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Inhibition of Cancer stem cell characterisitcs in Pancreatic Cancer

抑制胰腺癌中的癌症干细胞特征

基本信息

批准号：
8764701
负责人：
Sharmila Shankar
金额：
--
依托单位：
KANSAS CITY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-10-01 至 2016-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8764701
关键词：
Apoptosis Area BCL2 gene BIRC4 gene Binding Biological CD44 gene Cancer Patient Cell surface Cells Characteristics Chemopreventive Agent Data Development Disease Disease Progression Drug resistance Epithelial Event Failure Goals Growth Human Implant In Vitro Knowledge Lesion Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mesenchymal Modeling Molecular Mus Neoplasm Metastasis Oral Administration Outcome Pancreas Pancreatic Intraepithelial Neoplasia Patients Pharmaceutical Preparations Play Prevention Prevention strategy Preventive Primary Neoplasm Radiation therapy Research Reverse Transcriptase Polymerase Chain Reaction Role Signal Pathway Snails Sonic Hedgehog Pathway Staging Stem cells Sulforaphane Testing Therapeutic Transgenic Mice Undifferentiated Up-Regulation base cancer initiation cancer prevention cancer stem cell cancer therapy carcinogenesis cell behavior cell growth chemotherapy chromatin immunoprecipitation clinically significant cruciferous vegetable design empowered gemcitabine improved in vivo lapatinib migration mouse model notch protein novel novel strategies pancreatic cancer cells pancreatic neoplasm pluripotency precursor cell prevent prognostic public health relevance response self-renewal slug small hairpin RNA smoothened signaling pathway stemness tumor tumor growth tumor progression tumorigenic

项目摘要

DESCRIPTION (provided by applicant): ABSTRACT Cancer stem cells (CSCs) have been proposed recently to be the cause cancer initiation, progression and chemotherapy failure in pancreatic cancer. Abberant hedgehog signaling occurs in pancreatic cancer during the progression of PanIN lesions to metastatic tumors, suggesting that sonic hedgehog (Shh) signaling may be an early event leading to accumulation of undifferentiated precursor cells in pancreatic cancer. This project is based on the premise that sulforaphane (SFN), a natural compound from the cruciferous vegetables, can be used for prevention and/or treatment of human pancreatic cancer. Unfortunately, the intracellular mechanisms by which SFN inhibits growth and metastasis, and induces apoptosis in pancreatic cancer cells and CSCs have never been examined. Thus, the main objective of this application is to examine the molecular mechanisms by which sulforaphane inhibits pancreatic CSC characteristics, and assess the chemopreventive / therapeutic potential of sulforaphane against pancreatic cancer by targeting CSCs. These studies will empower us with new knowledge that will guide us in formulating strategies for prevention of human pancreatic cancer by targeting CSCs. We have recently demonstrated that human CD133+CD44+CD24+ESA+ CSCs express Nanog, Notch-1 and Oct-4 and are highly tumorigenic in mice. Our preliminary data indicate that: (i) SFN inhibits self-renewal capacity of pancreatic CSCs; (ii) SFN inhibits the expression of pluripotency maintaining factors (Nanog, Oct-4 and Sox-2), epithelial mesenchymal (EMT) markers (Zeb-1, Snail, Slug), Bcl-2 and XIAP in pancreatic CSCs; (iii) SFN inhibits the expression of Smo, Ptch as well as effector molecule Gli 1 and 2, suggesting the clinical significance of Shh pathway in pancreatic cancer; (iv) enforced activation of Shh pathway or inhibition of Gli1 plus Gli2 expression by shRNA blocked the inhibitory effects of SFN, suggesting these effects of sulforaphane are mediated through Shh pathway; and (v) SFN inhibits self-renewal capacity of CSCs (CD133+CD44+CD24+ESA+ cells with high Nanog) isolated from pancreas of human primary tumors and KrasG12D mice. Based on our preliminary findings, we hypothesize that sulforaphane alone or in combination with standard chemotherapeutic drugs inhibit pancreatic cancer stem cell characteristics by regulating pluripotency promoting factors and inhibiting the sonic hedgehog pathway. The above hypothesis will be tested by the following four specific aims: Aim 1. To examine the molecular mechanisms by which sulforaphane inhibits human pancreatic cancer stem cell characteristics and sensitizes drug- resistant cancer stem cells in vitro. Aim 2. To examine whether sulforaphane inhibits self-renewal capacity, migration, invasion and epithelial mesenchymal transition of pancreatic cancer stem cells through sonic hedgehog pathway and further to examine the involvement of Shh pathway in tumor-stroma interaction. Aim 3. To examine the effects of oral administration of sulforaphane on pancreatic carcinogenesis using a KrasG12D transgenic mouse model. Aim 4. To validate whether oral administration of sulforaphane is effective in inhibiting pancreatic cancer stem cell characteristics and tumor growth by inhibiting sonic hedgehog pathway, and to examine the interactive effects of sulforaphane with standard chemotherapeutic drugs in a NOD/SCID/IL2Rgammanull mouse model. Our studies are very novel and significant because they have prognostic relevance and inhibit pancreatic cancer initiation and progression by targeting CSCs.

描述（由申请人提供）：