Introduction: A significant problem associated with brain tumors is the capacity to invade adjacent, healthy neural tissue. Here we present evidence that the axon guidance factor (AGF) netrin-1 can directly influence the invasive capacity of brain tumors and that human tumor specimens are associated with increased levels of netrin-1.
Methods: Established human tumor cell lines underwent baseline characterization of invasion, migration, and proliferation using standardized assays. Variation from baseline was then evaluated following stimulation by administration of exogenous netrin-1. Levels of AGFs and effector molecules were also measured in patient samples (tissue, cerebrospinal fluid and urine) to evaluate potential efficacy as biomarkers. Results were subjected to univariate and multivariate statistical analyses.
Results: Netrin-1 administration significantly increased the invasive capacity of medulloblastoma cell lines. Secreted effector molecules varied predictably with pathway modulation and cell line data successfully identified candidate urinary biomarkers detected in patient samples. Netrin-1 levels were significantly elevated in tumor patient urine samples as compared to healthy controls, with source tumor tissue correlating netrin-1 expression compared to normal brain. Ratios of inhibitory (SEMA3F) to stimulatory (netrin-1) AGF levels as measured in patient urine samples were higher in healthy controls as compared to tumor patients, as predicted.
Conclusions: AGFs are a novel and potentially important class of molecules involved in brain tumor progression. Netrin-1 is able to significantly increase the invasive capacity of brain tumor cell lines. In addition to potential utility as innovative therapeutic targets, a select panel of these molecules demonstrated diagnostic utility as non-invasive biomarkers, with direct correlation in patient urine and tissue samples, strongly supporting the clinical applicability of this approach.
Patient Care: This work may lead to improved understanding, diagnosis and treatment of brain tumors.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of axon guidance factors in brain tumor development, 2) Discuss potential applications for urinary biomarkers in brain tumors 3) Identify potential therapeutics for brain tumors exploiting axon guidance factors
References: Urinary biomarkers predict brain tumor presence and response to therapy.
Smith ER, Zurakowski D, Saad A, Scott RM, Moses MA.
Clin Cancer Res. 2008 Apr 15;14(8):2378-86