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Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Manifestation of Novel Social Challenges of the European Union in the Teaching Material of Medical Biotechnology Master’s Programmes at the University of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Dr. Péter Balogh and Dr. Péter Engelmann Transdifferentiation and regenerative medicine – Lecture 13 CANCER STEM CELLS TÁMOP-4.1.2-08/1/A-2009-0011 Cancer and cancer stem cell theory Oncogenic events Therapy Cell of origin Pre-cancer Cancer-diagnosis Time Remission Relapse TÁMOP-4.1.2-08/1/A-2009-0011 History of Cancer Stem Cell (CSC) theory • Only a minority of malignant cells can induce tumors (1930-1950) • SCF-U: identification of individual normal hemopoietic precursors generating large number of mature cells (1960-es) • TFU: tumor-forming unit – malignant cells from one colony could generate large number of secondary colonies • The composition of most tumors is heterogeneous • AML – single cell source for an entire spectrum of malignant cells (1990-es) TÁMOP-4.1.2-08/1/A-2009-0011 Solid tissue tumor CSCs • • • • • • Breast cancer Brain tumor Pancreatic cancer Lung cancer Colonic cancer, etc. Melanoma: use of a more immunocompromised mouse recipient led to the identification of higher number of CSCs than in conventional SCID recipients TÁMOP-4.1.2-08/1/A-2009-0011 Solid tissue CSC markers Cancer CSC marker AML Brain tumor Breast cancer Prostate cancer CD34+/CD38CD133+ CD44+/CD24-/LinCD44+, CD133+ Retinoblastoma Lung cancer ABCG2+ SP-C+CCA+ Colon cancer CD133+ CSC development: stochastic or hierarchic evolution and clonal selection TÁMOP-4.1.2-08/1/A-2009-0011 Cancer stem cells Selective pressures TÁMOP-4.1.2-08/1/A-2009-0011 Altered niche for CSCs Under normal physiological conditions Self-renewal Niche Niche Transient signal Regulated proliferation and proper differentation Dominant signal Stem cell Quiescent Stem cell Active or in division, but still in the stage of slow cycling In cancers or tumors Niche Niche Dominant signal Transient signal Stem cell Quiescent Stem cell Active, but slow cycling Uncontrolled proliferation and impaired differentation poised for additional genetic mutation TÁMOP-4.1.2-08/1/A-2009-0011 AML niche characteristics Impaired normal HSC niche function • Direct invasion of niche • Secreted substances such as SCF Normal HSC (LKS+, CD34, CD150+, CD48-) • Pathway activation leading to enhanced self-renewal • Enforced LSC quiescence • Resistance to chemotherapy including secretion of antagonists Loss of traditional niche dependence and homing to alternative niche Dysregulated homing and engraftment • CXCR4/CXCR12 interactions • Up-regulation of adhesion molecules such as VLA-4 Sympathetic nervous system regulation LSC (human CD34+/CD38-; murine lin-, c-kit+, Sca-1-) • Enhanced cytokine responsiveness • Determination of Mature immunophenotype hematopoietic cells (paracrine cytokines) Endosteal regulatory elements (osteoblasts, Osteoclasts, bone matrix, osteopontin,calcium) Perivascular regulatory elements (endothelium, CAR, MSC) Combined treatment of cancers – CSCs and their niche TÁMOP-4.1.2-08/1/A-2009-0011 Targeting cancer stem cells DNA checkpoint kinases Notch signaling Depletion of cancer stem cells pathway NFkB signaling pathway ROS status Anti-angiogenic Tumor involution Depletion of blood vessels Failure to sustain cancer stem cells Rest of cells eventually cease proliferation BMPs Reduction of tumor load Differentation of cancer stem cells TÁMOP-4.1.2-08/1/A-2009-0011 Summary • Cancer stem cell represent a small compartment within the entire tumor tissue by the time of tumor diagnosis, that are capable for regenerating the entire tumor spectrum following cytoreduction; however, their adaptation to the current cytotoxic therapies poses a severe obstacle for efficient treatment. • Similarly to the physiological stem cell niches, the interaction of CSCs with their niche is vital to the survival of CSCs and it may represent a novel target in therapy.