Cohen Gadi, Chandran Parwathy, Lorsung Rebecca M, Aydin Omer, Tomlinson Lauren E, Rosenblatt Robert B, Burks Scott R, Frank Joseph A
Frank Laboratory, Radiology and Imaging Sciences, Clinical Center, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892-1074, USA.
Department of Biomedical Engineering, Erciyes University, Kayseri 38039, Turkey.
Cancers (Basel). 2021 Mar 27;13(7):1546. doi: 10.3390/cancers13071546.
Focused ultrasound (FUS) has shown promise as a non-invasive treatment modality for solid malignancies. FUS targeting to tumors has been shown to initiate pro-inflammatory immune responses within the tumor microenvironment. Pulsed FUS (pFUS) can alter the expression of cytokines, chemokines, trophic factors, cell adhesion molecules, and immune cell phenotypes within tissues. Here, we investigated the molecular and immune cell effects of pFUS on murine B16 melanoma and 4T1 breast cancer flank tumors. Temporal changes following sonication were evaluated by proteomics, RNA-seq, flow-cytometry, and histological analyses. Proteomic profiling revealed molecular changes occurring over 24 h post-pFUS that were consistent with a shift toward inflamed tumor microenvironment. Over 5 days post-pFUS, tumor growth rates were significantly decreased while flow cytometric analysis revealed differences in the temporal migration of immune cells. Transcriptomic analyses following sonication identified differences in gene expression patterns between the two tumor types. Histological analyses further demonstrated reduction of proliferation marker, Ki-67 in 4T1, but not in B16 tumors, and activated cleaved-caspase 3 for apoptosis remained elevated up to 3 days post-pFUS in both tumor types. This study revealed diverse biological mechanisms following pFUS treatment and supports its use as a possible adjuvant to ablative tumor treatment to elicit enhanced anti-tumor responses and slow tumor growth.
聚焦超声（FUS）已显示出作为实体恶性肿瘤非侵入性治疗方式的潜力。已证明靶向肿瘤的FUS可在肿瘤微环境中引发促炎性免疫反应。脉冲FUS（pFUS）可改变组织内细胞因子、趋化因子、营养因子、细胞粘附分子和免疫细胞表型的表达。在此，我们研究了pFUS对小鼠B16黑色素瘤和4T1乳腺癌胁腹肿瘤的分子和免疫细胞效应。通过蛋白质组学、RNA测序、流式细胞术和组织学分析评估超声处理后的时间变化。蛋白质组分析揭示了pFUS后24小时内发生的分子变化，这些变化与向炎症性肿瘤微环境的转变一致。pFUS后5天内，肿瘤生长速率显著降低，而流式细胞术分析揭示了免疫细胞时间迁移的差异。超声处理后的转录组分析确定了两种肿瘤类型之间基因表达模式的差异。组织学分析进一步证明，4T1肿瘤中增殖标志物Ki-67减少，而B16肿瘤中未减少，两种肿瘤类型在pFUS后3天内，用于凋亡的活化裂解型半胱天冬酶3仍保持升高。本研究揭示了pFUS治疗后的多种生物学机制，并支持将其用作消融性肿瘤治疗的可能辅助手段，以引发增强的抗肿瘤反应并减缓肿瘤生长。
