Kakkad Samata M, Penet Marie-France, Akhbardeh Alireza, Pathak Arvind P, Solaiyappan Meiyappan, Raman Venu, Leibfritz Dieter, Glunde Kristine, Bhujwalla Zaver M
JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Universität Bremen, Fachbereich 2, Bremen, Germany.
JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2013 Dec 12;8(12):e81869. doi: 10.1371/journal.pone.0081869. eCollection 2013.
Hypoxic tumor microenvironments result in an aggressive phenotype and resistance to therapy that lead to tumor progression, recurrence, and metastasis. While poor vascularization and the resultant inadequate drug delivery are known to contribute to drug resistance, the effect of hypoxia on molecular transport through the interstitium, and the role of the extracellular matrix (ECM) in mediating this transport are unexplored. The dense mesh of fibers present in the ECM can especially influence the movement of macromolecules. Collagen 1 (Col1) fibers form a key component of the ECM in breast cancers. Here we characterized the influence of hypoxia on macromolecular transport in tumors, and the role of Col1 fibers in mediating this transport using an MDA-MB-231 breast cancer xenograft model engineered to express red fluorescent protein under hypoxia. Magnetic resonance imaging of macromolecular transport was combined with second harmonic generation microscopy of Col1 fibers. Hypoxic tumor regions displayed significantly decreased Col1 fiber density and volume, as well as significantly lower macromolecular draining and pooling rates, than normoxic regions. Regions adjacent to severely hypoxic areas revealed higher deposition of Col1 fibers and increased macromolecular transport. These data suggest that Col1 fibers may facilitate macromolecular transport in tumors, and their reduction in hypoxic regions may reduce this transport. Decreased macromolecular transport in hypoxic regions may also contribute to poor drug delivery and tumor recurrence in hypoxic regions. High Col1 fiber density observed around hypoxic regions may facilitate the escape of aggressive cancer cells from hypoxic regions.
缺氧的肿瘤微环境会导致侵袭性表型和对治疗的抗性，进而导致肿瘤进展、复发和转移。虽然已知血管生成不良以及由此导致的药物递送不足会导致耐药性，但缺氧对通过间质的分子运输的影响以及细胞外基质（ECM）在介导这种运输中的作用尚未得到探索。ECM中存在的致密纤维网尤其会影响大分子的运动。胶原蛋白1（Col1）纤维是乳腺癌ECM的关键组成部分。在这里，我们使用工程改造为在缺氧条件下表达红色荧光蛋白的MDA-MB-231乳腺癌异种移植模型，表征了缺氧对肿瘤中大分子运输的影响以及Col1纤维在介导这种运输中的作用。大分子运输的磁共振成像与Col1纤维的二次谐波生成显微镜相结合。与常氧区域相比，缺氧肿瘤区域的Col1纤维密度和体积显著降低，大分子引流和聚集速率也显著降低。与严重缺氧区域相邻的区域显示出更高的Col1纤维沉积和增加的大分子运输。这些数据表明，Col1纤维可能促进肿瘤中的大分子运输，而它们在缺氧区域的减少可能会降低这种运输。缺氧区域大分子运输的减少也可能导致缺氧区域药物递送不良和肿瘤复发。在缺氧区域周围观察到的高Col1纤维密度可能有助于侵袭性癌细胞从缺氧区域逃逸。
