title: Tumor Microenvironment Versus Cancer Stem Cells in Cholangiocarcinoma: Synergistic Effects?
abstract: Cholangiocarcinoma (CCAs) may be defined as tumors that derived from the biliary tree with the differentiation in the biliary epithelial cells. This tumor is malignant, extremely aggressive with a poor prognosis. It can be treated surgically and its pathogenesis is poorly understood. The tumor microenvironment (TME) is a very important factor in the regulation of tumor angiogenesis, invasion, and metastasis. Besides cancer stem cells (CSCs) can modulate tumor growth, stroma formation, and migratory capability. The initial stage of tumorigenesis is characterized by genetic mutations and epigenetic alterations due to intrinsic factors which lead to the generation of oncogenes thus inducing tumorigenesis. CSCs may result from precancerous stem cells, cell de-differentiation, normal stem cells, or an epithelial-mesenchymal transition (EMT). CSCs have been found in the cancer niche, and EMT may occur early within the tumor microenvironment. Previous studies have demonstrated evidence of cholangiocarcinoma stem cells (CD133, CD24, EpCAM, CD44, and others) and the presence of these markers has been associated with malignant potential. The interaction between TME and cholangiocarcinoma stem cells via signaling mediators may create an environment that accommodates tumor growth, yielding resistance to cytotoxic insults (chemotherarapeutic). While progress has been made in the understanding of the mechanisms, the interactions in the tumorigenic process still remain a major challenge. Our review, addresses recent concepts of TME-CSCs interaction and will emphasize the importance of early detection with the use of novel diagnostic mechanisms such as CCA-CSC biomarkers and the importance of tumor stroma to define new treatments. J. Cell. Physiol. 231: 768-776, 2016. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Romano
authors.affiliation: Multidisciplinary Department of Medical-Surgical and Dental Specialties, Second University of Naples, Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: De Francesco
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Gringeri
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.|Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, Pennsylvania.
authors.forename: Antonio
authors.initials: A
authors.lastname: Giordano
authors.affiliation: Multidisciplinary Department of Medical-Surgical and Dental Specialties, Second University of Naples, Naples, Italy.
authors.forename: Giuseppe A
authors.initials: GA
authors.lastname: Ferraro
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Di Domenico
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, Hepatobiliary Surgery and Liver Transplantation, Padua University Hospital, Padua, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Cillo
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000473:pathology*; D006801:Humans; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000473:pathology*; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor