On the mechanisms and consequences of cell to cell DNA transfer
Author: Ehnfors, Jacob
Date: 2007-12-14
Location: Cancer Centrums Karolinskas föreläsningssal, entréplan, Karolinska Universitetssjukhsuet, Solna
Time: 09.30
Department: Institutionen för onkologi-patologi / Department of Oncology-Pathology
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thesis.pdf (845.4Kb)
Abstract
Development of cancer is a multistep process where an accumulation of
genetic alterations drives normal cells to malignancy. In most cancer
cells genetic changes can be observed both at the level of point
mutations and as gains and losses of chromosomes. The eukaryotic cell has
a complex protection system to recognize genetic alterations and, in the
case of oncogene activation or severe DNA damage, direct the cell to
undergo apoptosis. One of the morphological attributes initially used to
define apoptosis is the fragmentation of DNA and the formation of
apoptotic bodies. In healthy tissues apoptotic cells are rapidly
phagocytosed by neighboring cells. Dying cells can thereby be cleared
without leakage of harmful enzymes or eliciting an inflammatory response.
The fragmentation of DNA that occurs in apoptotic cells is complemented
by DNases in the phagocytosing cell, which ensure the destruction of
potentially harmful DNA. However, it has been recently demonstrated that
genes from apoptotic cells can avoid fragmentation and be salvaged and
reutilized by the phagocytosing cell. This newly recognized mechanism of
introducing foreign DNA is efficient since 15 percent of bovine aortic
endothelial cells have been demonstrated to display uptake of apoptotic
DNA and express this DNA. Furthermore, normal cells have been reported to
be protected from propagation of DNA recovered from dying cells by the
p53-p21 signaling pathway.
This thesis demonstrates that DNA from apoptotic cells can enter the
nucleus of phagocytosing cells by a previously undescribed mechanism of
nuclear fusion named Pirinosis as an acronym of the Greek words Pirinas
(nucleus) and Enosis (union). The degree of DNA fragmentation after
phagocytosis is demonstrated to be crucial for signaling via the
Chk2-p53-p21 pathway. Furthermore, DNA fragments within the nucleus of
phagocytes are demonstrated to co-localize with early markers of the DNA
damage pathway.
Others have shown that endothelial cells in the tumor microenvironment
display genetic alterations and aneuploidy and hence the dogma that
diploid cells of the blood vessel wall are stable is challenged. This
turned our focus to horizontal gene transfer between tumor cells and the
surrounding stroma. Tumor associated endothelial cells isolated from rat
tumors grown in mice displayed the same karyotype and inter-species
chromosome fusions as detected after uptake of DNA from apoptotic cells
in vitro. The hybrid tumor associated endothelial cells are shown to be
functional in forming blood vessels that anastamose with the host
circulatory system. We argue that phagocytosis of dying tumor cells by
endothelial cells may create viable hybrid cells that are capable of
creating functional vessels in vivo.
List of papers:
I. Bergsmedh A, Ehnfors J, Kawane K, Motoyama N, Nagata S, Holmgren L. (2006). "DNase II and the Chk2 DNA damage pathway form a genetic barrier blocking replication of horizontally transferred DNA." Mol Cancer Res 4(3): 187-95
Pubmed
II. Bergsmedh A, Ehnfors J, Spetz AL, Holmgren L. (2007). "A Cre-loxP based system for studying horizontal gene transfer." FEBS Lett 581(16): 2943-6
Pubmed
III. Ehnfors J, Kost-Alimova M, Bergsmedh A, Castro J, Levchenko-Tegnebratt T, Luna Persson N, Holmgren L (1970). "Horizontal gene transfer in the tumor microenvironment" (Submitted)
IV. Ehnfors J, Bergsmedh A, Kost-Alimova M, Holmgren L (1970). "Pirinosis: mechanism of horizontal transfer of DNA by uptake of apoptotic cells." (Submitted)
I. Bergsmedh A, Ehnfors J, Kawane K, Motoyama N, Nagata S, Holmgren L. (2006). "DNase II and the Chk2 DNA damage pathway form a genetic barrier blocking replication of horizontally transferred DNA." Mol Cancer Res 4(3): 187-95
Pubmed
II. Bergsmedh A, Ehnfors J, Spetz AL, Holmgren L. (2007). "A Cre-loxP based system for studying horizontal gene transfer." FEBS Lett 581(16): 2943-6
Pubmed
III. Ehnfors J, Kost-Alimova M, Bergsmedh A, Castro J, Levchenko-Tegnebratt T, Luna Persson N, Holmgren L (1970). "Horizontal gene transfer in the tumor microenvironment" (Submitted)
IV. Ehnfors J, Bergsmedh A, Kost-Alimova M, Holmgren L (1970). "Pirinosis: mechanism of horizontal transfer of DNA by uptake of apoptotic cells." (Submitted)
Issue date: 2007-11-23
Rights:
Publication year: 2007
ISBN: 978-91-7357-455-6
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