Differentiation and Elimination of Chemo-surviving Colon Tumors

化疗后存活的结肠肿瘤的分化和消除

• 批准号: 8803345
• 负责人: ADHIP P. N. MAJUMDAR
• 金额: --
• 依托单位: JOHN D DINGELL VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8803345
• 关键词: Alkaline Phosphatase; Apoptosis; Biological Availability; CD44 gene; Cancer Model; Cell Differentiation process; Cell model; Cells; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Complementary DNA; Curcumin; Data; Development; Diet; Differentiation Therapy; Down-Regulation; Drug resistance; Epidermal Growth Factor Receptor; Epithelial Cells; Excision; Exhibits; Failure; Fluorouracil; Growth; Health; Human; In Vitro; Large Intestine Carcinoma; Lead; Malignant Neoplasms; Medicine; MicroRNAs; Modeling; Mus; Natural regeneration; Neoplasm Metastasis; Oncogenes; Operative Surgical Procedures; Parents; Patients; Play; Population; Property; Recurrence; Recurrent disease; Refractory; Regimen; Reporting; Resistance; Role; SCID Mice; Signal Pathway; Signal Transduction; Testing; Therapeutic; Toxic effect; Transfection; Treatment Efficacy; Tumor Burden; Tumor Promotion; Undifferentiated; Vertebral column; Xenograft Model; Xenograft procedure; analog; beta catenin; cancer cell; cancer stem cell; chemotherapy; clinical remission; conventional therapy; cytokeratin 20; improved; in vivo; killings; neoplastic cell; novel; oxaliplatin; pre-clinical; preclinical study; prevent; response; self-renewal; stem; stemness; tumor

DESCRIPTION (provided by applicant): Despite the use of aggressive surgical resection and chemotherapy, nearly 50% of patients with colorectal carcinoma, the 3rd deadliest cancer in the US, will develop recurrent disease, highlighting the need for improved therapies. The failure to produce long-term clinical remission in CRC patients could reflect the inability to target cancer stem or stem-like cells (CSCs/CSLCs; that express cancer stem cell markers) efficiently since these cells are known to be resistant to conventional therapies. Differentiation therapy, which results in loss of self-renewal and induction of terminal differentiation or apoptosis in CSLCs, may be a valid option for the treatment of recurrent colorectal cancer. We have shown that miR-21, an emerging oncogene which induces stemness by activating Wnt/¿-catenin and EGFR signaling in colon cancer cells stimulates tumor promotion, invasion and metastasis. miR-21 is also greatly elevated in 5-FU + Oxaliplatin (FUOX) resistant colon cancer cells; downregulation of miR-21 leads to differentiation of these cells, as evidenced by increased CK-20 expression and alkaline phosphatase activity. Moreover, this downregulation renders the FUOX-resistant colon cancer cells susceptible not only to FUOX but also to 3, 4-difluorobenzo-curcumin or difluorinated curcumin (CDF) and the combination of CDF and FUOX. CDF is a novel analog of the dietary ingredient curcumin with much greater bioavailability and growth inhibitory properties than the parent compound. Additionally, we have observed that in response to CDF or the combination CDF and FUOX, miR-21-downregulated FUOX-resistant colon cancer cells exhibit decreased expression of EGFR and CD44 and increased apoptosis. CDF alone and the combination of CDF and FUOX were much more effective than FUOX alone. We propose to extend this differentiation therapy in a preclinical setting. Therefore, we will use SCID mice xenograft and orthotopic models of colon cancer to test the hypothesis that down regulation of miR-21 by antagomir-21 (antisense miR-21) in chemotherapy surviving colon tumors will lead to differentiation of chemotherapy-resistant tumor cells known to be enriched in CSCs/CSLCs. We further hypothesize that while subsequent treatment with FUOX will only be partially effective in obliterating the refractory colon tumors, treatment with either CDF or the combination of CDF and FUOX will be highly effective in causing a complete or near complete regression of the tumor by killing differentiating chemo-resistant colon CSCs/CSLCs through inhibition of Wnt/¿-catenin and EGFR signaling. Finally, we will demonstrate that miR-21 regulates ¿-Wnt/catenin and EGFR signaling pathways in colon cancer chemo-resistant cells in vitro.

描述（由申请人提供）： 尽管使用了侵略性的手术切除和化学疗法，但几乎50％的结直肠癌患者（美国第三个致命的癌症）将出现复发性疾病，强调需要改善疗法。在CRC患者中未能产生长期临床缓解可能会有效地反映出靶向癌症或茎样细胞（CSCS/CSLC；表达癌症干细胞标记物）的能力，因为已知这些细胞对常规疗法具有抗性。分化疗法导致自我更新和CSLC中终末分化或凋亡的诱导可能是治疗复发性结直肠癌的有效选择。我们已经表明，MiR -21是一种新兴的致癌基因，可通过激活结肠癌细胞中的Wnt/Catenin和EGFR信号传导诱导干性，从而刺激肿瘤促进，侵袭和转移。在5-FU +奥沙利铂（Fuox）抗性结肠癌细胞中，miR-21也非常升高。 miR-21的下调会导致这些细胞的分化，这是CK-20表达和酒精磷酸酶活性的增加所证明的。此外，这种下调使耐Fuox的结肠癌细胞不仅容易受到Fuox的影响，而且对3，4-二氟苯并核糖素或二氟化姜黄素（CDF）以及CDF和Fuox的组合敏感。 CDF是饮食成分姜黄素的新型类似物，其生物利​​用度和生长抑制特性比母体化合物要大得多。此外，我们已经观察到，在响应CDF或CDF和FUOX的组合时，miR-21降低了耐FUOX耐药的结肠癌细胞暴露的EGFR和CD44表达降低并增加了凋亡。单独使用CDF以及CDF和FUOX的组合比单独的Fuox更有效。我们建议在临床前的环境中扩展这种分化疗法。因此，我们将使用SCID小鼠的定征性结肠癌的特征和原位模型来检验以下假设：在存活的结肠肿瘤的化学疗法中，Antagonomir-21（反义miR-21）对miR-21的减少调节将导致化学疗法疗法的抗药性肿瘤细胞的分化，这将导致CSCS/CSLC中富集的抗化学疗法抑制肿瘤细胞。我们进一步假设，虽然随后对Fuox进行治疗只能部分有效地抑制难治性结肠肿瘤，但CDF或CDF和FUOX的组合的处理将非常有效地通过杀死通过区分化学抗性Colon cscs/cslcs and -cslcs and/eg的wnt/eg wnt -nnt -wnt -wnt -wnt -n n n n n n snive and/c.c.最后，我们将证明miR-21在体外在结肠癌化学抗性细胞中调节 - Wnt/catenin和EGFR信号通路。