Slit/Robo pathway: a promising therapeutic target for cancer

Abstract

Axon guidance molecules, slit glycoprotein (Slit) and Roundabout receptor (Robo), have implications in the regulation of physiological processes. Recent studies indicate that Slit and Robo also have important roles in tumorigenesis, cancer progression and metastasis. The Slit/Robo pathway can be considered a master regulator for multiple oncogenic signaling pathways. Herein, we provide a comprehensive review on the role of these molecules and their associated signaling pathways in cancer progression and metastasis. Overall, the current available data suggest that the Slit/Robo pathway could be a promising target for development of anticancer drugs.

Figure 1

Structure of the Slit/Robo protein family. (a) Structure of human Slit protein. It is a large molecular weight glycoprotein, comprising (from N to C terminal): four leucine-rich repeats (LRR), seven to nine EGF_[s4] repeats, laminin G domain and a cysteine-rich knot. (b) Structure of human Robo proteins. Robos are the receptors of Slit proteins, which contain immunoglobulin (Ig) motifs, three fibronectin (Fn III_[s5]) motifs, a transmembrane domain and a conserved cytoplasmic domain (CC0–CC3). Figure modified, with permission, _[s6]from [10].

Figure 2

Slit/Robo interactions and their roles in carcinogenesis. (a) Slit1,2/Robo1 can inhibit cell invasion by inhibiting the stromal-derived factor (SDF)-1/CXCR4 axis and can attenuate cell cycle progression by destruction of β-catenin and cell division control protein (CDC)42 expression. (b) Alternatively, Slit/Robo interactions suppress hepatocyte growth factor (HGF) expression leading to Met_[s7][s8]-dependent inhibition of cell cycle arrest. (c) Slit2/Robo1 axis antagonizes E-cadherin/β-catenin-mediated enhanced cell adhesion. (d) Binding of Slit2,3 with Robo4 releases netrin-1, activating DCC_[s9]-regulated activation of caspase-dependent apoptotic cell death. Solid lines represent reported studies and dotted lines represent putative functions. Figure modified _[s10]with permission, from [2]. Abbreviations: GRB, growth factor receptor bound protein; GSK, glycogen synthase kinase; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; N, nucleus; VEGF, vascular endothelial growth factor.

Figure 3

_[s11]. Slit/Robo pathway targets various key signaling pathways in cancer. The list of targeted agents that improve clinical therapeutic outcome of breast cancer (BC), non-small-cell lung cancer (NSLC), gastric cancer (GC), renal cell carcinoma (RCC), head and neck cancer (H&NC), pancreatic cancer (PC), medullary thyroid cancer (MTC), thyroid carcinoma (TC), GI stromal tumor (GIST), multiple hematologic malignancies (MHM), chronic mylogenous leukemia (CML), acute lymphoblastic leukemia (ALL), colorectal cancer (CC), glioblastoma (GB), chronic lymphocytic leukemia (CLL), among others. Inhibitors or agents that regulate the Slit/Robo pathway could be useful therapeutic molecules. Abbreviations: EGFR, _[s12]epidermal growth factor receptor; HER2, human epidermal growth factor; HCC, hepatocellular carcinoma; mTOR, mammalian target of rapamycin; NHL, non-Hodgkin lymphoma; PDGFR, plateletderived growth factor receptor; VEGFR, vascular endothelial growth factor receptor.