CM11-Smoczer-Oncogenesis

what is cancer

heterogeneous group of disorders marked by uncontrolled cell division

what causes the overgrowth of cells in cancer

genetic mutations that give cells an advantage over normal cells

is cancer inherited

no - it is a genetic disease, but not inherited

Cancer cells vs normal cells

Cancer cells: nondifferentiated cells, abnormal nuclei, do not undergo apoptosis, no contact inhibition, disorganized, multilayered, undergo metastasis and angiogenesis

Normal cells: differentiated cells, normal nuclei, undergo apoptosis, contact inhibition, one organized layer

what are the main categories of cancer risk factors

genetic predisposition, environmental factors, viral infections, and age

what are examples of environmental cancer risk factors

tobacco, diet, obesity, alcohol, UV radiation, ionizing radiation, and pollutants

how does age affect cancer risk

older age increases risk because mutations accumulate over time

what does multi-hit model of cancer state

cancer develops through the accumulation of mutations in multiple genes over time

what is an initial malignant cell

cell with multiple mutations, including “passenger” mutations (no growth effect) and “driver” mutations (promote growth”

what does clonality mean in cancer

all cells in tumor are clones of single mutated cell

what does autonomy mean in cancer

cancer cells can override normal regulatory mechanisms and grow independently

major classes of genes that can be mutated in cancer

proto-oncogenes

tumor suppressed genes

cell cycle genes

apoptotic genes

DNA repair genes

Telomerase regulating genes

vascularization-promoting genes

microRNAs

what happens when proto-oncogene mutates

it becomes oncogene → promotes uncontrolled growth

what happens when tumor suppressor gene mutates

the “brakes” on cell division are lost, allowing growth

why are DNA repair and apoptotic gene mutations dangerous

they prevent repair of damage and removal of faulty cells

how do telomerase and vascularization genes contribute to cancer

telomerase keeps cells dividing endlessly; vascularization genes promote blood supply to tumors

what happens when tumor suppressor genes lose function

cancer develops

role of tumor suppressor genes

suppress inappropriate cell proliferation and promote DNA repair

are tumor suppression genes dominant or recessive

recessive-acting → both copies must be lost or mutates

what does loss of heterozygosity (LOH) mean

second copy of tumor suppressor gene is lost, removing protection and promoting cancer

what is p53 (TP53) often called

“guardian of the genome” (tumor suppressor gene)

what syndrome is caused by germline mutation of TP53

Li-Fraumeni syndrome

what cancers are associated with Li-Fraumeni syndrome

colon, breast, and brain cancers

by what age do ~50% of Li-Fraumeni pts develop cancer

30

what type of mutation in oncogenes causes cancer

gain-of-function

what are proto-oncogenes

normal genes that control basic cellular functions like growth factors, receptors, kinases, and transcription factors

what happens when proto-oncogenes become oncogenes

they stimulate uncontrolled cell division

are oncogenes dominant or recessive

dominant-acting → one mutated copy is enough to cause cancer

what are the main mechanisms that activate oncogenes

promoter/enhancer insertion

gene amplification

point mutations

chromosomal translocations

how does promoter/enhancer insertion activate oncogenes

abnormal overexpression of gene

how does gene amplification activate oncogenes

produces too many copies of the gene → excess protein

how do point mutations activate oncogenes

change the protein structure, making it permanently active

how do chromosomal translocations activate oncogenes?

place gene under new promoter or create fusion protein

can both DNA and RNA viruses cause cancer?

yes - both can act as oncogenic viruses

how do viruses introduce oncogenes into host cells

by adding a new “transforming” gene or altering expression of host genes

how can viruses affect proto-oncogenes

by mutating or rearranging them

how do viral promoters contribute to cancer

they insert strong promoters near proto-oncogenes, causing overexpression

besides gene changes, how else can viruses promote cancer?

causing impaired DNA repair and chronic inflammation

what controls checkpoints in cell cycle

cycling expression of cyclins and Cdks

why are cyclins/Cdks important

act as downstream effectors that regulate passage through checkpoints

mutations in which checkpoint are found in ~80% of human cancers?

mutations that allow unregulated passage from G1 to S phase 

what do signal transduction pathways respond to in cell growth

growth factors (e.g., Ras/MAPK pathway)

what is the key example of growth-related signaling pathway

Ras/MAPK pathway

mutations in which components of signaling pathways can cause transformation (cancer)

growth factors

growth factor receptors

adaptor proteins

kinases

transcription factors

what happens if DNA-repair genes lose function

leads to cancer

why do cancer cells have higher mutation rates

low replication fidelity and inefficient repair

how can defective DNA repair cause chromosomal rearrangements?

faulty repair system may create double-stranded breaks, leading to rearrangements

in what percent of tumors is telomerase reactivated?

90%

in normal cells, where is telomerase usually active?

germ cells and stem cells

what is catalytic subunit of telomerase

hTERT (human telomerase reverse transcriptase)

what are the most common noncoding mutations in cancer

somatic mutations in proximal promoter of hTERT

what is apoptosis

programmed cell death

what initiates apoptosis

death receptors, growth factor deprivation, or loss of mitochondrial integriy

what happens during signal integration in apoptosis

cell balances pro-apoptotic vs anti-apoptotic signals to decide whether to proceed

what proteins carry out execution phase of apoptosis

caspases (proteases)

how do cancer cells evade apoptosis

inactivating caspases

what does methylation status influence

gene expression

what factors can change DNA methylation patterns

lifestyle and environmental exposures

what is the study of heritable changes in gene expression without altering DNA sequence

Epigenetics

angiogenesis

new blood vessel formation by endothelial cells and extracellular matrix

what are the defining characteristics of malignancy

invasion and metastasis

what happens during invasion

malignant cells break through basement membrane and enter underlying stroma

what molecular changes help invasion

low E-cadherin (loss of adhesion) and high MMPs (ECM proteolysis)

what is metastasis

malignant cells travel through tissue barriers and grow at distant sites

what is intravasation in metastasis

malignant cells enter circulation to migrate

what is extravasation in metastasis

malignant cells leave the circulation and invade local ECM