IDIBELL Cancer Conference on Metastasis and Angiogenesis

F. J. Carmona, M. Esteller
2011 Cancer Research  
gave the distinguished EMBO Lecture in which he focused on the role the epithelial-tomesenchymal transition (EMT) program plays in inducing dedifferentiation of committed cell populations into stem cell-like cells (SC). Differentiated human mammary epithelial cells can acquire self-renewal capacity upon EMT induction, drawing attention to the connection between EMT and stem cell biology in cancer. Translating these to tumor biology, EMT would be responsible for generating not only more invasive
more » ... and malignant features but also a stemness state that would support tumor development at distant metastases (1). There are 2 key components in this process. The first is the differentiation stage of the cell of origin, which determines diverse signaling requirements to induce an SC phenotype: fully differentiated human mammary epithelial cells require the expression of Slug transcription factor before entering an EMT program, whereas myoepithelial progenitors only require Sox9 expression to acquire stemness. The second component is the maintenance of this mesenchymal/SC state, which seems to be achieved through coordinated signaling pathways-canonical Wnt, noncanonical Wnt, and TGF-b. The surrounding stromal cells appear to be crucial to the stimulation and maintenance of these signaling networks, highlighting the value of an integrative investigation to understand the mechanisms of EMT as an interaction between tumor cells and the environment. Research Institute) outlined the relevance of epigenetic alterations in monitoring cancer progression and their involvement in the development of metastases, as revealed by the latest technologies for epigenomic profiling. Hypermethylation of the microRNA (miR) 200 family, which are modulators of EMT, was shown to be a determinant in triggering the metastatic cascade. The use of methylation arrays has enabled obtaining of the complete DNA methylation fingerprint of 1,600 human samples (2), and thereby the identification of signatures that can predict metastatic organ tropism of primary tumor cells. It has also revealed specific patterns useful for identifying the tumor type of origin of cancers of unknown primary (CUP), and helps clarify the various DNA methylation gains and losses at gene-promoter regions during tumorigenesis depending on the presence or absence of canonical CpG islands. Dr. Esteller also illustrated the profound differences that exist in the DNA methylation patterns of the colon cancer cell lines HCT-116 and the derived double knockout for DNA methyltransferases, compared with human normal colon samples (3). discussed the interplay between miRs and EMT in the generation of cancer stem cells. MiR-200 and ZEB1 regulate each other in a feedback loop that modulates the EMT/MET programs and, consequently, influence the motility, stemness, and survival of cancer cells (4). On one hand, ZEB1 is important for tumor initiation and metastasis establishment in pancreatic and colorectal cancer cells; on the other, miR-200, whose
doi:10.1158/0008-5472.can-11-2180 pmid:21933886 fatcat:lqu3giigfrdstfd2opaufgpwhq