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

CANCER STEM CELLS

Dr. Péter Balogh and Dr. Péter EngelmannTransdifferentiation and regenerative medicine – Lecture 13

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

TÁMOP-4.1.2-08/1/A-2009-0011

Cancer and cancer stem cell theory

Cell of origin

Oncogenic events Therapy

Pre-cancer Cancer-diagnosis Remission RelapseTime

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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)

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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

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Solid tissue CSC markers

Cancer CSC markerAML CD34+/CD38-

Brain tumor CD133+

Breast cancer CD44+/CD24-/Lin-

Prostate cancer CD44+, CD133+

Retinoblastoma ABCG2+

Lung cancer SP-C+CCA+

Colon cancer CD133+

TÁMOP-4.1.2-08/1/A-2009-0011CSC development: stochastic or hierarchic evolution and clonal selection

Cancerstem cells

Selective pressures

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Altered niche for CSCsUnder normal physiological conditions

In cancers or tumors

Transient signal

Dominant signal

Self-renewal

Active or in division, but stillin the stage of slow cycling

Regulated proliferation andproper differentation

Niche

Stem cellQuiescent

Niche

Stem cell

Dominant signal

Transient signal

Active, but slow cycling

Uncontrolled proliferation and

impaired differentation poised for

additional genetic mutation

Niche

Stem cellQuiescent

Niche

Stem cell

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AML niche characteristicsNormal 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)

TÁMOP-4.1.2-08/1/A-2009-0011Combined treatment of cancers – CSCs and their niche

Targeting cancer stem cellsDNA checkpoint kinasesNotch signaling pathwayNFkB signaling pathwayROS status Tumor involutionDepletion of cancer stem cells

Anti-angiogenic

BMPs

Differentation of cancer stem cells Reduction of tumor load

Depletion of blood vesselsFailure to sustain cancer stem cells

Rest of cells eventually cease proliferation

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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.