Daquinag Alexes C, Tseng Chieh, Zhang Yan, Amaya-Manzanares Felipe, Florez Fernando, Dadbin Ali, Zhang Tao, Kolonin Mikhail G
The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
Mol Ther. 2016 Feb;24(1):34-40. doi: 10.1038/mt.2015.155. Epub 2015 Aug 28.
Progression of many cancers is associated with tumor infiltration by mesenchymal stromal cells (MSC). Adipose stromal cells (ASC) are MSC that serve as adipocyte progenitors and endothelium-supporting cells in white adipose tissue (WAT). Clinical and animal model studies indicate that ASC mobilized from WAT are recruited by tumors. Direct evidence for ASC function in tumor microenvironment has been lacking due to unavailability of approaches to specifically inactivate these cells. Here, we investigate the effects of a proteolysis-resistant targeted hunter-killer peptide D-WAT composed of a cyclic domain CSWKYWFGEC homing to ASC and of a proapoptotic domain KLAKLAK2. Using mouse bone marrow transplantation models, we show that D-WAT treatment specifically depletes tumor stromal and perivascular cells without directly killing malignant cells or tumor-infiltrating leukocytes. In several mouse carcinoma models, targeted ASC cytoablation reduced tumor vascularity and cell proliferation resulting in hemorrhaging, necrosis, and suppressed tumor growth. We also validated a D-WAT derivative with a proapoptotic domain KFAKFAK2 that was found to have an improved cytoablative activity. Our results for the first time demonstrate that ASC, recruited as a component of tumor microenvironment, support cancer progression. We propose that drugs targeting ASC can be developed as a combination therapy complementing conventional cancer treatments.
许多癌症的进展与间充质基质细胞（MSC）的肿瘤浸润有关。脂肪基质细胞（ASC）是一种MSC，在白色脂肪组织（WAT）中作为脂肪细胞祖细胞和内皮支持细胞发挥作用。临床和动物模型研究表明，从WAT动员的ASC会被肿瘤招募。由于缺乏特异性灭活这些细胞的方法，ASC在肿瘤微环境中功能的直接证据一直缺失。在此，我们研究了一种抗蛋白水解的靶向猎捕杀伤肽D-WAT的作用，它由一个归巢至ASC的环状结构域CSWKYWFGEC和一个促凋亡结构域KLAKLAK2组成。利用小鼠骨髓移植模型，我们发现D-WAT处理可特异性消耗肿瘤基质细胞和血管周围细胞，而不会直接杀死恶性细胞或肿瘤浸润白细胞。在几种小鼠癌模型中，靶向ASC细胞消融可减少肿瘤血管生成和细胞增殖，导致出血、坏死，并抑制肿瘤生长。我们还验证了一种具有促凋亡结构域KFAKFAK2的D-WAT衍生物，发现其细胞消融活性有所提高。我们的结果首次证明，作为肿瘤微环境组成部分被招募的ASC会促进癌症进展。我们提出，靶向ASC的药物可作为一种联合疗法来补充传统癌症治疗方法进行开发。
