A Roundabout Way to Cancer

Abstract

The Slit family of secreted proteins and their transmembrane receptor, Robo, were originally identified in the nervous system where they function as axon guidance cues and branching factors during development. Since their discovery, a great number of additional roles have been attributed to Slit/Robo signaling, including regulating the critical processes of cell proliferation and cell motility in a variety of cell and tissue types. These processes are often deregulated during cancer progression, allowing tumor cells to bypass safeguarding mechanisms in the cell and the environment in order to grow and escape to new tissues. In the last decade, it has been shown that the expression of Slit and Robo is altered in a wide variety of cancer types, identifying them as potential therapeutic targets. Further, studies have demonstrated dual roles for Slits and Robos in cancer, acting as both oncogenes and tumor suppressors. This bifunctionality is also observed in their roles as axon guidance cues in the developing nervous system, where they both attract and repel neuronal migration. The fact that this signaling axis can have opposite functions depending on the cellular circumstance make its actions challenging to define. Here, we summarize our current understanding of the dual roles that Slit/Robo signaling play in development, epithelial tumor progression and tumor angiogenesis.

Axon Guidance Factor SLIT2 Inhibits Neural Invasion and Metastasis in Pancreatic Cancer

“…These observations suggest that SLIT2-ROBO signaling occurs physiologically in the pancreas, which is in line with the reported chemorepellent function of SLIT2 in epithelial differentiation and ductal morphogenesis during breast, lung, colon, and kidney development (20)(21)(22). In turn, loss of SLIT2 resulted in deregulated morphogenesis and aberrant epithelial growth in lung and breast cancer (10), which agrees with the current observation of reduced SLIT2 mRNA expression in PDAC. Moreover, the concept of SLIT2 as a tumor suppressor in PDAC is supported by the frequent loss of SLIT2 expression in PDAC cell lines (33,34).…”

“…By now, three mammalian SLIT homologues (SLIT1-3) have been characterized. The activity of secreted SLIT ligands is mediated through interaction with Robos, which are single-pass transmembrane receptors belonging to the immunoglobulin superfamily of cell adhesion molecules (8)(9)(10). Originally characterized as repulsive axon guidance cues in midline crossing of commissural axons during neural development (11,12), subsequent genetic studies confirmed SLITs and ROBOs as chemorepellent cues controlling axon guidance and branching (13), migration of neurons and glia (14,15), and navigation of neural crest cells during neurogenesis (16,17).…”

“…In addition, chemorepellent SLIT2 signaling has been implicated in the control of stereotypic and polarized branching morphogenesis during development of epithelial organs such as kidney, mammary gland, and lungs (20)(21)(22). The tightly regulated pathways that control morphogenesis are frequently corrupted in epithelial malignancies (9,10), and SLIT2 has indeed been implicated in a number of human tumors. Initial seminal studies reported overexpression of SLIT2 in human tumor samples and functionally linked SLIT2 with enhanced tumor growth and vascularization (23).…”

“…Initial seminal studies reported overexpression of SLIT2 in human tumor samples and functionally linked SLIT2 with enhanced tumor growth and vascularization (23). However, loss of SLIT2 expression by epigenetic inactivation was reported in tumors such as breast, colon, and lung cancer (24,25), and low SLIT2 mRNA expression was associated with distant metastasis and poor survival (9,10). Loss of SLIT2 was, furthermore, linked to aberrant growth and migration of tumor epithelial cells, thereby promoting tumor growth and metastatic spread in experimental settings (9,10).…”

“…However, loss of SLIT2 expression by epigenetic inactivation was reported in tumors such as breast, colon, and lung cancer (24,25), and low SLIT2 mRNA expression was associated with distant metastasis and poor survival (9,10). Loss of SLIT2 was, furthermore, linked to aberrant growth and migration of tumor epithelial cells, thereby promoting tumor growth and metastatic spread in experimental settings (9,10). To date, neither expression nor function of the SLIT2-ROBO system in PDAC has been studied in detail.…”