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Heparin and CXCL12 Dimerization

Hacettepe University Faculty of Medicine, Department of Medical Oncology, Ankara, Turkey
Houston, TX
Department of Neurosurgery, Baylor College of Medicine, Houston, TX

To the Editor:

We read with great interest the article by Lee et al¹ that investigated the influence of a low-molecular-weight heparin dalteparin on the survival of patients with active cancer and acute venous thromboembolism. They found that the use of dalteparin relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute venous thromboembolic event. Currently, the mechanisms for a potential antineoplastic effect of low-molecular-weight heparins remain unknown. As the authors implied in the article, one possibility might be the antiangiogenic effects of this drug. We want to propose a different mechanism of its action that may lead to increased survival, especially in patients who do not have metastatic disease. Chemokines and their respective receptors' expression have recently been demonstrated in the development of primary tumors and metastases.² In particular, chemokine receptors CXR4 and CCR7 are highly expressed in malignant breast tumors and metastases. Their respective ligands, stromal cell-derived factor-1 (CXCL12/SDF-1) and CCL21/6Ckine, are expressed in organs that represent important sites of breast cancer metastasis, such as bone marrow, liver, and lung.³ This mechanism has also been implicated in other cancers. Although it is not known whether the monomeric or dimeric structure of CXCL12 is responsible for signaling in vivo, a recent study found that acidic pH promotes the monomeric state of CXCL12 by destabilizing the dimeric structure, while heparin binding promotes CXCL12 dimer formation.⁴ Given the information above, we propose that heparin might prevent invasive and metastatic capacity of cancer cells by shifting CXCL12 monomer-dimer equilibrium to a dimerization state. This proposal remains to be explored by in vitro and in vivo studies.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Lee AY, Rickles FR, Julian JA, et al: Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 23:2123-2129, 2005[Abstract/Free Full Text]

2. Balkwill F: Cancer and chemokine network. Nat Rev Cancer 4:540-550, 2004[CrossRef][Medline]

3. Muller A, Homey B, Soto H, et al: Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50-56, 2001[CrossRef][Medline]

4. Veldkamp CT, Peterson FC, Pelzek AJ, et al: The monomer-dimer equilibrium of stromal cell-derived factor-1 (CXCL12) is altered by pH, phosphate, sulfate, and heparin. Protein Sci 14:1071-1081, 2005[CrossRef][Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Altundag, K. Articles by Atik, M. A. Search for Related Content PubMed PubMed Citation Articles by Altundag, K. Articles by Atik, M. A. Social Bookmarking                            What's this?