Tissue-specific promoters active in CD44+CD24-/low breast cancer cells.
It has been proposed that human tumors contain stem cells that have a central role in tumor initiation and posttreatment relapse. Putative breast cancer stem cells may reside in the CD44(+)CD24(-/low) population. Oncolytic adenoviruses are attractive for killing of these cells because they enter through infection and are therefore not susceptible to active and passive mechanisms that render stem cells resistant to many drugs. Although adenoviruses have been quite safe in cancer trials, preclinical work suggests that toxicity may eventually be possible with more active agents. Therefore, restriction of virus replication to target tissues with tissues-specific promoters is appealing for improving safety and can be achieved without loss of efficacy. We extracted CD44(+)CD24(-/low) cells from pleural effusions of breast cancer patients and found that modification of adenovirus type 5 tropism with the serotype 3 knob increased gene delivery to CD44(+)CD24(-/low) cells. alpha-Lactalbumin, cyclo-oxygenase 2, telomerase, and multidrug resistance protein promoters were studied for activity in CD44(+)CD24(-/low) cells, and a panel of oncolytic viruses was subsequently constructed. Each virus featured 5/3 chimerism of the fiber and a promoter controlling expression of E1A, which was also deleted in the Rb binding domain for additional tumor selectivity. Cell killing assays identified Ad5/3-cox2L-d24 and Ad5/3-mdr-d24 as the most active agents, and these viruses were able to completely eradicate CD44(+)CD24(-/low) cells in vitro. In vivo, these viruses had significant antitumor activity in CD44(+)CD24(-/low)-derived tumors. These findings may have relevance for elimination of cancer stem cells in humans.
Bauerschmitz
Gerd J
GJ
Cancer Gene Therapy Group, Molecular Cancer Biology Program and Transplantation Laboratory, University of Helsinki, Helsinki, Finland.
Ranki
Tuuli
T
Kangasniemi
Lotta
L
Ribacka
Camilla
C
Eriksson
Minna
M
Porten
Marius
M
Herrmann
Isabell
I
Ristimäki
Ari
A
Virkkunen
Pekka
P
Tarkkanen
Maija
M
Hakkarainen
Tanja
T
Kanerva
Anna
A
Rein
Daniel
D
Pesonen
Sari
S
Hemminki
Akseli
A
D017500:Adenovirus E1A Proteins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051927:CD24 Antigen / Q000096:biosynthesis*; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis*; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods; D050504:Oncolytic Viruses / Q000378:metabolism; D011401:Promoter Regions, Genetic
D017500:Adenovirus E1A Proteins; D000970:Antineoplastic Agents; D051927:CD24 Antigen; D018960:Hyaluronan Receptors