The mechanism of low molecular weight heparin (LMWH) inhibition of tumor growth

Abstract

13093 Background: Clinical studies show that LMWHs improve survival in cancer patients. There is compelling and mounting evidence that non-anticoagulation factors are at play, and that these may be contributing in a major way to improved patient outcome. Methods and Results: Dalteparin, enoxaparin, and tinzaparin were tested for their in vivo ability to inhibit tumor lines engineered for aggressive angiogenesis-driven growth. Therapeutic daily doses of drug administered the day following tumor inoculation resulted in significant angiogenesis and tumor inhibition. We previously showed that LMWHs inhibit fibroblast growth factor (FGF) -induced mitogenesis of Tumor Derived Endothelial Cells (TDECs) in a time and concentration dependent manner in vitro. We now show that this endothelial inhibition occurs through LMWHs-mediated reduction of phosphorylation and down stream signaling through ERK. The potency of LMWH was significantly reduced when TDECs were pretreated with heparinase- suggesting that the molecular target for LMWH may be the cell surface, low affinity FGF receptor system. Both our in vivo and in vitro studies demonstrate that angiogenesis and tumor inhibition are greatest for dalteparin > tinzaparin > enoxaparin. Clues to the heparin-TDECs interaction comes from tracking the real-time movement of FGF using a highly fluorescent nanocrystal bead decorated on its surface with FGF. High resolution video-microscopy shows FGF binding onto TDEC surfaces, but once heparin enters the environment, FGF detaches from the TDECs and migrates to the heparin. This ultimately results in significant TDEC growth inhibition as compared to controls. Conclusion: LMWH treatment at pharmacologic doses significantly blunts tumor growth and angiogenesis. This inhibition resides in part via heparin’s ability to sequester FGF from the low affinity receptor system on tumor endothelial cells. No significant financial relationships to disclose.

Anti-cancer properties of low-molecular-weight heparin: Preclinical evidence

“…Generally, preclinical studies have shown no effect of UFH on the growth of cancer cells in vitro or the growth of the primary tumour in animal models (10,34). The LMWH dalteparin, enoxaparin, and tinzaparin have been shown to inhibit downstream phosphorylation of the ERK kinase pathway in tumour-derived endothelial cells, and thus potentially the ability to interfere with cell proliferation (89). Inhibition of the ERK kinase pathway has been shown to be pivotal for several anti-cancer drugs, e.g.…”

Pleiotropic Effects of Heparins: From Clinical Applications to Molecular Mechanisms in Hepatocellular Carcinoma

“…They also documented interesting results highlighting the importance of types, duration, timing, and dose of heparin used, animal tumor model tested, and route of heparin administration in the course of disease [ 32 ]. Similarly, LMWH treatment was shown to inhibit FGF-induced mitogenesis of tumor derived endothelial cells in a time and concentration dependent manner [ 55 ]. Likewise, in Jha et al's study, to understand the effects of molecular weight and concentration of heparin on transforming growth factor (TGF)- β 1 signaling, they used heparin-containing hyaluronic acid based hydrogels to analyze growth factor affinity and retention [ 56 ].…”