Dynamic regulation of the cancer stem cell compartment by Cripto-1 in colorectal cancer

• Published in: Cell death and differentiation Vol. 22; no. 10; pp. 1700 - 1713
• Main Authors: Francescangeli, F, Contavalli, P, De Angelis, M L, Baiocchi, M, Gambara, G, Pagliuca, A, Fiorenzano, A, Prezioso, C, Boe, A, Todaro, M, Stassi, G, Castro, N P, Watanabe, K, Salomon, D S, De Maria, R, Minchiotti, G, Zeuner, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2015; Nature Publishing Group
• Subjects: 13/100; 13/106; 13/31; 631/67/71; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Colorectal cancer; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - physiopathology; Female; Gene Expression Regulation, Neoplastic; Genes, src; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; GPI-Linked Proteins - physiology; Humans; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - physiology; Life Sciences; Mice; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplasm Proteins - physiology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - physiology; Original Paper; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Spheroids, Cellular; Stem Cells; Tumor Cells, Cultured
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2015.19

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.