Download Cancer stem cells

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
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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 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
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Cancer
stem cells
Selective pressures
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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
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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
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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
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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.