2. oncogenesis

Cancer

Heterogeneous group of disorders characterized by uncontrolled cell division
resulting in overgrowth of cells with genetic mutations that give them
advantage over normal cells

Genetic disease, but not inherited!

cancer cells vs normal cells

cancer risk factors

Genetic predisposition

Viral infections

Age

Environmental:
– Tobacco
– Diet
– Obesity
– Alcohol
– UV-radiation
– Ionizing radiation
– Pollutants

cancer characteristics

multi-hit model

clonality

autonomy

Multi-hit model

accumulation of mutations in a number of genes over time

Initial malignant cell

accumulations of mutations

Clonality

all cells in a tumor are clones of a single cell

Autonomy

ability to override normal regulatory mechanisms

hallmarks of cancer

Genes mutated in cancers

Proto-oncogenes

Tumor-suppressor genes

Cell cycle controlling genes

Apoptotic genes

DNA-repair genes

Telomerase regulating genes

Vascularization–promoting genes

MicroRNAs

tumor suppressor genes

Loss-of-function = cancer (the brakes) 

Suppress inappropriate cell proliferation + induce the repair of damaged DNA

Recessive-acting genes

Loss of heterozygosity (LOH)

function of BRCA 1 + cancer related

TSG

DNA repair, transcription factor

breast + ovarian

function of p53 + cancer related

TSG that regulates cell division

many types

function of RB + cancer related

TSG that regulates cell division

retinoblastoma

TSG mutation is either ____ or ______

Li-Fraumeni

Germline mutation of TP53

Increased rate of colon, breast, brain cancers (50% by age 30)

Proto-oncogenes

Responsible for basic cellular functions

growth factors, receptors, intracellular kinases, TFs

gain of function → oncogenes (cancer, the gas)

Oncogenes

Stimulate cell division

Dominant-acting genes (need one copy)

myc

transcription factor (proto oncogene)

lymphomas,leukemia,neuroblastome (oncogene)

ras

GTP binding + GTPase (proto oncogene)

many types (oncogene) 

proto-oncogene activation mechanisms

Activation mechanisms

Promoter/enhancer insertion

Gene amplification

Point mutations

Chromosomal translocations

Viral-induced oncogenes

Both DNA and RNA viruses can cause cancer

Introduction of a new “transforming” gene into the host cell

Change in gene expression of host genes

• Mutating and rearranging proto-oncogenes

• Inserting strong promoters near proto-oncogenes

Induce impaired DNA repair and chronic inflammation

Cell-cycle regulatory genes

Cycling expression of cyclins/cdks (downstream effectors of those pathways) control different checkpoints in cell cycle

Mutations that promote unregulated passage from G1 to S phase are
oncogenic in ~80% of human cancers

Signal transduction pathways

Signaling pathways that respond to growth factors (Ras/MAPK pathway)

Transforming mutations:
– Growth factors
– Growth factor receptors
– Adaptor proteins
– Kinases
– Transcription factors

DNA-repair genes

loss of function = cancer

Cancer cells have higher-than-normal mutation rates
– Low replication fidelity
– Inefficient repair

DNA repair systems produce double-strand breaks, which can result in chromosomal rearrangements

Telomerase

Reactivation of telomerase in 90% of tumors

normally active only in germ cells and stem cells

what is the most common noncoding mutations in cancer?

Somatic mutations in the proximal promoter of the human telomerase reverse transcriptase gene (hTERT), the catalytic subunit of telomerase

Apoptosis

Programmed cell death

regulated energy-dependent sequence of events for cells to self-destruct

steps of apoptosis

1. Initiation: through death receptors (TNF1-R), GF deprivation, or loss of mitochondrial integrity

2. Signal integration –balance between proapoptotic and antiapoptotic signals to decide on whether to proceed

3. Execution mediated by caspases (proteases)

how do cancer cells bypass apoptosis

by inactivating caspases

epigenetics

Influence of life-style and environmental exposure on gene expression

Angiogenesis

New blood vessel formation by endothelial cells and extracellular matrix

Tumors >1mm3 need a new vessel

Angiogenic factors

VEGF, TGF-b, bFGF, IL-8

Angiogenesis inhibitors

interferons

Defining characteristics of malignancy

invasion + metastasis

Invasion

malignant cells disrupt the basement membrane and penetrate the underlying stroma

Loss of adhesion to basal membrane (low E-cadherin)

Local ECM proteolysis (high MMPs)

Metastasis

active transport of malignant cells through tissues barriers at distant sites

Intravasation

malignant cells enter the circulation and migrate to new location

Extravasation

migration from the circulation into the local ECM

Oral cancer – molecular pathways

1. p53/ Rb/ cyclin D

2. Promoter hypermethylation

3. Mitochondrial mutations

p53/ Rb/ cyclin D

75% missense p53 mutations = initiating event (already in pre-cancerous lesions)

Rb inactivation mostly in HPV-positive cancers

Cyclin D overexpression – poor prognosis factor for tongue

Mitochondrial mutations

variants of mitochondrial DNA