BIO - Section 2

mutation(s)

a base change in DNA

• not all base changes impact gene expression, but lots of mutations might

promoter methylation

promoter - on DNA

methyl - a sequence that RNAp binds to

promoter methylation - methyl group added to the DNA of promoters

methyl groups

H3C: covalent bond to bases in the promoter

• prevents RNAp from connecting to promoter and prevents transcription

histones

protein DNA wraps around to form tight chromosomes to fit inside cellsh

histone acetylation

acetyl groups added to histones

• more groups = loosely wrapped DNA

  • increased acetylation → increased transcription

miRNA (micro RNAs)

• short RNA strands that recognize mRNA produced, and send these mRNAs for degradation so they can’t translate

  • high amounts of mRNAs → decreased gene expression

oncogenes

genes that exist in all cells that promote growth and increase speed through the cell cycle

• ex. Proto-oncogenes

tumor suppressors

genes that exist in all cells that slow down growth and decrease speed through the cell cycle

Example 1:

Would a histone acetylation that promotes gene expression of an oncogene promote or prevent cancer?

Promote

Why:

Promoting gene expression of a cancerous cell

Example 2:

Would an miRNA targeting mRNA of a tumor suppressor promote or prevent cancer?

Promote

Why:

miRNAs send mRNAs for degradation, which blocks translation. If you don’t have translation, you cannot create the necessary proteins

• there are no ‘breaks to counter promotion-at-neutral gear’

Example 3:

When a promoter methylation is increased at a promoter of a gene that is a tumor suppressor, would this promote or prevent cancer?

Promote

Why:

• no transcription is occurring

• increased promoter methyl → decreased gene expression

  • preventing gene expression of a tumor suppressor → ‘removing breaks’

    • if you’re not increasing tumor suppressors, you’re increasing methylation

Precancerous

Not yet cancerous, but has a high likelihood of developing it

benign

noncancerous/precancerous

• has not yet crossed the basement membrane

malignant

cancerous

• has crossed the basement membrane

neoplasia

cells have crossed the basement membrane, and are invading neighboring tissues

• this can become cancerous, and is now considered malignant

hypertrophy

cells enlarge

• benign

atrophy

cells shrink

• benign

hyperplasia

cells increase in number

• benign

dysplasia

cells became disorganized, stacked on top of each other

• benign

metaplasia

cells look like others found in the body

• benign

initial tumor

primary tumor; where cells begin to cause issues

secondary tumor

the distant site in the body

metastisis

cancer cells travel from the initial tumor to a distance site in the body

cancer progression

from the development of a tumor, to metastasis to different sites

intravasation

cancer cells enter the blood or lymph vessels

extravasation

cancer cells exiting the blood/lymph vessels

microstatises

small secondary tumors

macrometastises

large secondary tumors

Requirements for metastasis to occur (7)

1. invasion of neighboring tissue

2. cancer cells make it to the blood stream or lymph vessels

3. intravasation

4. they travel in blood/lymph to other areas in the body

5. extravasation

6. form micrometastises

7. have macrometastises

What are the three most common sites for secondary tumors?

• lungs

• bones

• brain

metabolism

process of breaking down nutrients for energy

• a form of catabolism

catabolism

breaking down larger molecules into smaller ones

anabolism

building large molecules for smaller ones

What leads to changes in behavior between normal and cancerous cells?

it’s all due to differences in gene expression

differential gene expression

comparing expression of genes in a tumor cell to expression of genes in a normal cell so we can identify the alterations

• cancer cells begin to increase rate through the cell cycle

• also begin to metabolize differently

ATP

energy currency

• focusing on how sugar (glucose) is used for energy (ATP)

Steps of Cell Metabolism (3)

1. Glucose passes through the plasma membrane through glut receptors

• glycolysis - splits apart a C6 molecule of glucose → 2 C3 pyruvate molecules

• during glycolysis, ATP and NADH+ are produced

  • this happens in the cytoplasm

• pyruvate enters into the mitochondria matrix of the mitochondria. Pyruvate then enters…

2. Kreb’s Cycle

• ATP, NADH, FADH2, CO2 are produced (CO2 is what we breathe out)

  • NADH and FADH2 go to the inner mitochondrial membrane

    • they then enter the electron transport chain

      • this process is called oxidative phosphorylation

3. NADH and FADH2 donate electrons (e-) to proteins in the inner mitochondrial membrane

• these protons (H, H+) then build up in the intermembrane space

• H+ moves across ATP synthase like a windmill

  • when protons pass by, ATP is generated

At the end, this entire process creates 32-36 ATP for 1 cell. The range is not always the same and varies based on the amount of oxygen present

lactic acid

build up of glucose in the muscles/bloodstream instead of metabolizing properly when oxygen levels aren’t available as needed; lactic acid helps protect muscles from injury while being exerted

• contributes to soreness

• causes muscle cramps

lactic acid fermentation

pyruvate is converted to lactic acid instead of acetyl-CoA to produce NAD+ e- carriers for glycolysis

