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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-17530

Borsig, L. Selectins facilitate metastasis and the role of heparin in cancer. 2008, University of Zurich, Faculty of Medicine.

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Abstract

Metastatic disease is the primary cause of death for most cancer patients. Metastasis is facilitated by tumor cell interactions with the surrounding host cells. It is now clear that cell proliferation alone does not cause cancer, but the sustained proliferation in an environment consisting of inflammatory cells, growth factors and DNA-damaging agents promotes neoplastic progression. Causal interdependence between inflammation, innate immunity and cancer progression is widely accepted; however, many molecular and cellular mechanisms involved in metastasis have not been elucidated. Inflammatory cells were shown to promote tumor cell survival and migration. The tumor cell microenvironment consisting of platelets, leukocytes, endothelium and stromal cells actively participates in tumorigenesis and metastasis. Hematogenous carcinoma metastasis is supported by aggregated platelets and leukocytes, forming tumor cell emboli. The presence of tumor cells in circulation during hematogenous metastasis together with availability of vascular selectins is suggesting that selectin interactions with cancer cells may be implicated in metastasis (Figure). The physiological functions of selectins are well described in processes of initial tethering and rolling of leukocytes on endothelium which are supported by rapid and reversible interactions of selectins with their carbohydrate ligands. The participation of selectins in cancer progression is initiated by the findings that carcinomas, with enhanced selectin ligands expression on their mucins, confer to poor prognosis due to metastasis. We could show in several mouse models that early tumor cell-platelet interactions are mediated by P-selectin interactions with tumor cells, and this process can be blocked by heparin. The absence of P-selectin or its inhibition led to attenuation of metastasis. Reduction of metastasis was also observed in L-selectin deficient mice, indicating that leukocytes are directly implicated in the facilitation of this process. Finally, heparin treatment of cancer patients was shown to prolong their survival, which seems to be independent of anticoagulant activity. In parallel, heparin effectively attenuates metastasis in several pre-clinical models. The effect of heparin in this process remains under investigation, although observations from our laboratory strongly argue for primary inhibition of selectins to be responsible for attenuation of metastasis. In the enclosed work we studied and provided evidence for: a) the role of L-selectin in leukocytes participation on metastasis; b) contribution of selectin ligands to initiation of metastasis; c) characterization of heparin biological activities contributing to its anti-metastatic effect. We investigated how L-selectin facilitates establishment of pulmonary metastatic foci.

Item Type:Habilitation
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
DDC:570 Life sciences; biology
Language:English
Date:11 July 2008
Deposited On:05 Mar 2009 14:10
Last Modified:09 Jul 2012 03:44

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