Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice.

Gaspare Gulotta, Francesco Dieli, Giorgio Stassi, Matilde Todaro, Alessandro Scopelliti, Ylenia Lombardo, Lucia Ricci-Vitiani, Giorgio Stassi, Patrizia Cammareri, Ruggero De Maria

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166 Citazioni (Scopus)

Abstract

BACKGROUND & AIMS: The limited clinical response observed in many patients with colorectal cancer may be related to the presence of chemoresistant colorectal can- cer stem cells (CRC-SCs). Bone morphogenetic protein 4 (BMP4) promotes the differentiation of normal colonic stem cells. We investigated whether BMP4 might be used to induce differentiation of CRC-SCs and for therapeutic purposes. METHODS: CRC-SCs were isolated from 25 tumor samples based on expression of CD133 or using a selection culture medium. BMP4 expression and activity on CRC-SCs were evaluated in vitro; progeny of the stem cells were evaluated by immunofluorescence, immuno- blot, and flow cytometry analyses. The potential thera- peutic effect of BMP4 was assessed in immunocompro- mised mice after injection of CRC-SCs that responded to chemotherapy (n 4) or that did not (n 2). RESULTS: CRC-SCs did not express BMP4 whereas differentiated cells did. Recombinant BMP4 promoted differentiation and apoptosis of CRC-SCs in 12 of 15 independent experiments; this effect did not depend on Small Mothers against decapentaplegic (Smad)4 expression level or mi- crosatellite stability. BMP4 activated the canonical and noncanonical BMP signaling pathways, including phos- phoInositide 3-kinase (PI3K) and PKB (protein kinase B)/AKT. Mutations in PI3K or loss of Phosphatase and Tensin homolog (PTEN) in Smad4-defective tumors made CRC-SCs unresponsive to BMP4. Administration of BMP4 to immunocompromised mice with tumors that arose from CRC-SCs increased the antitumor effects of 5-fluorouracil and oxaliplatin. CONCLUSIONS: BMP4 promotes terminal differentiation, apoptosis, and chemosensitization of CRC-SCs in tumors that do not have simultaneous mutations in Smad4 and constitutive activation of PI3K. BMP4 might be de- veloped as a therapeutic agent against cancer stem cells in advanced colorectal tumors.
Lingua originaleEnglish
pagine (da-a)297-309
Numero di pagine13
RivistaGastroenterology
Volume140
Stato di pubblicazionePublished - 2011

All Science Journal Classification (ASJC) codes

  • ???subjectarea.asjc.2700.2721???
  • ???subjectarea.asjc.2700.2715???

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