• the only ATP produced now will be from glycolysis

  • result: less ATP

• lactic acid fermentation is seen in human cells

anaerobic respiration

oxygen isn’t present in cells

• this is a form of cell metabolism

  • as a result, they can’t do the electron transport chain (nothing is there to catch e- and p+)

    • instead: lactic acid fermentation

Steps of anaerobic respiration

1. Glucose enters cell through glut receptors

2. Glucose enters glycolysis, which occurs in the cell cytoplasm

• ATP and NADH are produced

3. Since NADH can’t be converted into ATP using the electron transport chain, because there’s no oxygen, NADH isn’t useful in this process

4. The goal: make all ATP from glycolysis to keep the glycolysis process running

• this would consume a lot of sugar

• we also need NAD+ so it can be converted to NADH, which is needed to be made during glycolysis

Things to note about anaerobic respiration:

• we want to get NAD+

• we end with 2 pyruvate seen as 2 C3 molecules

• 1 glucose = 4 ATP → inefficient compared to when oxygen is present

aerobic glycolysis or “Warberg Effect”

even though oxygen is present, they undergo lactic acid fermentation

angiogenesis

cancer cells build blood vessels

• when thinking about tumors, there is mass cell division, but still need nutrients, oxygen, etc that typically travel through the blood stream, so cancer cells need access to that

  • these new blood vessels are extremely hap-hazardous, leaky, and inefficient

Treatments for Cancer (3)

1. surgery - anatomical removal of all or part of a tumor/lesion/organ/tissue

• typically high success rate

  • goal(s): to cure cancer, manage illness, palliative - keep patient comfortable/relieve pain

2. chemotherapy - kills rapidly dividing cells

• cancer cells rapidly divide, but can kill healthy rapidly-dividing cells

  • ex. immune (white blood) cells, hair cells

    • cool caps - prevent chemotherapy from getting to hair cells because it will kill hair cells

      • decreases head temperature to decrease blood flow; chemo. is in bloodstream, so not as much will get to hair cells

3. targeted therapies - drugs targeted to specific proteins that are up-regulated in cancer

• ex. tamoxifen

4. radiation - energy transmitted through particles/waves that target tumor cells to promote cancer death

• multiple types an tends to be very successful

  • goal: target tour cells to promote cancer cell death

    • external source: patient go es to appointment and receives radiation

    • internal source: implant is inserted and can give radiation that way

  • Limitations: the organ affected has to be reachable and not under another organ

    • sometimes tumor radiation → other new tumors

    • radiation causes DNA damage; if radiation “hits” healthy tissue, could → mutations that cause new cancers, prevalent especially if it’s a young patient

    • high DNA damage → tumor; cells typically die off;

  • science of radiation: high DNA damage = cell death

5. immunotherapies - vaccines to treat cancer, using one’s immune cells to identify and eliminate cancer, or using antibodies to target certain drugs to an area to promote cancer elimination

Tamoxifen

drug for patients with high amounts of estrogen receptors

• estrogen with a receptor → promotes cell growth

• tamoxifen targets estrogen receptor, preventing estrogen from binding…prevents growth of cancer/tumor

Radiation

multiple types an tends to be very successful

• goal: target tour cells to promote cancer cell death

  • external source: patient go es to appointment and receives radiation

  • internal source: implant is inserted and can give radiation that way

• Limitations: the organ affected has to be reachable and not under another organ

  • sometimes tumor radiation → other new tumors

    • radiation causes DNA damage; if radiation “hits” healthy tissue, could → mutations that cause new cancers, prevalent especially if it’s a young patient

  • high DNA damage → tumor; cells typically die off;

    • science of radiation: high DNA damage = cell death

Mechanisms of cell death

• Apoptosis - commonly triggered by DNA damage

• Autophagy - when cell death is triggered → cells eat their own organelles → die

Circulatory system

transports gases and nutrients to different areas of the body

Arteries

vessels that carry blood away from the heart

Arterioles

smaller vessels that carry blood from the heart (‘carry old blood the heart produced’)

Capillaries

small vessels where nutrients are exchanged with cells and tissues

Venules

smaller vessels that carry blood back to the heart

• where capillaries go to

• then, venules dump their blood into veins

Veins

larger vessels that carry blood back to the heart

Heart

the major organ in the cardiovascular system

• it is a pump that pumps blood around the body

• humans have a 4-chambered heart

Blood Flow Through the Heart

• when blood returns through the veins, it enters the vena cava - these veins take blood back to the heart

  • this blood is low in oxygen (deoxygenated blood), but high in CO2

    • deoxygenated blood enters → right atrium

    • → deoxygenated blood → right ventricle

    • → deoxygenated blood → pulmonary artery - takes deoxygenated blood → lungs

    • → deoxygenated blood → enters capillaries of lungs; CO2 in blood now exits and

      • → enters lungs; oxygen in lungs goes → blood →

      • → blood is now oxygenated - high oxygen, and low in CO2 →

        • → oxygenated blood returns → heart through pulmonary veins - brings blood back to heart, then →

