CD44细胞
骨桥蛋白
癌症干细胞
癌症研究
肿瘤微环境
胰腺癌
生物
干细胞
干细胞标记物
癌症
化学
细胞生物学
细胞
免疫学
遗传学
肿瘤细胞
作者
Palanisamy Nallasamy,Rama Krishna Nimmakayala,Saswati Karmakar,Frank Leon,Parthasarathy Seshacharyulu,Imayavaramban Lakshmanan,Kavita Mallya,Chunmeng Zhang,Quan P. Ly,Molly Myers,Lindenberger Josh,Corinn E. Grabow,Shailendra K. Gautam,Sushil Kumar,Subodh M. Lele,Maneesh Jain,Surinder K. Batra,Moorthy P. Ponnusamy
出处
期刊:Gastroenterology
[Elsevier]
日期:2021-12-01
卷期号:161 (6): 1998-2013.e7
被引量:88
标识
DOI:10.1053/j.gastro.2021.08.023
摘要
Tumor-microenvironment factors and cancer stem cells (CSCs) play a critical role in the aggressiveness of pancreatic cancer (PC). However, the degree to which tumor-microenvironment factors promote stemness remains unexplored. Here, we examined whether cancer-associated fibroblasts (CAFs) promote CSC features in PC.PC cells were treated long-term (30, 60, and 90 days) with conditioned media (CM)-derived from normal human fibroblasts (NFs) and CAFs. The stemness features of tumorsphere formation and stemness populations, along with CSCs markers, were analyzed using 2-dimensional and 3-dimensional sodium alginate bead-based co-culture models. Immunohistochemistry and immunofluorescence staining were performed for CSCs and fibroblast markers in autochthonous KrasG12D/+; Trp53R172H/+; Pdx1-Cre mice and human pancreatic tumors. Polymerase chain reaction array and gene knockdown were performed to identify the mechanism of stemness enrichment.Long-term treatment of PC cells with CAF-CM enriched stemness, as indicated by significantly higher CD44+, ALDH+, and AF+ populations in PC cells. Increased tumorsphere formation and elevated CSC, self-renewal, and drug-resistance markers in CAF-CM-treated PC cells were observed. In addition, CAFs co-cultured with PC cells in the 3-dimensional model showed a substantial increase in stemness features. CD44 and α-smooth muscle actin were positively correlated and their expressions progressively increased from the early to late stages of KrasG12D/+; Trp53R172H/+; Pdx1-Cre mouse and human pancreatic tumors. Osteopontin/secreted phosphoprotein 1 was identified as the top differentially overexpressed gene in CAF-CM-treated PC cells and knockdown of osteopontin/secreted phosphoprotein 1 significantly reduced stemness characteristics in CAF-CM-treated PC cells.Our data uncovered novel insight into the interplay between CAF and enrichment of stemness population through the osteopontin/secreted phosphoprotein 1-CD44 axis in PC.
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