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