Dynamic regulation of the cancer stem cell compartment by Cripto-1 in colorectal cancer.
Stemness was recently depicted as a dynamic condition in normal and tumor cells. We found that the embryonic protein Cripto-1 (CR1) was expressed by normal stem cells at the bottom of colonic crypts and by cancer stem cells (CSCs) in colorectal tumor tissues. CR1-positive populations isolated from patient-derived tumor spheroids exhibited increased clonogenic capacity and expression of stem-cell-related genes. CR1 expression in tumor spheroids was variable over time, being subject to a complex regulation of the intracellular, surface and secreted protein, which was related to changes of the clonogenic capacity at the population level. CR1 silencing induced CSC growth arrest in vitro with a concomitant decrease of Src/Akt signaling, while in vivo it inhibited the growth of CSC-derived tumor xenografts and reduced CSC numbers. Importantly, CR1 silencing in established xenografts through an inducible expression system decreased CSC growth in both primary and metastatic tumors, indicating an essential role of CR1 in the regulation the CSC compartment. These results point to CR1 as a novel and dynamically regulated effector of stem cell functions in colorectal cancer.
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.|Regina Elena National Cancer Institute, Rome, Italy.
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Francescangeli
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
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Contavalli
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
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De Angelis
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
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Baiocchi
Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Section of Histology and Medical Embryology, La Sapienza University, Rome, Italy.
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Gambara
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
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Pagliuca
Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, Naples, Italy.
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Fiorenzano
Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, Naples, Italy.
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Prezioso
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
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Boe
Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
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Todaro
Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy.
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Stassi
Mouse Cancer Genetics Program, National Cancer Institute, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
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Castro
Department of Medicine, University of California, Irvine, USA.
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Watanabe
Mouse Cancer Genetics Program, National Cancer Institute, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
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Salomon
Regina Elena National Cancer Institute, Rome, Italy.
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De Maria
Institute of Genetics and Biophysics Adriano Buzzati-Traverso, CNR, Naples, Italy.
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Minchiotti
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
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Zeuner
D000818:Animals; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D016391:Genes, src; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured
D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; C070636:TDGF1 protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt