Molekulare Mechanismen der antiangiogenen Krebstherapie: Präklinische Entwicklung von anti-PIGF Antikörpern für das metastatische kolorektale Karzinom
Final Report Abstract
Following cardiovascular diseases, cancer represents the second most common cause of death in the western world. In 2008 the world health organization (WHO) estimated 12,7 million new cancer cases, of those cases 7.6 million people die of cancer. Cancer is a heterogeneous class of diseases, which arises from normal cells giving rise to a malignant neoplastic cell with uncontrolled growth and spread throughout the body. Most cancers form solid tumors like carcinomas, sarcomas, germ cell tumors, blastomas or lymphomas, however some cancer arise from the cells of the blood and bone marrow like leukemias. Currently individual types of therapy are available for the different subgroups of cancers. The main pillars of cancer therapy are based on surgery, chemotherapy including targeted and immunotherapy, and radiotherapy. These therapies are combined to achieve the optimal outcome, however not every patient can be cured and many cancers are either diagnosed already too late, or they can find escape mechanisms from the currently used treatments. In the last decades cancer research has vastly expanded our knowledge of the disease. Initially, research was focused on the malignant cell itself, however, this view did not take into account that a variety of mesenchymal and immune cell types as well as extracellular matrix surround and interact with the neoplastic cells. During the progression of cancer, this surrounding microenvironment develops into an activated state through continuous communication, and thereby creates a supportive surrounding that promotes cancer initiation and growth, and eventually the progress to a fatal disease. Interestingly this interaction with the tumor microenvironment does not only occur in solid tumors, but also in leukemias. This thesis was focused on the role of the receptor tyrosine kinase-ligands PlGF and Gas6 in the microenvironment of solid tumors and leukemias. In the first part of this work we found that PlGF plays a role in chronic myeloid leukemia. We discovered that the angiogenic factor PlGF is upregulated in the bone marrow plasma and peripheral blood of both CML mice as well as human CML patients. Also here the leukemia cells do not produce PlGF autonomously, but CML cells induce bone marrow stromal cells to upregulate PlGF in a NF-κB dependent manner. PlGF not only promoted CML cell proliferation and metabolism in a BCR-ABL1 independent pathway, but also stimulated bone marrow angiogenesis and fibrosis. Treatment of leukemic mice with an anti-PlGF antibody prolonged survival in both imatinib-sensitive as well as in resistant CML mice. CML models in PlGF-/- mice reconfirmed this. Interestingly this beneficial effect of anti-PlGF treatment acted additive to imatinib treatment, arguing for a BCR-ABL1 independent mechanism. In the second part of this work we discovered that bone marrow derived Gas6 promoted tumor growth and metastasis in different experimental cancer models via the Axl receptor. Already previously the tumor growth promoting and transforming properties of the tyrosine kinase receptor Axl, belonging to the TAMR (Tyro3, Axl and Mer receptor) family, were well recognized, however little was known about Gas6 in tumor biology. In this study we found that tumor-infiltrating leukocytes are educated by the tumor microenvironment to produce elevated levels of Gas6 and this upregulation took particularly place in macrophages. Elevated levels of Gas6 lead to tumor cell proliferation both in vitro and in vivo. Consistent with these finding, the reduced tumor growth in Gas6-/- mice could be rescued by the transplantation of wild-type bone marrow. Vice versa transplantation of Gas6-/- bone marrow into wild-type mice mimicked the impaired tumor growth in Gas6-/- mice. Mechanistically we found that tumor cells educated infiltrating leukocytes to upregulated Gas6 by expressing IL-10 and M-CSF leading to a positive amplification loop in the tumor. In summary we found that Gas6 and PlGF are stromal derived factor supporting tumor progression in solid tumors and leukemias respectively. Based on our results, both might represent interesting novel microenvironmental targets for cancer therapy.
