ReviewPost screenSlit/Robo pathway: a promising therapeutic target for cancer
Introduction
The development of the nervous system involves several progressive and regressive events that are mainly driven by axon guidance molecules [1], such as Slit and Roundabout (Robo) [2]. Slit/Robo signaling was first established as an extracellular signature to guide axon path finding, promote axon branching and control neuronal migration. The interaction of Slit and Robo proteins is crucially involved in the developmental processes of various vital organs such as breast, lung, liver, kidney, eye and reproductive systems. Slit proteins are highly conserved, secreted glycoproteins that mediate their functions by binding to the transmembrane receptors known as Robo recptors [1]. Slits and Robos are large proteins involved in several cell signaling pathways including axon guidance, cell proliferation, cell motility and angiogenesis 2, 3, 4. Slit and Robo proteins were first discovered as secreted proteins in Drosophila 5, 6, 7. Thereafter, homologs of Slit and Robo proteins have been discovered in rat, mice and humans [8]. Many reports have suggested that, in addition to axon guidance, the Slit/Robo pathway is also involved in the developmental processes and in the regulation of several physiological processes. An aberrant Slit/Robo expression in cells can lead to cancer development, progression and metastasis. Herein, we have reviewed recent advances regarding the roles of the Slit/Robo pathway and proteins in different types of cancer, molecular crosstalk and the modulation of oncogenic signaling pathways.
Section snippets
Structure of Slit and Robo proteins
In humans, Slits are composed of a single peptide of about 1500 amino acids, and there are three members: Slit1, Slit2 and Slit3 9, 10. The primary structure of Slit contains four domains at the N terminus (D1–D4) with leucine-rich repeats (LRR), six EGF-like sequences (EGF), a laminin-G domain and a C terminus with a cysteine-rich knot (Fig. 1) 9, 11, 12. All vertebrates have similar Slit family protein structures. The D2 region domain of LRR of Slits is highly conserved and plays an important
Slit/Robo pathway in cancer progression
The first link between Slit/Robo signaling and cancer was reported by Sundaresan et al. [14]. Subsequent studies indicated that the exon 2 of Robo1 was deleted in lung and breast tumor cell lines 14, 15. Subsequently, various studies have shown that Slit1–3 and Robo 1,3 promoters are hypermethylated (epigenetic inactivation) in several different types of cancers 9, 16, 17, 18, 19, 20. The activation or suppression of the Slit/Robo pathway modulates several oncogenic signaling pathways that are
Role of Slit/Robo pathway in different cancers
The tumor suppressor or antitumor activity of the Slit/Robo pathway is not unanimous, and how cancer-specific expression of Slit and Robo proteins govern the different type of cancers is not clearly comprehended. This section summarizes the recent updates on the regulation of oncogenesis by the Slit/Robo pathway in different cancer types.
Future prospects for Slit/Robo pathway as a drug target
Besides functioning as axon guidance molecules, the Slit/Robo pathway proteins also regulate functions such as morphogenesis of tissue as well as performing many non-neuronal roles such as cell growth, migration and cell survival [92]. Slit/Robo is often downregulated in the advanced stage of most tumors 36, 85, 86. In vitro studies suggested that expression of Slit can be regulated by stress and optimum function can be achieved by modulating the endoplasmic reticulum (ER), Ca2+ homeostasis and
Concluding remarks
The overall data suggest that the axon guidance molecule Slit/Robo has important roles in cancer metastasis, tumorigenesis in many tumors and that several possible tumor-specific expressions need to be explored in future studies. However, additional research is necessary before we can provide a robust, comprehensive mechanism to target the Slit/Robo pathway in the specific cancers. Tumor-specific discrepancy of Slit/Robo by previous authors might simply tempt one to apply neurobiological models
Conflict of interest
The authors have no conflict of interest to declare regarding this work.
Acknowledgements
The authors thank Cathy Christopherson (Sanford Research) for editorial assistance. This work was partially supported by grants from: the National Institutes of Health (R01 CA142736 to S.C.C. and U01 CA162106A to S.C.C. and M.J.); Department of Defense (PC073887 to S.C.C. and PC073643 to M.J.); and the College of Pharmacy (2013 Dean's Seed Grant of the University of Tennessee Health Science Center to M.J. and M.M.Y.).
References (95)
Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance
Cell
(1999)Slit: an EGF-homologous locus of D. melanogaster involved in the development of the embryonic central nervous system
Cell
(1988)Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors
Cell
(1998)Mutations affecting growth cone guidance in Drosophila: genes necessary for guidance toward or away from the midline
Neuron
(1993)- et al.
Role of Slit proteins in the vertebrate brain
J. Physiol.
(2002) - et al.
Modularity of the slit protein. Characterization of a conserved carboxy-terminal sequence in secreted proteins and a motif implicated in extracellular protein interactions
J. Mol. Biol.
(1992) Roundabout receptors are critical for foregut separation from the body wall
Dev. Cell
(2013)- et al.
