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In vivo histone H1 migration from necrotic to viable tissue.

ABSTRACT: Necrosis is induced by ischemic conditions within the core of many solid tumors. Using fluorescent fusion proteins, we provide in vivo evidence of histone trafficking among cancer cells in implanted tumors. In particular, the most abundant H1 isoform (H1.2) was found to be transported from necrotic tumor cells into surrounding viable cells where histones are selectively taken up by energy-dependent endocytosis. We propose that intercellular histone trafficking could function as a target for drug delivery. This concept was validated using an anti-histone antibody that was co-internalized with histones from dead cells into viable ones surrounding the necrotic regions of a tumor, where some of the most chemoresistant cells reside. These findings demonstrate that cellular translocation of conjugated drugs using anti-histone antibodies is a promising strategy for targeted drug delivery to chemoresistant tumors.

SUBMITTER: Luhrs KA

PROVIDER: S-EPMC5369962 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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In vivo histone H1 migration from necrotic to viable tissue.

Luhrs Keith A KA Pink Desmond D Schulte Wendy W Zijlstra Andries A Lewis John D JD Parseghian Missag H MH

Oncotarget 20170301 10

Necrosis is induced by ischemic conditions within the core of many solid tumors. Using fluorescent fusion proteins, we provide in vivo evidence of histone trafficking among cancer cells in implanted tumors. In particular, the most abundant H1 isoform (H1.2) was found to be transported from necrotic tumor cells into surrounding viable cells where histones are selectively taken up by energy-dependent endocytosis. We propose that intercellular histone trafficking could function as a target for drug ...[more]

PMID: 28187445

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Project description:Study questionIs it possible to establish an ex vivo endometriosis model using cryopreserved endometriotic tissue fragments?Summary answerCryopreserved endometriotic tissue fragments remain viable after thawing and during at least 3 days of culture and can therefore be used to establish an ex vivo endometriosis model to efficiently test potential therapeutic agents.What is known alreadyEndometriosis is the most prevalent benign gynecologic disease with an enormous societal burden; however, curative therapies are still lacking. To efficiently test potential new therapies, an ex vivo model based on previously cryopreserved endometriotic tissue that recapitulates the different endometriosis subtypes and their microenvironment is highly desirable.Study design, size, durationEndometriotic tissue fragments of three different subtypes were obtained from 28 patients by surgical resection. After cryopreservation and thawing, viability and metabolic activity of these tissue fragments were assessed. Viability was compared with fresh fragments from 11 patients directly after surgical removal. Experimental intervention studies were performed in cryopreserved and thawed tissue fragments from two patients to confirm the usability of these tissues for ex vivo intervention studies.Participants/materials, setting, methodsEndometriotic tissue fragments (n = 45) were cryopreserved according to three different protocols. After thawing, fragments were cultured for 24 h. A resazurin-based assay was performed to assess the metabolic activity of the tissue fragments. In addition, cell type-specific viability was analyzed by VivaFix, Hoechst 33342, and α-smooth muscle actin immunofluorescence staining and confocal microscopy. The presence of endometriosis was histologically confirmed based on hematoxylin-eosin staining. Cryopreserved and thawed tissue fragments were treated for 72 h with pirfenidone or metformin and COL1A1 and CEMIP gene expressions were assessed using RT-PCR and RT-qPCR, either in the whole tissue fragments or in myofibroblasts isolated by laser capture microdissection.Main results and the role of chanceMetabolic activity of endometriotic tissue fragments obtained from peritoneal (PER), ovarian (OMA), and deep (DE) endometriotic lesions was well preserved after cryopreservation in a dimethyl sulfoxide-based medium and was comparable with fresh tissue fragments. Relative metabolic activity compared to fresh tissue was 70% (CI: 92-47%) in PER, 43% (CI: 53-15%) in OMA and 94% (CI: 186-3%) in DE lesions. In fragments from PE lesions 92% (CI: 87-96%), from OMA lesions 95% (CI: 91-98%), and from DE lesions 88% (CI: 78-98%) of cells were viable after cryopreservation and thawing followed by a 24-h culture period. Differences in gene expression of fibrotic markers COL1A1 and CEMIP after 72-h treatment with pirfenidone or metformin could be detected in whole tissue fragments and in isolated myofibroblasts, indicating that cryopreserved and thawed endometriotic tissue fragments are suitable for testing anti-fibrotic interventions.Large scale dataN/A.Limitations, reasons for cautionViability and metabolic activity of the endometriotic tissue fragments may have been partially compromised by damage sustained during the surgical procedure, contributing to inter-sample variance.Wider implications of the findingsThe storage of viable endometriotic tissue fragments for later usage in an ex vivo model creates the possibility to efficiently test potential new therapeutic strategies and facilitates the exchange of viable endometriotic tissue between different research laboratories.Study funding/competing interest(s)This study was not financially supported by external funding. The authors declare no competing interest.Trial registration numberN/A.

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In vivo histone H1 migration from necrotic to viable tissue.

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In vivo histone H1 migration from necrotic to viable tissue.

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