Publications
- Genetics, epigenetics and pharmaco-(epi)genomics in angiogenesis. J Cell Mol Med. 2008 Dec;12(6B):2533-51
Buysschaert I, Schmidt T, Roncal C, Carmeliet P, Lambrechts D
- Influence of two different resection techniques (conventional liver resection versus anterior approach) of liver metastases from colorectal cancer on hematogenous tumor cell dissemination - prospective randomized multicenter trial. BMC Surg. 2008 Mar 5;8:6
Schmidt T, Koch M, Antolovic D, Reissfelder C, Schmitz-Winnenthal FH, Rahbari NN, Schmidt J, Seiler CM, Büchler MW, Weitz J
- Ischemic colitis: analysis of risk factors for postoperative mortality. Langenbecks Arch Surg. 2008 Jul;393(4):507-12
Antolovic D, Koch M, Hinz U, Schöttler D, Schmidt T, Heger U, Schmidt J, Büchler MW, Weitz J
- "Antimyeloangiogenic" therapy for cancer by inhibiting PlGF. Clin Cancer Res. 2009 Jun 1;15(11):3648-53
Loges S, Schmidt T, Carmeliet P
- Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization. Cell. 2009 Mar 6;136(5):839-51
Mazzone M, Dettori D, Leite de Oliveira R, Loges S, Schmidt T, Jonckx B, Tian YM, Lanahan AA, Pollard P, Ruiz de Almodovar C, De Smet F, Vinckier S, Aragonés J, Debackere K, Luttun A, Wyns S, Jordan B, Pisacane A, Gallez B, Lampugnani MG, Dejana E, Simons M, Ratcliffe P, Maxwell P, Carmeliet P
- IVC CLAMP: infrahepatic inferior vena cava clamping during hepatectomy--a randomised controlled trial in an interdisciplinary setting. Trials. 2009 Oct 13;10:94
Rahbari NN, Zimmermann JB, Koch M, Bruckner T, Schmidt T, Elbers H, Reissfelder C, Weigand MA, Büchler MW, Weitz J
- Meta-analysis of standard, restrictive and supplemental fluid administration in colorectal surgery. Ann Surg Oncol. 2009 Mar;16(3):630-9
Rahbari NN, Zimmermann JB, Schmidt T, Koch M, Weigand MA, Weitz J
- Meta-analysis of the clamp-crushing technique for transection of the parenchyma in elective hepatic resection: back to where we started? Ann Surg Oncol. 2009 Mar;16(3):630-9
Rahbari NN, Koch M, Schmidt T, Motschall E, Bruckner T, Weidmann K, Mehrabi A, Büchler MW, Weitz J
- Regulation of angiogenesis by oxygen and metabolism. Dev Cell. 2009 Feb;16(2):167-79
Fraisl P, Mazzone M, Schmidt T, Carmeliet P
- Bridges that guide and unite. Nature. 2010 Jun 10;465(7299):697-9
Schmidt T, Carmeliet P
- Further pharmacological and genetic evidence for the efficacy of PlGF inhibition in cancer and eye disease. Cell. 2010 Apr 2;141(1):178-90
Van de Veire S, Stalmans I, Heindryckx F, Oura H, Tijeras-Raballand A, Schmidt T, Loges S, Albrecht I, Jonckx B, Vinckier S, Van Steenkiste C, Tugues S, Rolny C, De Mol M, Dettori D, Hainaud P, Coenegrachts L, Contreres JO, Van Bergen T, Cuervo H, Xiao WH, Le Henaff C, Buysschaert I, Kharabi Masouleh B, Geerts A, Schomber T, Bonnin P, Lambert V, Haustraete J, Zacchigna S, Rakic JM, Jiménez W, Noël A, Giacca M, Colle I, Foidart JM, Tobelem G, Morales-Ruiz M, Vilar J, Maxwell P, Vinores SA, Carmeliet G, Dewerchin M, Claesson-Welsh L, Dupuy E, Van Vlierberghe H, Christofori G, Mazzone M, Detmar M, Collen D, Carmeliet P
- Malignant cells fuel tumor growth by educating infiltrating leukocytes to produce the mitogen Gas6. Blood. 2010 Mar 18; 115(11):2264-73
Loges S, Schmidt T, Tjwa M, van Geyte K, Lievens D, Lutgens E, Vanhoutte D, Borgel D, Plaisance S, Hoylaerts M, Luttun A, Dewerchin M, Jonckx B, Carmeliet P
- Mechanisms of resitance to anti-angiogenic therapy and development of third generation anti-angiogenic drug candidates. Genes & Cancer 2010 Jan 1(1):12-2
Loges S, Schmidt T, Carmeliet P
- Infrahepatic inferior vena cava clamping for reduction of central venous pressure and blood loss during hepatic resection: A randomized controlled trial. Ann Surg 2011 Jun; 253(6):1102-10
Rahbari NN, Koch M, Zimmermann JB, Elbers H, Bruckner H, Contin P, Reissfelder C, Schmidt T, Weigand MA, Martin E, Büchler MW, Weitz J
- Loss or inhibition of stroma-derived PlGF prolongs survival of mice with imatinib-resistant BCR-AL1+ leukemia. Cancer Cell (2011)
Schmidt T, Kharabi Masouleh B, Loges S, Cauwenberghs S, Fraisl P, Maes C, Jonckx B, de Keersmaecker K, Kleppe M, Tjwa M, Schenk T, Vinckier S, Fragoso R, de Mol M, Beel K, Dias S, Verfaillie C, Clark RH, Bummendorf TH, Vandenberghe P, Rafii S, Holyoake T, Hochhaus A, Cools J, Karin M, Carmeliet G, Dewerchin M, Carmeliet P
(See online at https://doi.org/10.1016/j.ccr.2011.05.007)