Metastatic colonization: settlement, adaptation and propagation of tumor cells in a foreign tissue environment
Semin. Cancer Biol.
(2011) Targeting the metabolic microenvironment of tumors
Adv. Pharmacol.
(2012)Slit protein-mediated inhibition of CXCR4-induced chemotactic and chemoinvasive signaling pathways in breast cancer cells
J. Biol. Chem.
(2004)
Cytokines secreted by macrophages isolated from tumor microenvironment of inflammatory breast cancer patients possess chemotactic properties
Int. J. Biochem. Cell Biol.
Slit2 inhibits growth and metastasis of fibrosarcoma and squamous cell carcinoma
Neoplasia
Modulation of inflammation by slit protein in vivo in experimental crescentic glomerulonephritis
Am. J. Pathol.
The Spiegelmer NOX-A12, a novel CXCL12 inhibitor, interferes with chronic lymphocytic leukemia cell motility and causes chemosensitization
Blood
CXCL12/SDF1 expression by breast cancers is an independent prognostic marker of disease-free and overall survival
Eur. J. Cancer
SLIT/ROBO1 signaling suppresses mammary branching morphogenesis by limiting basal cell number
Dev. Cell
Wnt modulates MCL1 to control cell survival in triple negative breast cancer
BMC Cancer
CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway
Biochem. Biophys. Res. Commun.
Regulation of cortical dendrite development by Slit–Robo interactions
Neuron
Signal transduction in neuronal migration: roles of GTPase activating proteins and the small GTPase Cdc42 in the Slit–Robo pathway
Cell
Anti-semaphorin 3A antibodies rescue retinal ganglion cells from cell death following optic nerve axotomy
J. Biol. Chem.
Robo1 regulates the development of major axon tracts and interneuron migration in the forebrain
Development
The SLIT–ROBO pathway: a regulator of cell function with implications for the reproductive system
Reproduction
Extension of the Caenorhabditis elegans pharyngeal M1 neuron axon is regulated by multiple mechanisms
G3 (Bethesda)
Epigenetic inactivation of SLIT3 and SLIT1 genes in human cancers
Br. J. Cancer
Potential role of the Slit/Robo signal pathway in angiogenesis
Vasc. Med.
Slit: an extracellular protein necessary for development of midline glia and commissural axon pathways contains both EGF and LRR domains
Genes Dev.
Somatic genetic changes in lung cancer and precancerous lesions
Ann. Oncol.
Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers
Oncogene
Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/beta-catenin pathway
Cancer Res.
Slit2 involvement in glioma cell migration is mediated by Robo1 receptor
J. Neurooncol.
Hypoxia-mediated metastasis
Adv. Exp. Med. Biol.
Axonal guidance signaling pathway interacting with smoking in modifying the risk of pancreatic cancer: a gene- and pathway-based interaction analysis of GWAS data
Carcinogenesis
Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
Nature
Hierarchical organization of guidance receptors: silencing of netrin attraction by slit through a Robo/DCC receptor complex
Science
Netrin-1 up-regulation in inflammatory bowel diseases is required for colorectal cancer progression
Proc. Natl. Acad. Sci. U. S. A.
DCC constrains tumour progression via its dependence receptor activity
Nature
Expression and roles of Slit/Robo in human ovarian cancer
Histochem. Cell Biol.
The neuronal guidance cue Slit2 induces targeted migration and may play a role in brain metastasis of breast cancer cells
Breast Cancer Res. Treat.
Quantification of expression of netrins, slits and their receptors in human prostate tumors
Int. J. Cancer
The Slit/Robo system suppresses hepatocyte growth factor-dependent invasion and morphogenesis
Mol. Biol. Cell
Lung Kruppel-like factor (LKLF) is a transcriptional activator of the cytosolic phospholipase A2 alpha promoter
Biochem. J.
Hepatocyte growth factor modulates motility and invasiveness of ovarian carcinomas via Ras-mediated pathway
Br. J. Cancer
The role of MET receptor tyrosine kinase in non-small cell lung cancer and clinical development of targeted anti-MET agents
Oncologist
Slit3 inhibits activator protein 1-mediated migration of malignant melanoma cells
Int. J. Mol. Med.
A tumor suppressor role for srGAP3 in mammary epithelial cells
Oncogene
Frequent epigenetic inactivation of the SLIT2 gene in gliomas
Oncogene
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2021, Journal of Surgical ResearchCitation Excerpt :In contrast, aberrant expression of Slit/Robo proteins disrupts normal regulatory pathways and allows abnormal cellular proliferation. Some cancer cells have been found to have altered Slit/Robo signaling, which permits malignant lesions to grow rapidly.9,15-17 More specifically, suppression of Slit3 has been associated with tumor proliferation in multiple types of cancer.18,19
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These authors contributed equally to this work.