A direct pancreatic cancer xenograft model as a platform for cancer stem cell therapeutic development

Molecular Cancer Therapeutics - Tập 8 Số 2 - Trang 310-314 - 2009
Antonio Jimeno1, Georg Feldmann1, Magdalena Adrados2, Zeshaan A. Rasheed1, Anna Solomon1, Gang-Ming Zou1, Belén Rubio‐Viqueira1,2, Elena García-García2, Fernando López‐Ríos2, William Matsui1, Anirban Maitra1, Manuel Hidalgo1,2
11Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, Maryland and
22Laboratorio de Dianas Terapéuticas, Centro Integral Oncológico Clara Campal, Hospital Madrid Norte Sanchinarro, Madrid, Spain

Tóm tắt

Abstract There is an enormous gap between the antiproliferative and in vivo antitumor efficacy of gemcitabine in cell line-based models and its clinical efficacy. This may be due to insensitiveness of the precursor, cancer stem cell (CSC) compartment to cytotoxic agents. The hedgehog pathway is associated with CSC signaling and control. We used a direct xenograft model of pancreatic cancer and a two-stage approach was used to test the hypotheses that targeting CSC could increase the efficacy of gemcitabine. Tumors from a gemcitabine-sensitive xenograft were treated with gemcitabine first, and randomized, after tumor regression to continuing treatment with gemcitabine, a hedgehog inhibitor alone or in combination with gemcitabine. We tested markers described as associated with CSC such as CD24, CD44, ALDH, nestin, and the hedgehog pathway. After induction with gemcitabine, treated tumor showed an enrichment in CSC markers such as ALDH and CD24. Subsequently, a release from gemcitabine prompted a repopulation of proliferating cells and a decrease in such markers to equilibrate from pretreatment levels. Combined treatment with gemcitabine and cyclopamine induced tumor regression and decrease in CSC markers and hedgehog signaling. Cytoplasmic CD24 and ALDH were inversely and strongly associated with growth and were expressed in a minority of cells that we propose constitute the CSC compartment. Hedgehog inhibitors as part of a dual compartment therapeutic approach were able to further reduce tumor growth and decreased both static and dynamic markers of CSC. Direct tumor xenografts are a valid platform to test multicompartment therapeutic approaches in pancreatic cancer. [Mol Cancer Ther 2009;8(2):310–4]

Từ khóa


Tài liệu tham khảo

Carpelan-Holmstrom M, Nordling S, Pukkala E, et al. Does anyone survive pancreatic ductal adenocarcinoma? A nationwide study re-evaluating the data of the Finnish Cancer Registry. Gut 2005;54:385–7.

Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008;58:71–96.

Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet 2004;363:1049–57.

Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res 2007;67:1030–7.

Thayer SP, di Magliano MP, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003;425:851–6.

Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003;425:846–51.

Parisi MJ, Lin H. The role of the hedgehog/patched signaling pathway in epithelial stem cell proliferation: from fly to human. Cell Res 1998;8:15–21.

Peacock CD, Wang Q, Gesell GS, et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci U S A 2007;104:4048–53.

Huang P, Wang CY, Gou SM, Wu HS, Liu T, Xiong JX. Isolation and biological analysis of tumor stem cells from pancreatic adenocarcinoma. World J Gastroenterol 2008;14:3903–7.

Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007;1:555–67.

Korkaya H, Paulson A, Iovino F, Wicha MS. HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 2008;27:6120–30.

Rubio-Viqueira B, Jimeno A, Cusatis G, et al. An in vivo platform for translational drug development in pancreatic cancer. Clin Cancer Res 2006;12:4652–61.

Jimeno A, Rubio-Viqueira B, Amador ML, et al. Dual mitogen-activated protein kinase and epidermal growth factor receptor inhibition in biliary and pancreatic cancer. Mol Cancer Ther 2007;6:1079–88.

Thông tin
Thông tin xuất bản

Molecular Cancer Therapeutics

Tập 8 Số 2

310-314

Thông tin tác giả