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

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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

164 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 cancer 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, immunoblot, and flow cytometry analyses. The potential therapeutic effect of BMP4 was assessed in immunocompromised 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 microsatellite stability. BMP4 activated the canonical and noncanonical BMP signaling pathways, including phosphoInositide 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 developed as a therapeutic agent against cancer stem cells in advanced colorectal tumors. © 2011 AGA Institute.
Lingua originaleEnglish
pagine (da-a)297-309
Numero di pagine13
RivistaGastroenterology
Volume140
DOI
Stato di pubblicazionePubblicato - 2011

Keywords

  • AC133 Antigen
  • Adenomatous Polyposis Coli
  • Aged
  • Aged, 80 and over
  • Animals
  • Antigens, CD
  • Antineoplastic Agents
  • Apoptosis
  • Bone Morphogenetic Protein 4
  • Cell Differentiation
  • Cells, Cultured
  • Colon Cancer
  • Colorectal Neoplasms
  • Drug Resistance
  • Female
  • Fluorouracil
  • Gastroenterology
  • Glycoproteins
  • Humans
  • Male
  • Mice
  • Microsatellite Instability
  • Middle Aged
  • Mutation
  • Neoplasia
  • Neoplastic Stem Cells
  • Organoplatinum Compounds
  • PTEN Phosphohydrolase
  • Peptides
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Smad4 Protein
  • Tumor Resistance to Chemotherapy

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