and growth factors. We also evaluated biopsies of murine and pancreatic cancer patients to investigate HA and collagen content, important contributors to drug resistance. In immunodeficient and immunocompetent mice, increasing tumor HA content is accompanied by increasing collagen content, vascular collapse, hypoxia, and increased metastatic potential, as reflected by increased α-SMA. In vivo treatment of HA-high tumors with PEGylated recombinant human hyaluronidase (PEGPH20) dramatically reversed these changes and depleted stores of VEGF-A165, suggesting that PEGPH20 may also diminish the angiogenic potential of the TME. Finally, we observed in xenografts and in pancreatic cancer patients a coordinated increase in HA and collagen tumor content. The accumulation of HA in tumors is associated with high tIP, vascular collapse, hypoxia, and drug resistance. These findings may partially explain why more aggressive malignancy is observed in the HA-high phenotype. We have shown that degradation of HA by PEGPH20 partially reverses this phenotype and leads to depletion of tumor-associated VEGF-A165. These results encourage further clinical investigation of PEGPH20.