title: Mesenchymal stem cells expressing therapeutic genes induce autochthonous prostate tumour regression.
abstract: Mesenchymal stem cells (MSC) as vehicles of therapeutic genes represent a unique tool to activate drugs within a neoplastic mass due to their property to home and engraft into tumours. In particular, MSC expressing the cytosine deaminase::uracil phosphoribosyltransferase (CD-MSC) have been previously demonstrated to inhibit growth of subcutaneous prostate cancer xenografts thanks to their ability to convert the non-toxic 5-fluorocytosine into the antineoplastic 5-fluorouracil. Since both the immune system and the tumour microenvironment play a crucial role in directing cancer progression, in order to advance towards clinical applications, we tested the therapeutic potential of this approach on animal models that develop autochthonous prostate cancer and preserve an intact immune system. As cell vectors, we employed adipose-tissue and bone-marrow MSC. CD-MSC toxicity on murine prostate cancer cells and tumour tropism were verified in vitro and ex-vivo before starting the preclinical studies. Magnetic Resonance Imaging was utilised to follow orthotopic tumour progression. We demonstrated that intravenous injections of CD-MSC cells, followed by intraperitoneal administration of 5-fluorocytosine, caused tumour regression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, which develops aggressive and spontaneous prostate cancer. These results add new insights to the therapeutic potential of specifically engineered MSC in prostate cancer disease.
authors: Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Alberto
authors: A
authors: Abrate
authors: Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Roberta
authors: R
authors: Buono
authors: Department of Radiology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Tamara
authors: T
authors: Canu
authors: Department of Radiology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Antonio
authors: A
authors: Esposito
authors: Department of Radiology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Alessandro
authors: A
authors: Del Maschio
authors: Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Department of Pathology, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Roberta
authors: R
authors: Lucianò
authors: Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Arianna
authors: A
authors: Bettiga
authors: Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Giorgia
authors: G
authors: Colciago
authors: Department of Urology, IRCCS Ospedale San Raffaele, Turro, Milan, Italy.
authors: Giorgio
authors: G
authors: Guazzoni
authors: Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Fabio
authors: F
authors: Benigni
authors: Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy; Department of Clinical Pharmacology, Linköping University, Sweden.
authors: Petter
authors: P
authors: Hedlund
authors: Cancer Research Institute, Slovak Academy of Sciences and St. Elisabeth Cancer Institute, Bratislava, Slovakia.
authors: Cestmir
authors: C
authors: Altaner
authors: Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy.
authors: Francesco
authors: F
authors: Montorsi
authors: Urological Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy. Electronic address: cavarretta.ilaria@hsr.it.
authors: Ilaria T R
authors: IT
authors: Cavarretta
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D043525:Cytosine Deaminase / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005437:Flucytosine / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010430:Pentosyltransferases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D011355:Prodrugs; D005437:Flucytosine; D010430:Pentosyltransferases; C023269:uracil phosphoribosyltransferase; D043525:Cytosine Deaminase
keywords: Magnetic resonance imaging; Mesenchymal stem cells; Prodrug activating enzymes; Prostate cancer; TRAMP mice