Universität zu Köln

Meumann, Nadja, Schmithals, Christian, Elenschneider, Leroy, Hansen, Tanja, Balakrishnan, Asha, Hu, Qingluan, Hook, Sebastian, Schmitz, Jessica ORCID: 0000-0001-9843-7339, Braesen, Jan Hinrich, Franke, Ann-Christin, Olarewaju, Olaniyi, Brandenberger, Christina, Talbot, Steven R., Fangmann, Josef, Hacker, Ulrich T., Odenthal, Margarete ORCID: 0000-0002-2424-0960, Ott, Michael, Piiper, Albrecht and Buening, Hildegard (2022). Hepatocellular Carcinoma Is a Natural Target for Adeno-Associated Virus (AAV) 2 Vectors. Cancers, 14 (2). BASEL: MDPI. ISSN 2072-6694

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Abstract

Simple Summary Gene therapy is a novel approach to treat diseases by introducing corrective genetic information into target cells. Adeno-associated virus vectors are the most frequently applied gene delivery tools for in vivo gene therapy and are also studied as part of innovative anticancer strategies. Here, we report on the natural preference of AAV2 vectors for hepatocellular carcinoma (HCC) compared to nonmalignant liver cells in mice and human tissue. This preference in transduction is due to the improved intracellular processing of AAV2 vectors in HCC, resulting in significantly more vector genomes serving as templates for transcription in the cell nucleus. Based on this natural tropism for HCC, novel therapeutic strategies can be designed or existing therapeutic approaches can be strengthened as they currently result in only a minor improvement of the poor prognosis for most liver cancer patients. Although therapeutic options are gradually improving, the overall prognosis for patients with hepatocellular carcinoma (HCC) is still poor. Gene therapy-based strategies are developed to complement the therapeutic armamentarium, both in early and late-stage disease. For efficient delivery of transgenes with antitumor activity, vectors demonstrating preferred tumor tropism are required. Here, we report on the natural tropism of adeno-associated virus (AAV) serotype 2 vectors for HCC. When applied intravenously in transgenic HCC mouse models, similar amounts of vectors were detected in the liver and liver tumor tissue. In contrast, transduction efficiency, as indicated by the level of transgene product, was moderate in the liver but was elevated up to 19-fold in mouse tumor tissue. Preferred transduction of HCC compared to hepatocytes was confirmed in precision-cut liver slices from human patient samples. Our mechanistic studies revealed that this preference is due to the improved intracellular processing of AAV2 vectors in HCC, resulting, for example, in nearly 4-fold more AAV vector episomes that serve as templates for gene transcription. Given this background, AAV2 vectors ought to be considered to strengthen current-or develop novel-strategies for treating HCC.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Meumann, Nadja UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmithals, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Elenschneider, Leroy UNSPECIFIED UNSPECIFIED UNSPECIFIED Hansen, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Balakrishnan, Asha UNSPECIFIED UNSPECIFIED UNSPECIFIED Hu, Qingluan UNSPECIFIED UNSPECIFIED UNSPECIFIED Hook, Sebastian UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmitz, Jessica UNSPECIFIED orcid.org/0000-0001-9843-7339 UNSPECIFIED Braesen, Jan Hinrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Franke, Ann-Christin UNSPECIFIED UNSPECIFIED UNSPECIFIED Olarewaju, Olaniyi UNSPECIFIED UNSPECIFIED UNSPECIFIED Brandenberger, Christina UNSPECIFIED UNSPECIFIED UNSPECIFIED Talbot, Steven R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Fangmann, Josef UNSPECIFIED UNSPECIFIED UNSPECIFIED Hacker, Ulrich T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Odenthal, Margarete UNSPECIFIED orcid.org/0000-0002-2424-0960 UNSPECIFIED Ott, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Piiper, Albrecht UNSPECIFIED UNSPECIFIED UNSPECIFIED Buening, Hildegard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-691398
DOI:	10.3390/cancers14020427
Journal or Publication Title:	Cancers
Volume:	14
Number:	2
Date:	2022
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEPATOCYTE GROWTH-FACTOR; HEPARAN-SULFATE PROTEOGLYCAN; IN-VIVO TRANSDUCTION; GENE-EXPRESSION; LIVER-CANCER; FACTOR RECEPTOR; THERAPY; TUMORIGENESIS; MODEL; PROGRESSION Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69139