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

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

Risultato della ricerca: Contributo in rivistaArticolo in rivista

166 Citazioni (Scopus)


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
Stato di pubblicazionePubblicato - 2011


  • 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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