title: The Role of Hypoxia and Cancer Stem Cells in Renal Cell Carcinoma Pathogenesis.
abstract: The cancer stem cell (CSC) model has recently been approached also in renal cell carcinoma (RCC). A few populations of putative renal tumor-initiating cells (TICs) were identified, but they are indifferently understood; however, the first and most thoroughly investigated are CD105-positive CSCs. The article presents a detailed comparison of all renal CSC-like populations identified by now as well as their presumable origin. Hypoxic activation of hypoxia-inducible factors (HIFs) contributes to tumor aggressiveness by multiple molecular pathways, including the governance of immature stem cell-like phenotype and related epithelial-to-mesenchymal transition (EMT)/de-differentiation, and, as a result, poor prognosis. Due to intrinsic von Hippel-Lindau protein (pVHL) loss of function, clear-cell RCC (ccRCC) develops unique pathological intra-cellular pseudo-hypoxic phenotype with a constant HIF activation, regardless of oxygen level. Despite satisfactory evidence concerning pseudo-hypoxia importance in RCC biology, its influence on putative renal CSC-like largely remains unknown. Thus, the article discusses a current knowledge of HIF-1α/2α signaling pathways in the promotion of undifferentiated tumor phenotype in general, including some experimental findings specific for pseudo-hypoxic ccRCC, mostly dependent from HIF-2α oncogenic functions. Existing gaps in understanding both putative renal CSCs and their potential connection with hypoxia need to be filled in order to propose breakthrough strategies for RCC treatment.
authors.affiliation: Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Myszczyszyn
authors.affiliation: Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland. anna.czarnecka@gmail.com.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Czarnecka
authors.affiliation: Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.|School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Damian
authors.initials: D
authors.lastname: Matak
authors.affiliation: Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.|Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Szymanski
authors.affiliation: Emory School of Medicine, Atlanta, GA, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Lian
authors.affiliation: Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.|School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.|Department of General Surgery and Transplantology, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Kornakiewicz
authors.affiliation: Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland.|Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Bartnik
authors.affiliation: Department of Otolaryngology, Czerniakowski Hospital, Medical University of Warsaw, Warsaw, Poland.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Kukwa
authors.affiliation: Centre de Biophysique Moléculaire, CNRS UPR 4301, Orléans, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Kieda
authors.affiliation: Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.
authors.forename: Cezary
authors.initials: C
authors.lastname: Szczylik
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000473:pathology*; D054337:Cell Dedifferentiation / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007680:Kidney Neoplasms / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000473:pathology*; D015398:Signal Transduction; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C497446:VHL protein, human
keywords: Cancer stem cells; Epithelial-to-mesenchymal transition; Hypoxia-inducible factors (HIF-1α, HIF-2α); Renal cancer; von Hippel-Lindau protein (pVHL)