Hoshiba Takashi, Tanaka Masaru
Frontier Center for Organic Materials, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan; International Center for Materials Nanoarchitectonics, National Institute for Materials Science, 1-1 Namiki, Tsukuba, Ibaraki 305-0044, Japan.
Frontier Center for Organic Materials, Yamagata University, 4-3-16 Jonan, Yonezawa, Yamagata 992-8510, Japan; Institute for Materials Chemistry and Engineering, Kyushu University, 744 Motooka, Nishi-ku, Fukuoka, Fukuoka 819-0395, Japan.
Biochim Biophys Acta. 2016 Nov;1863(11):2749-2757. doi: 10.1016/j.bbamcr.2016.08.009. Epub 2016 Aug 21.
Chemoresistance is a major barrier for tumor chemotherapy. It is well-known that chemoresistance increases with tumor progression. Chemoresistance is altered by both genetic mutations and the alteration of extracellular microenvironment. Particularly, the extracellular matrix (ECM) is remodeled during tumor progression. Therefore, ECM remodeling is expected to cause the acquisition of chemoresistance in highly malignant tumor tissue. Here, we prepared cultured cell-derived decellularized matrices that mimic native ECM in tumor tissues at different stages of malignancy, and 5-fluorouracil (5-FU) resistance was compared among these matrices. 5-FU resistance of colorectal tumor cells increased on the matrices derived from highly malignant tumor HT-29 cells, although the resistance did not increase on the matrices derived from low malignant tumor SW480 cells and normal CCD-841-CoN cells. The resistance on HT-29 cell-derived matrices increased through the activation of Akt and the upregulation of ABCB1 and ABCC1 without cell growth promotion, suggesting that ECM remodeling plays important roles in the acquisition of chemoresistance during tumor progression. It is expected that our decellularized matrices, or "staged tumorigenesis-mimicking matrices", will become preferred cell culture substrates for in vitro analysis of comprehensive ECM roles in chemoresistance and the screening and pharmacokinetic analysis of anti-cancer drugs.
化疗耐药是肿瘤化疗的主要障碍。众所周知，化疗耐药性会随着肿瘤进展而增加。化疗耐药性会因基因突变和细胞外微环境的改变而发生变化。特别是，在肿瘤进展过程中细胞外基质（ECM）会发生重塑。因此，预计ECM重塑会导致高度恶性肿瘤组织中获得化疗耐药性。在此，我们制备了模拟不同恶性程度肿瘤组织中天然ECM的培养细胞来源的脱细胞基质，并比较了这些基质之间的5-氟尿嘧啶（5-FU）耐药性。尽管来自低恶性肿瘤SW480细胞和正常CCD-841-CoN细胞的基质上5-FU耐药性没有增加，但结直肠肿瘤细胞对来自高度恶性肿瘤HT-29细胞的基质的5-FU耐药性增加。HT-29细胞来源的基质上的耐药性通过Akt的激活以及ABCB1和ABCC1的上调而增加，且没有促进细胞生长，这表明ECM重塑在肿瘤进展过程中获得化疗耐药性方面发挥着重要作用。预计我们的脱细胞基质，即“模拟肿瘤发生阶段的基质”，将成为体外分析ECM在化疗耐药中的综合作用以及抗癌药物筛选和药代动力学分析的首选细胞培养底物。
