M402, a novel heparan sulfate mimetic, targets multiple pathways implicated in tumor progression and metastasis.

Abstract

Heparan sulfate proteoglycans (HSPGs) play a key role in shaping the tumor microenvironment by presenting growth factors, cytokines, and other soluble factors that are critical for host cell recruitment and activation, as well as promoting tumor progression, metastasis, and survival. M402 is a rationally engineered, non-cytotoxic heparan sulfate (HS) mimetic, designed to inhibit multiple factors implicated in tumor-host cell interactions, including VEGF, FGF2, SDF-1α, P-selectin, and heparanase. A single s.c. dose of M402 effectively inhibited seeding of B16F10 murine melanoma cells to the lung in an experimental metastasis model. Fluorescent-labeled M402 demonstrated selective accumulation in the primary tumor. Immunohistological analyses of the primary tumor revealed a decrease in microvessel density in M402 treated animals, suggesting anti-angiogenesis to be one of the mechanisms involved in-vivo. M402 treatment also normalized circulating levels of myeloid derived suppressor cells in tumor bearing mice. Chronic administration of M402, alone or in combination with cisplatin or docetaxel, inhibited spontaneous metastasis and prolonged survival in an orthotopic 4T1 murine mammary carcinoma model. These data demonstrate that modulating HSPG biology represents a novel approach to target multiple factors involved in tumor progression and metastasis.

• Authors: He Zhou, Sucharita Roy, Edward Cochran, Radouane Zouaoui, Chia Lin Chu, Jay Duffner, Ganlin Zhao, Sean Smith, Zoya Galcheva-Gargova, Juliane Karlgren, Nancy Dussault, Rain Y Q Kwan, Erick Moy, Marishka Barnes, Alison Long, Chris Honan, Yi Wei Qi, Zachary Shriver, Tanmoy Ganguly, Birgit Schultes, Ganesh Venkataraman, Takashi Kei Kishimoto
• Journal: PloS one (PLoS One) Vol. 6 Issue 6 Pg. e21106 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 21698156 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• M402 heparan sulfate
• Heparitin Sulfate

Topics

• Animals
• Cell Line, Tumor
• Disease Progression
• Flow Cytometry
• Heparitin Sulfate (analogs & derivatives, pharmacology)
• Melanoma, Experimental (blood supply, pathology)
• Mice
• Molecular Mimicry
• Neoplasm Metastasis
• Surface Plasmon Resonance