Olsson P Olof, Gustafsson Renata, In 't Zandt René, Friman Tomas, Maccarana Marco, Tykesson Emil, Oldberg Åke, Rubin Kristofer, Kalamajski Sebastian
Department of Laboratory Medicine, Translational Cancer Research, Lund University, Lund, Sweden.
Bioimaging Center, Lund University, Lund, Sweden.
Mol Cancer Ther. 2016 Oct;15(10):2455-2464. doi: 10.1158/1535-7163.MCT-16-0026. Epub 2016 Jul 29.
A typical obstacle to cancer therapy is the limited distribution of low molecular weight anticancer drugs within the carcinoma tissue. In experimental carcinoma, imatinib (STI571) increases efficacy of synchronized chemotherapy, reduces tumor interstitial fluid pressure, and increases interstitial fluid volume. STI571 also increases the water-perfusable fraction in metastases from human colorectal adenocarcinomas. Because the mechanism(s) behind these effects have not been fully elucidated, we investigated the hypothesis that STI571 alters specific properties of the stromal extracellular matrix. We analyzed STI571-treated human colorectal KAT-4/HT-29 experimental carcinomas, known to have a well-developed stromal compartment, for solute exchange and glycosaminoglycan content, as well as collagen content, structure, and synthesis. MRI of STI571-treated KAT-4/HT-29 experimental carcinomas showed a significantly increased efficacy in dynamic exchanges of solutes between tumor interstitium and blood. This effect was paralleled by a distinct change of the stromal collagen network architecture, manifested by a decreased average collagen fibril diameter, and increased collagen turnover. The glycosaminoglycan content was unchanged. Furthermore, the apparent effects on the stromal cellular composition were limited to a reduction in an NG2-positive stromal cell population. The current data support the hypothesis that the collagen network architecture influences the dynamic exchanges of solutes between blood and carcinoma tissue. It is conceivable that STI571 reprograms distinct nonvascular stromal cells to produce a looser extracellular matrix, ultimately improving transport characteristics for traditional chemotherapeutic agents. Mol Cancer Ther; 15(10); 2455-64. ©2016 AACR.
癌症治疗的一个典型障碍是低分子量抗癌药物在癌组织内的分布有限。在实验性癌中，伊马替尼（STI571）可提高同步化疗的疗效，降低肿瘤间质液压力，并增加间质液体积。STI571还可增加人结肠腺癌转移灶中的水可灌注部分。由于这些效应背后的机制尚未完全阐明，我们研究了STI571改变基质细胞外基质特定特性的假说。我们分析了经STI571处理的人结肠KAT-4/HT-29实验性癌，已知其具有发育良好的基质区室，检测了溶质交换、糖胺聚糖含量以及胶原蛋白含量、结构和合成情况。对经STI571处理的KAT-4/HT-29实验性癌进行的磁共振成像显示，肿瘤间质与血液之间溶质的动态交换效率显著提高。这种效应与基质胶原网络结构的明显变化同时出现，表现为胶原纤维平均直径减小，胶原周转增加。糖胺聚糖含量未发生变化。此外，对基质细胞组成的明显影响仅限于NG2阳性基质细胞群体的减少。目前的数据支持胶原蛋白网络结构影响血液与癌组织之间溶质动态交换的假说。可以想象，STI571可对不同的非血管基质细胞进行重新编程，以产生更疏松的细胞外基质，最终改善传统化疗药物的转运特性。《分子癌症治疗》；15(10)；2455 - 64。©2016美国癌症研究协会。
