ITEM METADATA RECORD
Title: Ontrafelen van de rol van autofagie in cutane maligne melanomen
Other Titles: Unraveling the role of autophagy in cutaneous malignant melanoma
Authors: Maes, Hannelore
Issue Date: 16-Dec-2013
Abstract: Patrizia 14.00 <span style="font-size:12.0pt;line-height:150%;font-family:&quot;Times New Roman&quot;,&quot;serif&quot;;mso-ansi-language:EN-US" lang="EN-US">In advanced cancer, autophagy, an evolutionaryconserved catabolic process, has been reported to support tumor progression.Based on this premise, clinical trials have been initiated to evaluate thepossible benefit of the autophagy blocker chloroquine (CQ) for the treatment ofadvanced cancers, with promising results. However, studies addressing theresponsible mechanism of action of CQ are scarce and the effect of CQ cannotalways be reproduced by knocking down key autophagy genes. Moreover,preclinical studies addressing the role of autophagy inhibition –eitherpharmacological or genetic- mainly focus on tumor cells themselves, althoughthe tumor micro-environment is emerging as an important determinant in tumorprogression and therapy resistance. Therefore, in this study we set out toelucidate the mechanisms underlying the effects of CQ in anti-cancer therapy aswell as to compare the impact of chloroquine or genetic inhibition of autophagyon the tumor-microenvironment. <span style="font-size:12.0pt;line-height:150%;font-family:&quot;Times New Roman&quot;,&quot;serif&quot;;mso-ansi-language:EN-US" lang="EN-US">Here, using 2 transplantable mouse melanoma models, wereport that in vivo knockdown of thekey autophagy gene Atg5 in the cancer cells or knockout of ATg5 in theendothelial cells, significantly decreased tumor growth, whereas the effect ofCQ on tumor growth was dependent on the cancer cell line and the doseadministered. Intriguingly, detailed analysis of the tumors revealed that CQhad a striking effect on the tumor micro-environment, which was not phenocopiedby reducing autophagic flux in the cancer cells (shRNA Atg5) or in theendothelial cells (shRNA targeting ATg5 invitro and an endothelial-cell specific Atg5 knockout mouse model in vitro). CQ treated tumors were lesshypoxic and necrotic, and displayed reduced invasiveness and metastasis. CQtreatment also significantly improved the response to chemotherapy. We foundthat the beneficial effects exerted by CQ on the tumor micro-environment weremediated by its ability to ameliorate tumor vessel structure and function, aphenomenon described as tumor vessel normalization. At the mechanistic level, thevascular normalizing effects of CQ were ascribed to the unique ability of CQ toinduce a quiescent endothelial cell phenotype by increasing Notch signaling inthe late endosomal compartment. These results provide new insights into theunderlying mechanism of CQ anti-tumor action and further support the use of CQas a new tumor “vessel normalization” agent in the clinic. 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Publication status: published
KU Leuven publication type: TH
Appears in Collections:Laboratory of Cell Death Research & Therapy
Laboratory of Dermatology

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