Cancer stem cells

1. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identificationnumber: TÁMOP-4.1.2-08/1/A-2009-0011

2. Manifestation of Novel Social Challenges of the European Unionin the Teaching Material ofMedical Biotechnology Master’s Programmesat theUniversity of Pécs and at the University of Debrecen Identification number: TÁMOP-4.1.2-08/1/A-2009-0011 Dr. PéterBalogh and Dr. Péter Engelmann Transdifferentiation and regenerative medicine – Lecture 13 Cancerstemcells

3. Cancer and cancerstemcelltheory Oncogenicevents Therapy Cell of origin Pre-cancer Cancer-diagnosis Remission Relapse Time

4. History of CancerStemCell(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)

5. 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. Solidtissue CSC markers

7. CSC development: stochastic or hierarchic evolution and clonal selection Cancer stemcells Selectivepressures

8. Altered nicheforCSCs Undernormalphysiologicalconditions Self-renewal Niche Niche Transientsignal Regulatedproliferation and properdifferentation Dominant signal Stemcell Stemcell Quiescent Activeorindivision, butstill inthestage of slowcycling Incancersortumors Niche Niche Dominantsignal Uncontrolledproliferation and impaireddifferentationpoisedfor additionalgeneticmutation Transient signal Stemcell Stemcell Active, but slow cycling Quiescent

9. AML niche characteristics Normal HSC (LKS+, CD34, CD150+, CD48-) • Impaired normal HSC niche function • Direct invasion of niche • Secreted substances such as SCF Loss of traditional niche dependence and homing to alternative niche • Pathway activation leading to enhanced self-renewal • Enforced LSC quiescence • Resistance to chemotherapy including secretion of antagonists • Dysregulated homing and engraftment • CXCR4/CXCR12 interactions • Up-regulation of adhesion molecules such as VLA-4 Sympathetic nervous system regulation LSC (human CD34+/CD38-; murinelin-, c-kit+, Sca-1-) • Enhanced cytokine responsiveness • Determination of immunophenotype Mature hematopoietic cells (paracrine cytokines) Endosteal regulatory elements (osteoblasts, Osteoclasts, bone matrix, osteopontin,calcium) Perivascular regulatory elements (endothelium, CAR, MSC)

10. Combinedtreatment of cancers – CSCs and theirniche Targetingcancerstemcells DNA checkpointkinases Notchsignalingpathway NFkBsignalingpathway ROS status Tumor involution Depletion of cancerstemcells Anti-angiogenic Depletion of bloodvessels Failuretosustaincancerstemcells Rest of cellseventuallyceaseproliferation BMPs Reduction of tumor load Differentation of cancerstemcells

11. 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 andit may represent a novel target in therapy.