Preclinical Study Reveals Heparan Sulfate Suppresses Growth of Neuroblastoma
A heparin derivative differentiated cancer cells and caused neuroblastomas to regress without causing severe bleeding, according to the findings of a preclinical study presented in The Journal of Clinical Investigation. Knelson et al identified novel roles for heparan sulfate proteoglycans in neuroblastoma pathogenesis and stromal biology, which ultimately may include the use of heparin derivatives as prognostic and therapeutic biomarkers for this and potentially other cancers.
Although neuroblastoma is the most common cancer in infancy, survival rates for patients with late-stage disease are below 40%. Disease recurrence and residual tumor cells after cytotoxic therapy are possible reasons for these outcomes. Furthermore, the prognosis of those with neuroblastoma may depend on both the differentiation state and the stromal content of the tumor.
The investigators recently found that expression of receptors called heparan sulfate proteoglycans—also known as the type III TGF-beta receptor (TbRIII)—promotes differentiation of neuroblasts. Structurally similar to heparin, heparan sulfate proteoglycans appear to suppress the proliferation, growth, and metastasis of neuroblastomas, but their exact role in regulating neuroendocrine differentiation in development has remained unclear.
Study Details
Knelson and colleagues explored the role of heparan sulfate proteoglycans and basic fibroblast growth factor 2 (FGF2) in the pathogenesis of neuroblastoma in a preclinical study. They used a publicly available microarray meta-dataset (n = 213) that distinguished tumors as either stroma-rich or stroma-poor. Immunohistochemical analysis was performed on patient samples to investigate the localization of heparan sulfate proteoglycans. In addition, immunofluorescent and serum enzyme-linked immunosorbent assay analyses focused on the two major families of heparan sulfate proteoglycans: glypicans and syndecans.
The investigators obtained the neuroblastoma serum and tissue samples from the Children’s Oncology Group Biorepository. They included five control samples from patients under the age of 1 year and five samples from patients aged 5 to 11 years.
Heparin Derivative Slows the Growth of Tumors
By identifying the critical growth-limiting components of the differentiating stroma secretome, the investigators were able to use a heparin derivative (2-O, 3-O-desulfated heparin) as a potential therapeutic strategy targeting their central mechanism of action without causing anticoagulation. They found that expression of heparan sulfate proteoglycans (including GPC1, GPC3, SDC3, and SDC4) appeared to be localized to the stroma and was decreased in neuroblasts. Further evaluation of the data showed a connection between high expression of heparan sulfate proteoglycans and improved prognosis.
In addition, soluble heparan sulfate proteoglycans promoted the expression of neuronal differentiation markers in multiple neuroblastoma cell lines, and these effects seemed to be dose-dependent and increased over time (from 48 to 96 hours of treatment). Other study findings centered on FGF2, a critical component of the differentiating stroma secretome and a potential serum prognostic marker; soluble heparan sulfate proteoglycans enhanced FGF2 signaling in neuroblasts. Furthermore, the investigators demonstrated that serum FGF2 levels were elevated in a subset of patients with neuroblastoma compared with pediatric controls.
Closing Thoughts
These study data appear to support the key role of heparin sulfation in the pathogenesis of neuroblastoma and the potential use of heparan sulfate signaling intermediates as prognostic and therapeutic biomarkers. Moreover, high tumor expression levels and serum concentrations of heparan sulfate proteoglycans and their ligand FGF2 may be associated with improved prognosis.
The investigative team is working to move their research into clinical trials in humans. Clinical implications of these preliminary study findings suggest caution in the use of nonspecific tyrosine kinase inhibitors, which may inhibit this differentiation pathway and potentially lead to tumor recurrence, according to Knelson and colleagues, from Duke University Medical Center, Durham, North Carolina.
“We want to repurpose a drug that’s already out there for the benefit of patients. What’s exciting about that is there are other tumors in which differentiation is useful, so there’s the potential to apply these insights to other cancers,” declared Gerard C. Blobe, MD, of the Department of Pharmacology and Cancer Biology, Duke University Medical Center, in a recent press release. Dr. Blobe is the corresponding author of the article in The Journal of Clinical Investigation.
This study was supported in part by grants from the National Institutes of Health as well as a Reach Award from Alex’s Lemonade Stand. Stephen G. Marcus, MD, is an employee and equity owner of Cantex Pharmaceuticals. The other study authors reported no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
