BACKGROUND: Signaling through stromal cell-derived factor-1α (SDF-1α), strongly secreted by bone marrow stromal cells and the CXC chemokine receptor 4 (CXCR4) exposed on tumor cells has pivotal roles in proliferation, metastasis, and tumor cell "dormancy." Dormancy is associated with cytostatic drug resistance and is probably a property of tumor stem cells and minimal residual disease. Thus, hampering the SDF-1α/CXCR4 cross talk by a CXCR4 antagonist like Plerixafor (AMD3100) should overcome tumor cell dormancy bymobilization of tumor cells from "sanctuary" niches. Our aim was to elucidate the direct effects exerted by SDF-1α and Plerixafor on proliferation, chemosensitivity, and apoptosis of CXCR4-expressing tumor cells. METHODS: The ability of SDF-1α and Plerixafor to regulate intracellular signaling, proliferation, and invasion was investigated using two colon cancer cell lines (HT-29 and SW480) with either high endogenous or lentiviral expression of CXCR4 compared to their respective low CXCR4-expressing counterparts as a model system. Efficacy of Plerixafor on sensitivity of these cell lines against 5-fluorouracil, irinotecan, or oxaliplatin was determined in a cell viability assay as well as stroma-dependent cytotoxicity and apoptosis assays. RESULTS: SDF-1α increased proliferation, invasion, and ERK signaling of endogenously and lentivirally CXCR4-expressing cells. Exposure to Plerixafor reduced proliferation, invasion, and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Combination of chemotherapy with Plerixafor showed an additive effect on chemosensitivity and apoptosis in CXCR4-overexpressing cells. An SDF-1-secreting feeder layer provideda"protective niche" for CXCR4-overexpressing cells resulting in decreased chemosensitivity. CONCLUSION: CXCR4-antagonistic therapy mobilizes and additionally sensitizes tumor cells toward cytoreductive chemotherapy.
BACKGROUND: Signaling through stromal cell-derived factor-1α (SDF-1α), strongly secreted by bone marrow stromal cells and the CXC chemokine receptor 4 (CXCR4) exposed on tumor cells has pivotal roles in proliferation, metastasis, and tumor cell "dormancy." Dormancy is associated with cytostatic drug resistance and is probably a property of tumor stem cells and minimal residual disease. Thus, hampering the SDF-1α/CXCR4 cross talk by a CXCR4 antagonist like Plerixafor (AMD3100) should overcome tumor cell dormancy bymobilization of tumor cells from "sanctuary" niches. Our aim was to elucidate the direct effects exerted by SDF-1α and Plerixafor on proliferation, chemosensitivity, and apoptosis of CXCR4-expressing tumor cells. METHODS: The ability of SDF-1α and Plerixafor to regulate intracellular signaling, proliferation, and invasion was investigated using two colon cancer cell lines (HT-29 and SW480) with either high endogenous or lentiviral expression of CXCR4 compared to their respective low CXCR4-expressing counterparts as a model system. Efficacy of Plerixafor on sensitivity of these cell lines against 5-fluorouracil, irinotecan, or oxaliplatin was determined in a cell viability assay as well as stroma-dependent cytotoxicity and apoptosis assays. RESULTS:SDF-1α increased proliferation, invasion, and ERK signaling of endogenously and lentivirally CXCR4-expressing cells. Exposure to Plerixafor reduced proliferation, invasion, and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Combination of chemotherapy with Plerixafor showed an additive effect on chemosensitivity and apoptosis in CXCR4-overexpressing cells. An SDF-1-secreting feeder layer provideda"protective niche" for CXCR4-overexpressing cells resulting in decreased chemosensitivity. CONCLUSION:CXCR4-antagonistic therapy mobilizes and additionally sensitizes tumor cells toward cytoreductive chemotherapy.
Authors: Mauricio P Pinto; Melanie M Badtke; Michelle L Dudevoir; J Chuck Harrell; Britta M Jacobsen; Kathryn B Horwitz Journal: Cancer Res Date: 2010-03-23 Impact factor: 12.701
Authors: Joseph Kim; Hiroya Takeuchi; Stella T Lam; Roderick R Turner; He-Jing Wang; Christine Kuo; Leland Foshag; Anton J Bilchik; Dave S B Hoon Journal: J Clin Oncol Date: 2005-04-20 Impact factor: 44.544
Authors: Jiayu Chen; Zijun Y Xu-Monette; Lijuan Deng; Qi Shen; Ganiraju C Manyam; Azahara Martinez-Lopez; Li Zhang; Santiago Montes-Moreno; Carlo Visco; Alexandar Tzankov; Lihui Yin; Karen Dybkaer; April Chiu; Attilio Orazi; Youli Zu; Govind Bhagat; Kristy L Richards; Eric D Hsi; William W L Choi; J Han van Krieken; Jooryung Huh; Maurilio Ponzoni; Andrés J M Ferreri; Xiaoying Zhao; Michael B Møller; John P Farnen; Jane N Winter; Miguel A Piris; Lan Pham; Ken H Young Journal: Oncotarget Date: 2015-03-20
Authors: Yang Zeng; Binghao Li; Yingying Liang; Patrick M Reeves; Xiying Qu; Chongzhao Ran; Qiuyan Liu; Michael V Callahan; Ann E Sluder; Jeffrey A Gelfand; Huabiao Chen; Mark C Poznansky Journal: FASEB J Date: 2019-02-25 Impact factor: 5.834