Targeting CXCR4/SDF-1a using phytochemicals to inhibit progression and metastasis of pancreatic cancer
Mentor: Jin-Rong Zhou, PhD (DFCI)
Pancreatic cancer (PANC) is one of the deadliest cancers with its metastasis being the primary cause of death. It has been recognized that pancreatic cancer stem cells (CSCs) are primarily responsible for metastasis initiation and expansion to secondary sites. Recent research indicates that C-X-C chemokine receptor type 4 (CXCR4) plays a central role in cancer progression and metastasis. Overexpression of CXCR4 is a major cause of the direction of PANC metastasis to specific organs that overexpress the CXCR4 ligand, stromal-derived-factor-1α (SDF-1α). CXCR4 is overexpressed and the CXCR4/SDF-1α axis is activated in pancreatic CSCs. Therefore, effective regimens against PANC progression and metastasis should directly inhibit pancreatic CSCs and inactivate the CXCR4/SDF-1α signaling axis. There are preliminary studies that show that the bioactive compound tanshinone I (T1) has had potent activity against pancreatic CSCs and with down-regulating SDF-1α expression. We also found that the bioactive compound ampelopsin (AMP) inhibited metastasis and down-regulated CXCR4 expression. Moreover, T1 and AMP showed minimal adverse effects. Therefore, our hypothesis is that the T1 and AMP combination can have a synergistic effect on inhibiting growth and metastasis of PANC by inactivating cooperatively the CXCR4/SDF-1α axis. In this study, we will first apply the in vitro system to determine the effect of T1 and AMP, alone and in combinations, on the growth and invasion of PANC cells, and expression levels of CXCR4 and SDF-1α. We will then determine the effect of T1 and AMP combinations on self-renewal of pancreatic CSCs and expression levels of CXCR4 and SDF-1α.
Analysis of SDF-1 and its receptor CXCR4. Staining of SDF-1 (a,b) and the SDF-1-CXCR4 complex (c,d) in mammary tissues. The left panels show normal tissues, and the right panels show tumor tissues. Source: www.medscape.com Source: