BIMM 134

cancer stats for men

1:2

most common: prostate, lung, colorectal

cancer stats for women

1:3

most common: breast, lung, colorectal

deadliest cancers

1. lung

2. prostate/breast

3. colorectal

4. pancreatic

what is the impact of tobacco use?

cause of 90% of lung cancer cases

1/3 of cancer death associated with tobacco use

what is the U.S. budget for cancer research?

0.1%

what percentage of cancer has already metastasized at time of diagnosis?

70%

metastasis and its effect on cancer death

metastasis = spread of cancer cells from origin

• more than 90% of cancer deaths is due to metastasis

carcinoma

epithelial, most deadly

adenocarcinoma

malignant glandular growth

sarcoma

cancer that originates in connective tissue (bone, fat, muscles)

leukemia/lymphoma

blood/lymph node

adenoma

benign glandular growth

adeno-

gland

chrondro-

cartilage

erythro-

red blood cell

hemanglo-

blood vessels

hepato-

liver

lipo-

fat

lympho-

lymphocyte

melano-

pigment cell

myelo-

bone marrow

myo-

muscle

osteo-

bone

what are the 4 characteristics of grading?

1. mitotic rate: how many/fast cells dividing (fast = bad)

2. nuclear grade: abnormal nuclei shape = bad

3. cellular differentiation: loss of cell specialization = worse grade

4. surgical margins: how close are tumor cels to surgical edge (positive = cells at edge = bad)

tumor grade vs tumor stage

grade = appearance of cells during biopsy

stage = how far cancer has spread

tumor grades

0/x = cannot be assessed/no evidence

1 = well differentiated (low grade)

2 = moderately differentiated (intermediate grade)

3 = poorly differentiated (high grade)

4 = undifferentiated (high grade)

TNM stage I

tumor location only (hasn’t spread or metastasized) (T # 2-4)

TNM stage II & III

locally invasive, includes absence/presence of regional lymph nodes (T #2-4, N #1-3)

TNM stage IV

distant metastasis, (T #2-4, N #1-3, M #1)

T1-T4

size/extent of the primary tumor

N1-N3

involvement of regional lymph nodes (number of lymph nodes and/or extent of spread)

M1

distant metastasis is present

impact of genetics and environmental factors?

10% of cancers are inherited genetic mutations

90% are caused by environmental factors

why does risk of cancer increase with age?

longer exposure to carcinogens, more time to acquire mutations needed to develop cancer

carcinogens

substances known to promote cancer development

two classes of carcinogens

mutagens: can directly cause DNA mutation

promoters: increase the chances of acquiring DNA mutations

• work together synergistically to produce a great effect

what do promoters do?

• increase proliferation

• chronic inflammation

• cell damage

• infectious agents

what is cancer?

• 100+ forms of disease

• caused by cell division, cell death, cell differentiation, metabolism, motility

• multistep process

• requires 4-7 mutations for malignant transformation

patient specific mutations

genetically unstable, intratumor variations and variations in metastases

describe the basic pathway that produces cancer diversity

• increase proliferation/decrease senescence (stop dividing/aging but do not die)

• increase survival/decrease apoptosis

• decrease differentiation

• increase cell motility (metastasis)

hallmarks of cancer

1. gain oncogenes

2. loss of tumor suppressors

3. spread/growth to distant sites

4. gain telomerase

5. gain blood supply

6. loss apoptosis

7. constant growth signaling

8. loss of apoptosis: increase survival/decrease death

9. decrease differentiation = increase proliferation

10. increase motility = metastasis

malignant tumors

cancer; cells invade neighboring tissues, enter blood vessels, and metastasize to different sites

benign tumors

not cancer; tumor cells grow locally and cannot spread through metastasis

what is hypertrophy

increase in cell size = not precancerous

how do differences in microenvironment contribute to cancer?

influencing the behavior of cancer cells through interactions with surrounding cells, extracellular matrix (ECM) components, and signaling molecules, which can promote tumor growth, invasion, metastasis, and even resistance to therapy.

how do differences in genetic mutations contribute to cancer?

alters the function of proteins that control cell growth, division, and death; can cause cell to grow uncontrollably and form tumors; changes DNA sequence

how do differences in epigenetic mutations contribute to cancer?

modify DNA packing, leading to abnormal gene activity that can promote cancer development by silencing tumor suppressor genes or activating oncogenes

• histone modification through acetylation and methylation

how do environmental stresses contribute to cancer?

exposure to ROS (reactive oxygen species) and chemical mutagens

responses will differ based on the cell type, cytoplasmic pathway, etc

oncogenes

gain of function (stuck accelerator)

dominant phenotype

increases RAS activity, increases proliferation

proto-oncogenes

promote normal cell division; RAS with normal function

tumor suppressors

loss of function (cutting the brakes)

recessive phenotype

what is p53

tumor supressor

what are telomeres and how to they relate to cancer?

telomeres = ends of chromosomes that provide protection from damage

• cancer cells re-express telomerase = unlimited cell division

• endless tank of gas

how does the loss of apoptosis induce cancer?

apoptosis = programmed cell death characterized with chromatin condensation (fragmentation of DNA)

• cancer cells decrease apoptosis:

  • gain of anti-apoptotic proteins (Bcl-2)

  • loss of pro-apoptotic proteins (BAX or p53)

necrotic cell death

messier, membrane distruption and scattering of cellular debris

why do cancer cells initiate an “angiogenic switch”?

tumors limited in growth due to diffusion of oxygen/nutrients and removal of waste and the switch is activated to increase release of pro-angiogenic molecules (VEGF)/decrease release of anti-angiogenic molecules (thrombospondin)

what does activating the angiogenic switch do?

results in new blood vessel growth, growth of cancer, invasion into bloodstream, metastasis

metastatic cascade

loss of E-cadherin; gain of N-cadherin

primary tumor formation → local invasion → intravasation → extravasation → arrest at distant organ site → survival in circulation → micrometastasis formation → metastatic colonization → clinically detectable macroscopic metastases

warburg effect

aerobic glycolysis, glucose reliance

• healthy cells use aerobic respiration (mitochondria+oxygen), more efficient and produces a lot ATP

• cancer cells use a different way of producing energy compared to normal cells even when oxygen is present (glycolysis)

  • less efficient, produces less ATP

  • instead of fully breaking down glucose into ATP, cancer cells break it down into lactic acid

  • why? faster growth, creates acidic environment to promote cancer spread, glycolysis provides raw materials (carbon) for cancer cells (anabolic processes)

reverse warburg effect

cancer cells utilize nearby stromal (supporting) cells to perform glycolysis and produce lactate → saves them energy

• cancer cells send signals (ROS) to nearby stromal cells

• these cells will shift to glycolysis, breaking down glucose and producing lactic acid

• the intermediates are then released into the environment to be used bby cancer cells for energy and rapid growth

what are tumor-promoting inflammatory responses?

• inflammatory cells (macrophages) are attracted to tumors

• cancer cells will release factors to activate inflammatory cells to release factors that promote tumor growth, angiogenesis, other hallmarks

enzyme-linked receptors

binding of ligand activates TKR → activated receptors add P to proteins on tyrosine residues → triggers intracellular cascade

• used by growth factors

• important for control of cell division and growth

• these are often mutated in cancer cells

protein kinases

add phosphates to activate cascade

protein phosphotases

remove phosphates/deactivates pathway

tyrosine kinases

add phosphates to tyrosines

serine/threonine kinases

add phosphates to serine/threonines

dual kinases

has both tyrosine kinase and ser/thr kinase activity

lipid kinase

adds phosphates to lipids

explain the pathway for tyrosine kinase receptors

1. messenger (EGF) binds and activates tyrosine kinase receptor

2. TKR adds P to intracellular signal proteins to activate

3. intracellular proteins then activate proteins in nucleus

   1. transcription factors turn genes on/off for protein production

4. proteins made increase cell division

5. phosphatases remove P to inactivate

intracellular pathway convergence and divergence

some signals can activate several receptors and some receptors can be activated by multiple ligands

