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The Opposing Function of Leukocytes in Liver and Lung Metastases


Protsyuk, Darya. The Opposing Function of Leukocytes in Liver and Lung Metastases. 2017, University of Zurich, Faculty of Medicine.

Abstract

Metastasis is a step during cancer progression that is clinically challenging to determine and treat. The association of tumor cells with leukocytes influences successful tumor cell seeding and their survival in the metastatic niche. Selectins are vascular adhesion receptors that facilitate the recruitment of leukocytes to metastatic sites, and mediate interactions between tumor and stromal cells. Particularly the absence of L-selectin on leukocytes decreases the infiltration of immune cells in the lungs and reduces pulmonary metastasis. Our aim was to elucidate the contribution of L-selectin during metastatic development in lungs and liver.
While pulmonary metastasis was attenuated, liver metastasis was increased in L-selectin deficient mice. We determined that the selectin-dependent recruitment of inflammatory monocytes induced vascular permeability, promoted the extravasation of tumor cells and supported tumor cell survival in the lungs. The adoptive transfer of wild type bone marrow-derived monocytes into L-selectin deficient mice ameliorated metastatic development in the lungs.
In the liver, we observed increased amounts of Kupffer and γδ T cells in the absence of L-selectin. Furthermore, L-selectin facilitated the recruitment of neutrophils into the metastatic liver. We showed that liver neutrophils produce reactive oxygen species in vivo, and increased tumor cell apoptosis in vitro. Depleting neutrophils at later metastatic stages increased liver metastasis, confirming the cytotoxic function of neutrophils.
In summary, we identified an opposing role of L-selectin on metastatic development in the lungs and the liver. In the lungs, L-selectin mediates the recruitment of monocytes that promote tumor cell extravasation and support metastatic development. Our study demonstrated the contribution of myeloid cell populations to tissue-specific metastasis and defined a novel role of L-selectin during metastatic progression.

Abstract

Metastasis is a step during cancer progression that is clinically challenging to determine and treat. The association of tumor cells with leukocytes influences successful tumor cell seeding and their survival in the metastatic niche. Selectins are vascular adhesion receptors that facilitate the recruitment of leukocytes to metastatic sites, and mediate interactions between tumor and stromal cells. Particularly the absence of L-selectin on leukocytes decreases the infiltration of immune cells in the lungs and reduces pulmonary metastasis. Our aim was to elucidate the contribution of L-selectin during metastatic development in lungs and liver.
While pulmonary metastasis was attenuated, liver metastasis was increased in L-selectin deficient mice. We determined that the selectin-dependent recruitment of inflammatory monocytes induced vascular permeability, promoted the extravasation of tumor cells and supported tumor cell survival in the lungs. The adoptive transfer of wild type bone marrow-derived monocytes into L-selectin deficient mice ameliorated metastatic development in the lungs.
In the liver, we observed increased amounts of Kupffer and γδ T cells in the absence of L-selectin. Furthermore, L-selectin facilitated the recruitment of neutrophils into the metastatic liver. We showed that liver neutrophils produce reactive oxygen species in vivo, and increased tumor cell apoptosis in vitro. Depleting neutrophils at later metastatic stages increased liver metastasis, confirming the cytotoxic function of neutrophils.
In summary, we identified an opposing role of L-selectin on metastatic development in the lungs and the liver. In the lungs, L-selectin mediates the recruitment of monocytes that promote tumor cell extravasation and support metastatic development. Our study demonstrated the contribution of myeloid cell populations to tissue-specific metastasis and defined a novel role of L-selectin during metastatic progression.

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Additional indexing

Item Type:Dissertation
Referees:Borsig Lubor, Müller Anne, Hennet Thierry, Halin Cornelia
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:12 September 2017
Deposited On:19 Dec 2017 13:46
Last Modified:30 Jul 2018 04:14
Funders:Swiss National Science Foundation
OA Status:Green
Project Information:
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSwiss National Science Foundation

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