Die Auswirkungen des Vascular Endothelial Growth Factors aus myeloischen Zellen und des Mikromilieus auf Tumorrezidive und Metastasierung nach Therapie
Final Report Abstract
Chemotherapy remains a mainstay of cancer treatment but its use is often limited by the development of adverse reactions. Severe loss of body weight (cachexia) is a frequent cause of death in cancer patients and is exacerbated by chemotherapy. Surprisingly, we found that genetic inactivation of vascular endothelial growth factor (VEGF)-A in myeloid cells prevents chemotherapy-induced cachexia by inhibiting skeletal muscle loss and the lipolysis of white adipose tissue. It also improves clearance of senescent tumour cells by natural killer cells and inhibits tumour regrowth after chemotherapy. The effects depend on the chemoattractant chemerin, which is released by the tumour endothelium in response to chemotherapy. The findings define chemerin as a critical mediator of the immune response, as well as an important inhibitor of cancer cachexia. Targeting myeloid cell-derived VEGF signalling should impede the lipolysis and weight loss that is frequently associated with chemotherapy, thereby substantially improving the therapeutic outcome. Our study reveals that chemotherapy with cisplatin simulates tumour endothelial cells to release chemerin. We show further that chemerin is a critical mediator of NK cell-mediated antitumour defenses as well as of cachexia. VEGF-A derived from myeloid cells suppresses the stimulation of endothelial chemerin release by chemotherapy. Hence, targeting VEGF signaling should impede the lipolysis and weight loss that is frequently associated with chemotherapy. Our study therefore offers novel therapeutic avenues to improve the overall outcome of chemotherapy.
Publications
- Resolution of liver fibrosis requires myeloid cell-driven sinusoidal angiogenesis. Hepatology 2015; 61(6):2042-55
Kantari-Mimoun S, Castells M, Klose R, Meinecke Ak, Lemberger Uj, Rautou Pe, Pinot-Roussel H, Badoual C, Schrödter K, Osterreicher Ch, Fandrey J, Stockmann C
(See online at https://doi.org/10.1002/hep.27635) - VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med 2015 Feb 9;212(2):139-48
Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, Latreche S, Bergaya S, Benhamouda N, Tanchot C, Stockmann C, Combe P, Berger A, Zinzindohoué F, Yagita H, Tartour E, Taieb J, Terme M
(See online at https://doi.org/10.1084/jem.20140559) - Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Coordinately Improve Remodeling After Myocardial Infarction via Local Delivery of Vascular Endothelial Growth Factor. Circulation. 2016 Mar 1;133(9):826-39
Howangyin KY, Zlatanova I, Pinto C, Ngkelo A, Cochain C, Rouanet M, Vilar J, Lemitre M, Stockmann C, Fleischmann BK, Mallat Z, Silvestre JS
(See online at https://doi.org/10.1161/CIRCULATIONAHA.115.020857) - STAT5 Is a Key Regulator in NK Cells and Acts as a Molecular Switch from Tumor Surveillance to Tumor Promotion. Cancer Discov. 2016 Apr;6(4):414-29
Gotthardt D, Putz EM, Grundschober E, Prchal-Murphy M, Straka E, Kudweis P, Heller G, Bago- Horvath Z, Witalisz-Siepracka A, Cumaraswamy AA, Gunning PT, Strobl B, Müller M, Moriggl R, Stockmann C, Sexl V
(See online at https://doi.org/10.1158/2159-8290.CD-15-0732) - Targeting VEGF-A in myeloid cells enhances natural killer cell responses to chemotherapy and ameliorates cachexia. Nat Commun 2016; 7:12528
Ralph Klose, Ewelina Krzywinska, Magali Castells, Dagmar Gotthardt, Eva Maria Putz, Chahrazade Kantari-Mimoun, Naima Chikdene, Anna-Katharina Meinecke, Katrin Schrödter, Iris Helfrich, Joachim Fandrey, Veronika Sexl & Christian Stockmann
(See online at https://doi.org/10.1038/ncomms12528) - Boosting the hypoxic response in myeloid cells accelerates fibrosis resolution and regeneration of the liver in mice. Oncotarget. 2017 Feb 28;8(9):15085-15100
Chahrazade Kantari-Mimoun, Ewelina Krzywinska, Magali Castells, Ralph Klose, Anna- Katharina Meinecke, Ursula Lemberger, Milos Gojkovic, Katrin Schrödter, Christoph Österreicher, Joachim Fandrey, Helene Rundqvist, Christian Stockmann
(See online at https://doi.org/10.18632/oncotarget.14749) - Loss of HIF-1α in Natural Killer cells inhibits tumour growth by stimulating non-productive angiogenesis. Nat Commun 2017 Nov 17;8(1):1597
Krzywinska E, Kantari-Mimoun C, Kerdiles Y, Sobecki M, Isagawa T, Gotthardt D, Castells M, Haubold J, Millien C, Viel T, Tavitian B, Takeda N, Fandrey J, Vivier E, Sexl V, Stockmann C
(See online at https://doi.org/10.1038/s41467-017-01599-w)
