Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice
| Autor: | Mauro Delorenzi, Alan Guichard, Roberta Bianchi, Sabrina Cavin, Sina Nassiri, Alejandra González-Loyola, Borja Prat-Luri, Jaeryung Kim, Matthias P. Lutolf, Mario Leonardo Squadrito, David Barras, Jean Yannis Perentes, Michele De Palma, Laureline Wetterwald, Guillermo Oliver, Tatiana V. Petrova, Giancarlo Marra, Nikolce Gjorevski, Simone Ragusa, Emily Corse |
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| Přispěvatelé: | University of Zurich, Petrova, Tatiana V |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Vascular Endothelial Growth Factor A Stromal cell Angiogenesis Colorectal cancer medicine.medical_treatment Adenomatous Polyposis Coli Protein 610 Medicine & health Angiogenesis Inhibitors 2700 General Medicine Cell Line Angiopoietin-2 03 medical and health sciences Mice 0302 clinical medicine Antineoplastic Agents Immunological Cancer immunotherapy medicine Matrix Metalloproteinase 14 Animals Humans Homeodomain Proteins Neovascularization Pathologic business.industry Tumor Suppressor Proteins 10061 Institute of Molecular Cancer Research Wnt signaling pathway General Medicine Immunotherapy Neoplasms Experimental medicine.disease Vascular endothelial growth factor A 030104 developmental biology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer cell Cancer research Commentary 570 Life sciences biology business Colorectal Neoplasms |
| Zdroj: | J Clin Invest Journal of Clinical Investigation |
| ISSN: | 1558-8238 |
| Popis: | Mutations in APC promote colorectal cancer (CRC) progression through uncontrolled WNT signaling. Patients with desmoplastic CRC have a significantly worse prognosis and do not benefit from chemotherapy, but the mechanisms underlying the differential responses of APC-mutant CRCs to chemotherapy are not well understood. We report that expression of the transcription factor prospero homeobox 1 (PROX1) was reduced in desmoplastic APC-mutant human CRCs. In genetic Apc-mutant mouse models, loss of Prox1 promoted the growth of desmoplastic, angiogenic, and immunologically silent tumors through derepression of Mmp14. Although chemotherapy inhibited Prox1-proficient tumors, it promoted further stromal activation, angiogenesis, and invasion in Prox1-deficient tumors. Blockade of vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2) combined with CD40 agonistic antibodies promoted antiangiogenic and immunostimulatory reprogramming of Prox1-deficient tumors, destroyed tumor fibrosis, and unleashed T cell–mediated killing of cancer cells. These results pinpoint the mechanistic basis of chemotherapy-induced hyperprogression and illustrate a therapeutic strategy for chemoresistant and desmoplastic CRCs. |
| Databáze: | OpenAIRE |
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