1. 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

2. CANCER STEM CELLS Dr. Péter Balogh and Dr. Péter Engelmann Transdifferentiation and regenerative medicine – Lecture 13 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

3. TÁMOP-4.1.2-08/1/A-2009-0011 Cancer and cancer stem cell theory Cell of origin Oncogenic events Therapy Pre-cancerCancer-diagnosisRemissionRelapse Time

4. 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:SCF-U: identification of individual normal hemopoietic precursors generating large number of mature cells (1960-es) TFU:TFU: tumor-forming unit – malignant cells from one colony could generate large number of secondary colonies The composition of most tumors is heterogeneous AMLAML – single cell source for an entire spectrum of malignant cells (1990-es)

5. 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

6. TÁMOP-4.1.2-08/1/A-2009-0011 Solid tissue CSC markers CancerCSC marker AMLCD34+/CD38- Brain tumorCD133+ Breast cancerCD44+/CD24-/Lin- Prostate cancerCD44+, CD133+ RetinoblastomaABCG2+ Lung cancerSP-C+CCA+ Colon cancerCD133+

7. TÁMOP-4.1.2-08/1/A-2009-0011 CSC development: stochastic or hierarchic evolution and clonal selectionCancer stem cells Selective pressures

8. TÁMOP-4.1.2-08/1/A-2009-0011 Altered niche for CSCs Under normal physiological conditions In cancers or tumors Transient signal Dominant signal Self-renewal Active or in division, but still in the stage of slow cycling Active or in division, but still in the stage of slow cycling Regulated proliferation and proper differentation Regulated proliferation and proper differentation Niche Stem cell Quiescent Niche Stem cell Dominant signal Transient signal Active, but slow cycling Uncontrolled proliferation and impaired differentation poised for additional genetic mutation Uncontrolled proliferation and impaired differentation poised for additional genetic mutation Niche Stem cell Quiescent Niche Stem cell

9. TÁMOP-4.1.2-08/1/A-2009-0011 AML niche characteristics Normal HSC (LKS +, CD34, CD150 +, CD48 - ) Impaired normal HSC niche function Direct invasion of niche Secreted substances such as SCF Pathway activation leading to enhanced self-renewal Enforced LSC quiescence Resistance to chemotherapy including secretion of antagonists Sympathetic nervous system regulation Endosteal regulatory elements (osteoblasts, Osteoclasts, bone matrix, osteopontin,calcium) 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 LSC (human CD34 + /CD38 - ; murine lin -, c-kit +, Sca-1 - ) Mature hematopoietic cells (paracrine cytokines) Enhanced cytokine responsiveness Determination of immunophenotype Perivascular regulatory elements (endothelium, CAR, MSC)

10. TÁMOP-4.1.2-08/1/A-2009-0011 Combined treatment of cancers – CSCs and their niche Targeting cancer stem cells DNA checkpoint kinases Notch signaling pathway NFkB signaling pathway ROS status Tumor involution Depletion of cancer stem cells Anti-angiogenic BMPs Differentation of cancer stem cells Reduction of tumor load Depletion of blood vessels Failure to sustain cancer stem cells Rest of cells eventually cease proliferation

11. 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.