Noh Jinok, Yu Jinyeong, Kim Wootak, Park Aran, Park Ki-Sook
Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul 02447, Korea.
Graduate School of Biotechnology, Kyung Hee University, Yongin 17104, Korea.
Biomedicines. 2021 Oct 29;9(11):1572. doi: 10.3390/biomedicines9111572.
The prostate tumor microenvironment plays important roles in the metastasis and hormone-insensitive re-growth of tumor cells. Bone marrow-derived mesenchymal stem cells (BM-MSCs) are recruited into prostate tumors to facilitate tumor microenvironment formation. However, the specific intrinsic molecules mediating BM-MSCs' migration to prostate tumors are unknown. BM-MSCs' migration toward a conditioned medium (CM) of hormone-insensitive (PC3 and DU145) or hormone-sensitive (LNCaP) prostate tumor cells was investigated using a three-dimensional cell migration assay and a transwell migration assay. PC3 and DU145 expressed transforming growth factor-β (TGF-β), but LNCaP did not. Regardless of TGF-β expression, BM-MSCs migrated toward the CM of PC3, DU145, or LNCaP. The CM of PC3 or DU145 expressing TGF-β increased the phosphorylation of Smad2/3 in BM-MSCs. Inactivation of TGF-β signaling in BM-MSCs using TGF-β type 1 receptor (TGFBR1) inhibitors, SB505124, or SB431542 did not allow BM-MSCs to migrate toward the CM. The CM of PC3 or DU145 enhanced N-cadherin expression on BM-MSCs, but the LNCaP CM did not. SB505124, SB431542, and TGFBR1 knockdown prevented an increase in N-cadherin expression. N-cadherin knockdown inhibited the collective migration of BM-MSCs toward the PC3 CM. We identified N-cadherin as a mediator of BM-MSCs' migration toward hormone-insensitive prostate tumor cells expressing TGF-β and introduced a novel strategy for controlling and re-engineering the prostate tumor microenvironment.
前列腺肿瘤微环境在肿瘤细胞的转移和激素不敏感再生长中发挥着重要作用。骨髓来源的间充质干细胞（BM-MSCs）被招募到前列腺肿瘤中以促进肿瘤微环境的形成。然而，介导BM-MSCs迁移至前列腺肿瘤的特定内在分子尚不清楚。使用三维细胞迁移试验和Transwell迁移试验研究了BM-MSCs向激素不敏感（PC3和DU145）或激素敏感（LNCaP）前列腺肿瘤细胞的条件培养基（CM）的迁移。PC3和DU145表达转化生长因子-β（TGF-β），但LNCaP不表达。无论TGF-β表达如何，BM-MSCs都向PC3、DU145或LNCaP的CM迁移。表达TGF-β的PC3或DU145的CM增加了BM-MSCs中Smad2/3的磷酸化。使用TGF-β1型受体（TGFBR1）抑制剂SB505124或SB431542使BM-MSCs中的TGF-β信号失活后，BM-MSCs无法向CM迁移。PC3或DU145的CM增强了BM-MSCs上N-钙黏蛋白的表达，但LNCaP的CM没有。SB505124、SB431542和TGFBR1敲低可阻止N-钙黏蛋白表达的增加。N-钙黏蛋白敲低抑制了BM-MSCs向PC3 CM的集体迁移。我们确定N-钙黏蛋白是BM-MSCs向表达TGF-β的激素不敏感前列腺肿瘤细胞迁移的介质，并引入了一种控制和重新构建前列腺肿瘤微环境的新策略。
