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Molecular tumor biology 5.Molecular basics of tumor growth and
spreadingDr. Gábor Mátis
University of Veterinary MedicineDivision of Biochemistry
11 April 2018
Main topics
I. Molecular basics of tumor growth– Cell proliferation and cell death– The prerequisites of tumor growth
• Hypoxia – HIF-1 signalling• Vascularisation – angiogenesis, VEGF signaling
II. Molecular basics of tumor spreading– Local invasion– Metastasis formation
I. Molecular basics of tumor growth
Tumor growth – cell proliferation andcell death
Tumor-forming cells can be:• Proliferating cells proliferative pool• Nem-proliferating cells non-proliferative pool
– Differentiation– Cell death– G0 phase cells
Tumor growth depends on both cell proliferationand cell death rate!
Veteriankey.com
Tumor growth – cell proliferation andcell death
Cell proliferation
• Proliferating cells:– Active cell cycle– S phase (DNA replication) cell detection:
• Ki-67 proliferation marker: immunhistochemicaldetection a factor influencing tumor prognosis
• PCNA protein
Detection of Ki-67 proliferation marker(immunfluorescence, HeLa cells;
Ki-67: purple, tubulin: green, DNA: blue)
En.wikipedia.org
Role of PCNA protein in DNAreplication
• PCNA =Proliferating CellNuclear Antigen
• Increasing theactivity of DNApolimerase δ
En.wikipedia.org; researchgate.net
The kinetics of tumor growth
Thefutureofthings.com
The prerequisites of tumor growth• Hypoxia
– HIF-1 (Hypoxia-induced Factor-1) transcriptionfactors HIF-1 signaling
• Vascularisation: angiogenesis!
Flipper.diff.org
The HIF-1signalingpathway
The most important target genes ofHIF-1 signaling in tumor cells
Therapeutical significance of HIF-1signaling
• Tumor goal: inhibiting HIF-1 signalingdecreased angiogenesis, less adapted cells tohypoxia slower growth
• Ischaemia goal: stimulating HIF-1 signalingincreased angiogenesis, better adaptation tohypoxia
• Main therapeutical targets of HIF-1 signaling:– Proline hydroxylases– Binding of HIF-1α to its coactivators– HIF-1α gene expression (gene therapy)
Inhibitors of HIF-1 signaling pathway
Vascularisation of tumors
• The main ways of tumor vascularisation:– (Neo)angiogenesis– Vasculogenesis: from bone marrow progenitor
cells– Co-option = vessel incorporation– Vascular mimicry
The main ways of tumor vascularisation
researchgate.net
Vascularisation of tumors• Factors influencing tumor vascularisation:
– The vascularisation of the original tissue– The angiogenic cytokine profile of the tumor: e.g.
VEGF, PDGF, TGFβ, leptin…• Hypoxia HIF-1 signaling cytokine production• Genetic/epigenetic pattern
researchgate.net
Types of VEGF and VEGF receptors
The VEGFsignalingpathway
Genecopoeia.com
Inhibiton of VEGF signaling: anti-angiogenic chemotherapy
• 2 main drug types:– VEGF inhibitors
(antibodies!): e.g.bevacizumab
– Tyrosine kinaseinhibitors (TKIs): e.g.sorafenib
alcethron.com; indiamart.com
circresearch.com
Inhibiton of VEGF/PDGF signaling:anti-angiogenic chemotherapy
Mechanisms of resistance against anti-angiogenic chemotherapy
cell.com