Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Cell Death Dis. 2019 Mar 19;10(4):267. doi: 10.1038/s41419-019-1493-5.
Accumulating evidence suggests that cancer cells with stem cell-like features have higher resistance to chemotherapeutic agents. Herein, we identified T-lymphoma invasion and metastasis-inducing protein-1 (TIAM1) as one of the Wnt-signaling associated genes which drives self-renewal and its expression is upregulated by cancer associated fibroblasts (CAFs). TIAM1 expression was assessed in resected colorectal cancer (CRC) tissues from 300 patients who did or did not respond to chemotherapy. siRNA and CRISPR/Cas9 was used to examine whether the inhibition of TIAM1 affects chemosensitivity of CRC. We demonstrate that stemness through Wnt signaling regulates chemosensitivity and this phenomenon occurs exclusively in cancer stem cells. Subsequently, we established patient-derived CAFs and tested whether the drug sensitivity of CRC cell lines is altered with CAF-derived conditioned medium. High-TIAM1 expression correlated significantly with poor prognosis of CRC patients, and was overexpressed in patients who did not respond to chemotherapy. We demonstrated that the inhibition of TIAM1 enhanced sensitivity to chemotherapeutic drugs and reduced tumor invasiveness in a series of experiments in vitro. Moreover, CAF-derived conditioned media increased stemness and chemoresistance in CRC cell lines through TIAM1 overexpression. In addition, we validated TIAM1 associated drug sensitivity using a xenograft model. We have demonstrated that TIAM1 is overexpressed in CRC tumors from patients who did not respond to chemotherapeutic drugs and levels of TIAM1 expression served as an independent prognostic factor. Mechanistically, CAFs enhanced CRC chemoresistance through TIAM1 overexpression. Collectively, these results suggest that TIAM1 regulates chemosensitivity in tumors and stroma and thus may be an attractive therapeutic target.
越来越多的证据表明，具有干细胞样特征的癌细胞对化疗药物具有更高的抗性。在这里，我们鉴定出 T 淋巴细胞瘤侵袭和转移诱导蛋白 1（TIAM1）是与 Wnt 信号相关的基因之一，它驱动自我更新，其表达受癌症相关成纤维细胞（CAF）上调。评估了 300 名接受或未接受化疗的结直肠癌（CRC）患者切除组织中的 TIAM1 表达。使用 siRNA 和 CRISPR/Cas9 来检查抑制 TIAM1 是否影响 CRC 的化疗敏感性。我们证明，通过 Wnt 信号的干性调节化疗敏感性，这种现象仅发生在癌症干细胞中。随后，我们建立了患者来源的 CAF，并测试了 CAF 衍生的条件培养基是否改变 CRC 细胞系的药物敏感性。高 TIAM1 表达与 CRC 患者的预后不良显著相关，并且在未对化疗有反应的患者中过度表达。我们证明，抑制 TIAM1 可增强一系列体外实验中化疗药物的敏感性并降低肿瘤侵袭性。此外，CAF 衍生的条件培养基通过 TIAM1 过表达增加了 CRC 细胞系的干性和化疗耐药性。此外，我们使用异种移植模型验证了 TIAM1 相关的药物敏感性。我们已经证明，在对化疗药物无反应的患者的 CRC 肿瘤中 TIAM1 过度表达，并且 TIAM1 表达水平作为独立的预后因素。从机制上讲，CAF 通过 TIAM1 过表达增强了 CRC 的化疗耐药性。总之，这些结果表明 TIAM1 调节肿瘤和基质中的化疗敏感性，因此可能是一个有吸引力的治疗靶点。
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