CH26 Cancer Cell Biology

how are cancers named

based on cell type that became cancerous

carcinomas

90% from epithelial cells

sarcomas

come from supporting tissues

leukemias

from blood or lymphatic cells

common causes of cancer mutations

base substitution or chromosome abberation

usually not inherited

2 phenotypes of cancer

loss of ability to regulate growth - proliferation

no longer restricted to certain locations - metastasis

benign vs malignant tumor

benign: localized, only proliferation control lost (growth)

malignant: proliferation and metastasis control lost (cancer)

conditions met for normal cell growth

contact with ECM through integrins

no contact with other cells

anchorage independent growth

cancerous cells do not require contact with the ECM

density independent growth

cancerous cells are not inhibited by contact with other cells

mechanisms where proliferation control is lost

DNA damage repair

Cell cycle regulation

chromosomal telomere integrity

apoptosis pathway

fundamental defect leading to cancer

inability to maintain a cell’s DNA

does not cause cancer itself but increases likelihood

mutator phenotype

cells with a high level of genomic instability

example of myeloid leukemia

cancer type arises from a specific DNA alteration

chromosome translocation in this case

types of DNA modification that can cause deleterious changes

not nucleotide sequence alteration

methylation

modification of histone proteins

speed of cell cycle throughout life

embryo: rapid

maturity: cells in G₀

neurons remain in G₀, RBCs constantly divide

2 commonly disrupted signaling pathways

pathway that links growth hormone receptors to cell cycle

inhibitory pathways that restrict proliferation

checkpoints of cell cycle are where

G₁/S

G₂/M

main cell cycle regulation mechanisms

series of kinase

cyclin proteins → interact with cyclin dependent kinases

vascularization of tumors

body tumors are extensively vascularized

tumors can activate blood vessel formation

outside of the body, tumor cells only form small tumors due to lack of diffusion

VEGF and FGF

angiogenesis activating molecules

activate local blood vessel growth

important to tumors

inhibitors of angiotensin

context of tumor growth

angiostatin, thrombospondin, endostatin

tumor has to inactivate inhibitors or overproduce growth factors

most common cancers

breast, lung, prostate, colorectal

fist mentions of cancer in history

Egypt 3000 years ago

Hippocrates

Oncos 180 AD

most effective mechanism to remove skin cancer

surgery

radiation if metastasized

photodynamic therapy, biological therapy (immune system)

most common cancers present at birth

most commonly in gonadal refion

not common

first step of metastasis

invasion: leaving original location to surrounding tissues

how is motility for invasion possible

microfilament based amoeboid movement

must be activated

what do cancer cells do after invasion

penetrate wall of blood vessel and move into new tissue; true metastasis

how do cadherins play into metastasis

cadherins normally bind cells to prevent migration

in metastasis they are reduced

what do cancer cells produce to migrate through basal lamina

proteases

steps of cancer cell spread

1) invasion: leave OG tissue to the surroundings

2) travel blood stream

3) metastasis: invade new tissue

4) move through ECM

plasaminogen (plasmin)

common protease in the ECM which can also activate other proteases to amplify effect

effects of proteases on blood vessel walls

loosen connections between blood endothelial cells to allow access through circulatory and lympahtic systems

where do cancer cells translocate to through blood stream

most die

system they arrive at first

most supportive tissue for growth

immune surveillance theory about cancer

debate

most cancers are destroyed by the immune system

debated about if immune system can recognize cancer cells

effect of immunosurpressed transplant and HIV in regards to cancer rate

IT patients: higher cancer rate

HIV: same cancer rate

amount of genes involved in cancer

average is 90 with 10 contributing to cancerous phenotype

two general types of gene mutation shown in cancer analysis

mutation in genes that promote cell growth and development (active in embryogenesis but not adults)

mutation in proto-oncogenes which drive proliferation when activated

common protooncogenes

involved in growth signaling pathways

growth factors and their receptors, G-protein signaling components, pathway signal protein kinases, transcription factors

Ras protein normal vs cancer

normal: transduces signals from growth hormones to activate proliferation

cancer: active even without hormone signal

cyclins normal vs cancer

normal: regulate progression through cell cycle

cancer: high level of cyclins allow cell cycle to continue when it shouldn’t

tumor supressor genes

shut off proto-oncogenes

can be mutated to loss-of-function and allow proliferation

p53 tumor surpressor

normally low in cells so as not to alarm

increased in cells that have sustained DNA damage

activates transcription of cell cycle arrest genes and slowing DNA replication

mutated in over 50% of cancers so it cannot repress

p53 relation to apoptosis

if DNA damage is severe, p53 will activate apoptosis

pRB protein

normally sequesters transcription factors to keep cell cycle in arrest

block at G1/S stage

when mutated, S phase continues and there is proliferation

carcinogen

compound or condition that can damage DNA

natural carcinogen example

aflatoxin is made by mold

ames test

analyzes a compound for ability to create mutation based on rate of mutated bacteria

combined with liver extract which has enzymes to activate potential carcinogens

risk factor of viral gene transfer

retroviruses integrate into a host and can convert a proto-oncogene to an oncogene based on proximity of integration

capture of genes by retroviruses

pick up cellular DNA and copy oncogene form then transfer oncogene to new cell

significant cancers from viral infection

HPV - cervical cancer

Hepatitis B - liver cancer

inherited mutations often need more mutations to cause cancer

inherited mutations often need more mutations to cause cancer

early detection

cancer treatment is highly successful if caught early

routine physicals

cancer treatment

surgery

radiation and chemotherapy to target dividing cells

novel cancer treatments

boosting immune system with antigens, interferons, and antibodies

molecular targeting to inactivate cancer — possible because of genetic testing to have better cancer characterization

marijuana

may reduce cancer symptoms

anti-angiogenesis therapy

increase angiogenesis inhibitors so tumor can’t vascularize

limits ability to move and survive

stabilizer, doesn’t cure