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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

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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)

Cancer and cancer stem cell theory

Cell of origin

Oncogenic events Therapy

Pre-cancer Cancer-diagnosis Remission Relapse

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: 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)

TÁMOP-4.1.2-08/1/A-2009-0011

Solid tissue CSC markers

Cancer CSC marker

AML CD34+/CD38-

Brain tumor CD133+

Breast cancer CD44+/CD24-/Lin- Prostate cancer CD44+, CD133+

Retinoblastoma ABCG2+

Lung cancer SP-C+CCA+

Colon cancer CD133+

(7)

CSC development: stochastic or hierarchic evolution and clonal selection

Cancer

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

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 Niche

Stem cell Quiescent

Niche

Stem cell

(9)

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)

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.

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