• intracellular pathways have numerous effects depending on the pathway activated

draw the EGF-RTK-RAS-MAPK pathway and briefly explain how it works

EGF binds to its receptor → binding causes conformational change in receptor by exposing extracellular dimerization domain → autophosphorylation of key tyrosines needed to recruit signal molecules

• activating these tyr levels will result in the binding of numerous intracellular molecules

• explains activation of multiple downstream pathways/cellular effects

intracellular protein interactions in the RTK-RAS-MAPK pathway

mediated by specific protein modular domains

• SH2 - 100 amino acids that interact with specific amino acids near P tyrosine

• SH3 - 50 amino acids that interact with proline and hydrophobic residues on proteins

RTK-RAS-MAPK pathway

protein recruitment to membrane/receptor

• adaptor GRB2 binds to EGFR through SH2 domain

• SH3 domains of GRB2 binds SOS and recruits to membrane

• leads to activation of RAS through transferring GTP

• RAS-GTP activates RAF (MAPKKK)

• RAF phosphorylates MEK (MAPKK)

• MEK phosphorylates ERK (MAPK)

• ERK enters nucleus and activates transcription factors (Myc, Fos, Jun) to change gene expression that will promote cell proliferation, differentiation, and survival

what is sos and how does it work?

SOS = Guanine nucleotide exchange factor

• transfers GTP to RAS to activate it

  • RAS is inactivated by GTPase (proteins that turn GTP → GDP)

farnesyl lipid

addition of farnesyl lipid and methylation to RAS targets needed for full RAS activity

RAF

serine/threonine kinase

adds P and activates MEK

what are some alternative MAPK pathways

JNK and P38 MAPK pathways

• respond to cellular damage/stress

• triggers apoptosis

• type/severity of signals can lead to cellular survival or cell death

what is RAS and how does it work?

RAS = small GTPase that acts as a molecular switch in cell signaling pathways

• Inactive State: Ras is bound to GDP (Guanosine Diphosphate) → "OFF"

• Active State: Ras binds to GTP (Guanosine Triphosphate) → "ON"

• Signal Transmission: When Ras is "ON," it activates downstream proteins like Raf (MAPKKK), triggering a cascade that leads to gene expression and cell proliferation.

• Turning Off: Ras has intrinsic GTPase activity, meaning it can hydrolyze GTP → GDP, switching itself back "OFF." This process is enhanced by GAPs (GTPase-activating proteins).

draw the RAS-P13K-AKT pathway

Receptor Activation (RTK - Receptor Tyrosine Kinase)

• A growth factor (e.g., insulin, EGF, PDGF) binds to a Receptor Tyrosine Kinase (RTK) on the cell surface.

• RTK dimerizes and auto-phosphorylates, creating docking sites for signaling proteins.

Ras and PI3K Activation

• Ras (a small GTPase) is activated, switching from Ras-GDP (inactive) to Ras-GTP (active).

• PI3K (Phosphoinositide 3-Kinase) binds to the activated RTK and converts PIP2 → PIP3 in the cell membrane.

• PIP3 acts as a second messenger to recruit downstream proteins.

Akt Activation

• PIP3 recruits PDK1 and Akt (Protein Kinase B) to the membrane.

• PDK1 phosphorylates and activates Akt, triggering its full activation.

Cellular Responses

• Cell Survival: Akt inhibits pro-apoptotic proteins (e.g., Bad, FoxO, p53), preventing programmed cell death.

• Cell Growth & Proliferation: Akt activates mTOR (mammalian target of rapamycin), stimulating protein synthesis and cell growth.

• Metabolism Regulation: Akt promotes glucose uptake and glycolysis.

what is mTOR

activation of the serine/threonine kinase, mTOR leads to activation of cancer hallmarks

• proliferation, motility/metastasis

• angiogenesis and decreased apoptosis

what is the most common pathways mutated in human cancers?

p13k pathway

loss of PTEN results in?

PTEN = phosphatase

• most abundant tumor suppressor mutation

• converts PIP3 back into PIP2, inhibiting pathway

point mutations

deletions of receptors, causing ligand-independent dimerization/activation

gene amplification

over expression of receptors, ligand independent dimerization/activation