title: Harnessing the BMP signaling pathway to control the formation of cancer stem cells by effects on epithelial-to-mesenchymal transition.
abstract: Cancer stem cells (CSCs) persist in tumors as a distinct population and may be causative in metastasis and relapse. CSC-rich tumors are associated with higher rates of metastasis and poor patient prognosis. Targeting CSCs therapeutically is challenging, since they seem to be resistant to standard chemotherapy. We have shown that a novel peptide agonist of bone morphogenetic protein (BMP) signaling, P123, is capable of inhibiting the growth of primary tumor cells by interacting with type I receptors selectively [activin receptor-like kinase 2 (ALK2) and ALK3, but not ALK6] and type II BMP receptors, activating SMAD 1/5/8 signaling and controlling the cell cycle pathway. Furthermore, the compound is capable of blocking transforming growth factor-β induced epithelial-to-mesenchymal transition (EMT) in primary tumor cells, a critical step for tumor progression and metastasis. In addition, we have investigated the effects of P123 on self-renewal, growth, differentiation (reversal of EMT) and apoptosis of isolated human breast CSCs. We have shown that P123 and BMP-7 reverse the EMT process in human breast CSCs, and inhibit self-renewal and growth. Moreover, compared with single treatment with paclitaxel, co-treatment with paclitaxel and P123 showed an increase in cell apoptosis. Together, these findings suggest that P123 has the therapeutic potential to suppress both bulk tumor cells and CSCs. We believe that P123 represents a new class of drugs that have the potential to eliminate the primary tumor, prevent reoccurrence and metastasis, and enhance the treatment of breast cancer.
authors.affiliation: Albany Medical College, Albany, NY, U.S.A.
authors.forename: Ashish
authors.initials: A
authors.lastname: Bosukonda
authors.affiliation: Massachusetts General Hospital/Harvard Medical School, Boston, MA, U.S.A. wcarlson@partners.org wcarlson@MGH.Harvard.edu.|Therapeutics by Design, Cambridge, MA, U.S.A.
authors.forename: William D
authors.initials: WD
authors.lastname: Carlson
mesh_terms: D029404:Activin Receptors / Q000378:metabolism; D030201:Activin Receptors, Type I; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D055419:Bone Morphogenetic Protein 7 / Q000819:agonists / Q000378:metabolism; D052004:Bone Morphogenetic Protein Receptors / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000819:agonists / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D010455:Peptides; C498932:ACVR1B protein, human; D029404:Activin Receptors; D030201:Activin Receptors, Type I; D052004:Bone Morphogenetic Protein Receptors; D017239:Paclitaxel
keywords: BMP signaling; breast cancer; cancer stem cells; epithelial-to-mesenchymal transition; growth factor