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Carcinogenesis
Beata Mladosievicova
Cancer is diagnosed to 1 in 3 people in EU
In USA – 1 in 2 men, 1 in 3 women
The most common cancer
Men
• Lung Ca
• Colorectal Ca
• Prostate Ca
Women
• Breast Ca
• Colorectal Ca
• Cervical and ovarian Ca
>2/3 of the pts who develop
cancer are over age 65
> 80% of cancer patients are older
than 55 yrs
Survival more than 5 yrs after dg of cancer in developed countries
30% 66%
Increased number of newdg oncologic pts
In 2010 worldwide 12 million new pts with cancer (WHO)
it is expected that in 2030 -
26 million
Cancer
•Disease of cells
•Disease of genes
•Disease of genome
•Disease of signal pathways
•Disease of organism – komunikácie buniek s
prostredím, interakcie medzi bb. (2010-....)
p-onc (350)
tsg (150)
Protooncogens
mutation
chromosomal translocation
amplification
RAS, HER2, BCR, ABL
Activation of protooncogenes
ErbB2
• New molecules on and within cancer cells have been identified for targeted therapy
Targeted therapy
• monoclonal antibodies against GF
• monoclonal antibodies against receptors for GF
• tyrosine kinase inhibitors targeted to signal molecules
• expensive
• has effects on targets on healthy tissues
Tumor Tumor supressupresssor or genesgenes
mutation
deletion
p53, APC, BRCA1 a 2, Rb
Cell cycle
• duplication of a genetic material
• separation of chromosomes
• separation of DNA copies into daughter cells
The Cell Cycle
Damaged DNA and activation p53
•Genetic predisposition to cancer –
- single tumor supressor gene abnormalities
- bilaterality of tumors (breast, eyes),
- early onset in age less than 40 -50 yrs
Hereditary predisposition to cancer
BRCA1 DNA repair Breast Ca/ovarian Ca
BRCA2 DNA repair Breast Ca /Ca prostate
APC regulation prolif. Ca GIT/Ca thyreoidea
adhesion
CDKN2A control cell.c. melanoma/Ca pancr.
CDK4 melanoma
MET TKR Ca kidney
MSH2 DNA repair Ca colorectal/endometrial
Epigenetic control of cancer
genes
• Epigenetics: ▫ Mechanisms of gene expression control
that can be passed from one cell to its offspring, that are not reflected in changes in DNA sequence
• Examples: ▫ DNA methylation ▫ Histone modification ▫ Noncoding RNAs
Great percentage of genome is unknown
Proliferácia Metastázy Angiogenéza Apoptóza
Shc
PI3-K
Raf MEKK-1
MEK MKK-7
JNK
ERK
Ras
mTOR
Grb2
AKT
Sos-1
Signal pathways in cancer cells
Tumour
Cancer stem cells - target for modern therapy
Microenvironment of cancer cells –
signalling system Hannahan and Weinberg, 2010
Cancer stem cells • are tumorigenic
• usually a minor subpopulation of tumor cells
• are forming by the epithelial-mesenchymal transition
• may arise from progenitor cells
• their increased presence in tumor is associated with worse prognosis
Epithelial-mesenchymal transition – necessary for invasivity and migration
• Loss of epithelial Ag
• Mesenchymal phenotype
• Loss of contacts
• CSC- like (cancer stem cell)
• Resistance to therapy
• Specific genetic control
• Self renewal
• Creation of new clones of tumor
Angiogenesis • the main pro-angiogenic factors is VEGF-A
• excessive production of pro-angiogenic
factors is due to hypoxia • solid tumors greater than 1- 2 mm3 need
vascularization • angiogenesis can be interrupted by
inhibiting of MMP • angiogenesis can be interrupted by
inhibiting of endothelial cell proliferation
• an abnormal vascular permeability
Proangiogenic factors
• FGF
• VEGF
• PDGF
• HIF-1 alfa
Antiangiogenic therapy
• uses tyrosine kinase inhibitors
• uses VEGF blocking antibodies
• causes immature blood vessels damage
• is usually used in combination with chemotherapy
• prevents the formation of new blood vessels in tumors
• causes normalization of leaky walls of immature vessels
Metastases - are responsible for 90% cases of deaths in cancer patients
Chiang A, Massagué J: NEJM, 2008
Detachment of cancer cell
downregulation
- cadherine
- catenin
- integrin
Stromal invasivity
Metaloproteinases (MMP)
Serine proteinases
Intravasation
Tumour vessels
-rapid growth
-leakage of fluid
CTC (circulating tumor cells) • CTC from primary tumors (from 1g of
tumor millions daily)
• CTC – intermediates
Loss of CTC - NK, hemodynamic ff. Or capture in capillaries (diameter), interaction with Tr, chemoatraction to distant sites Chaffer et al., Science 2011
CTC
Extravasation
• Iná vaskulatúra - iné bariéry pre extravazáciu
• Proteins (ANGPTL4, MMP1,2, EREG...) responsible for endothelial dysruption
• Products of prim. tumors (VEGF,PIF, MMP3,10) lead to hyperpermeability before arrival of CTC
Hypoxia a mts
• Hypoxia – HIF – stimul for activation of genes for invasion and angiogenesis
• Hypoxia – increased expression of CXCR4 on
cancer cells – increased SDF1 activity in organs (lungs) – activation chemokine pathway SDF1/CXCR4 – homing in distant places
Organ specificity of mts – genetic determinants
Pulmonary mts
• ANGPTL 4
• MMP 1,2
• ID1
• EREG
• VCAM1
Bone mts • CXCR4
• RANKL
Stromal - derived growth factor SDF- e.g. from
bones ) binds to receptor CXCR4
Expression of receptor CXCR4 on e.g. Breast Ca
cells determines development of bone mts
Disseminated tumor cells • in the bone marrow and lymph nodes can
exist in a quiescent (dormant) state for many years
• may be detected many years after completion
of anticancer therapy • can escape from a dormant state • can be used for prediction of outcome and
risk for cancer relapse
Tumours Loss of cancer cells
hyperuricemia hyperkalemia
Consumption of iron
anemia
Consumption of glucose
acidosis angiogenesis
Hormonal changes
Testosteron gastrín
TSH
ADH
STH aldosteon insulin
cachectic sy
Disorders of coagulation
Cancer – malignant neoplasia
– group of >100 diseases characterized by genetic changes that cause
abnormal proliferation
abnormal differentiation
ability to invade
ability to create metastases
Causes
• Chemicals –tobacco, diet,air pollution,
• Radiation – ionizing, UVB
• Viruses – Epstein-Barr, HPV (16,18, 31,32) HBV...
• Failure of immunosurveillance
Diet?
Smoking
External factors vs hereditary
predisposition vs bad luck mutations
during replications (EHR)
Higher effect of external ff
• Breast cancer
• Colorectal cancer
Lower effect of external ff
• Prostate cancer
• Testicular tumors
• Hematologic malignancies
Conclusions
Progress in therapy – from better understanding of molecular pathogenesis of primary tumours and mts
Knowing of new genes, molecules, interconnections Some malignancies have „molecular driver“- target for
therapy
Most types of cancers –many targets in several signal pathways
New attractive target – microenvironment