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