        • → enters left atrium, then → left ventricle →

          • → now, oxygenated blood goes out the aorta - dumps blood into arteries

Explain the two (2) types of gas exchange that occur in the entire circulatory system

1. external respiration - capillaries of lungs: take CO2 from blood and go to lungs, then O2 from lungs to the blood

   1. getting cases from outside the lung capillaries

2. internal respiration - capillaries by the cells deep in the body; oxygenated blood has left heart → arteries → arterioles → capillaries at cells deep in body; O2 leaves blood → cells; CO2 leaves cells → blood

   1. no external interaction; all deep in body now (capillaries → lungs)

List the steps of blood circulation and where they take place (9)

Deoxygenated blood:

1. Enters vena cava (1)

2. goes to right atrium (2)

3. passes through tricuspid valve and enters right ventricle (3)

4. enters pulmonary artery (4) and exits into the lungs (5)

5. in the lungs: (O2 leaves and enters bloodstream; CO2 leaves bloodstream and enters lungs)

Oxygenated blood:

1. enters from bloodstream through the pulmonary veins (6) and enters the left atrium (7)

2. passes through bicuspid valve and into the left ventricle (8)

3. exits through the aorta

circulatory vs. lymphatic system

Circulatory - brings blood around the body

Lymphatic - drains fluid in the body (ex. decreases swelling)

• liquid is called lymph: lymph vessels → passes through lymph nodes

  • is consistently draining; recirculating → immune system, or eventually the kidneys

Cells in the blood and what they do

Red blood cells:

• anucleate (no nucleus)

• replenish a lot

• carrying oxygen → if they can’t, then → metabolic issues (eg. electron transport chain)

White blood cells:

• immune system

• lots of different kinds (B-, T-, macrophages, granulate…)

List and define the different blood cancers discussed (2)

1. lymphomas - cancers developed in lymphatic system

2. leukemias - cancer developed form abnormal cell division of white blood cells

List and define the types of lymphomas (2)

note: any type results from uncontrollable multiplication of lymphocytes at the nodes or other tissue (ie. tonsils)

1. Hodgkin’s - large white blood cell with 2 nuclei

• less common; often I adolescents and young adults

2. Non-Hodgkin’s - also just called ‘lymphoma’

• more common (often in adults 65+)

• one nucleus

List and define the types of leukemia discussed

1. acute lymphoblastic (A.L.L.) - large # of lymphocyte cells

• common in kids ages 3-6 and 65+

• prognosis is good, usually → chemotherapy treatment

2. acute myeloid (A.M.L.) - most common in 65+

• success/prognosis varies

3. chronic lymphatic (C.L.L.) - overproduction of B-cells

• most common in North America

• many don’t realize they have it for years

4. chronic myelogenous (C.M.L.) - overproduction of granulocytes

• often in older adults

• prognosis/survival rate 90%

• (chromosomal) translocation b/w chromosomes. 9 (BCR) and 22 (ABL) → Philadelphia chromosome

• increased cell division - proliferation

• treatment: Gleevac

Gleevac

targeted therapy onto the BCRABL protein

• cures over 90% of patients

• inhibits protein from promoting cell division

Describe the kidney function

• filters blood, specifically at nephrons - tells the body what to keep or get rid of

• waste products and liquid sent out of nephron to ureter - makes up urine

• bladder - stores urine

• urine released from bladder out the urethra

What is the goal of the respiratory system?

to bring air (O2) into the body and remove ‘waste’ (CO2)

Inhalation vs. exhalation

inhalation - process of bringing air in

exhalation - process of forcing air out

Respiratory system process

1. Air enters nares (openings of nose) →

2. nasal cavity (warms air and hairs catch particles/bacteria/viruses and prevent their furthering into the body) →

3. pharynx (back of the mouth) →

4. glottis (opening to the respiratory tract), covered by the epiglottis (prevents food from entering glottis) →

5. larynx (vocal cords) →

6. trachea (windpipe; has cartilage rings (help ensure trachea doesn’t collapse); also has small openings along the back, capable of passing small amounts of food to digestive tract) →

7. bronchus/bronchi (cartalige-rung to prevent collapse) →

8. bronchioles (inside lung) →

9. alveoli (starchy circular organs; covered with capillaries; this is where gas exchange occurs)

   1. at alveoli, O2 → capillaries, CO2 exits and → alveoli [external respiration]

How does CO2 leave capillaries to enter alveoli, and how does O2 leave alveoli to enter capillaries?

diffusion - matter will go where it’s less concentrated

• CO2 is highly concentrated in capillaries → will move to less concentrated (alveoli)

• O2 is very concentrated in alveoli → will want a less concentrated area (capillaries)

What brings air in and what pushes air out?

• inhalation:

1. diaphragm ( sits below ribs, pulls downward)

2. when it pulls down, → makes more room in chest cavity

3. pull air into lungs

• exhalation:

1. diaphragm relaxes upward

2. makes chest cavity smaller

3. as a result, this process forces air out

What contracts breathing rate?

• at brain stem, CO2 levels are monitored

  • higher levels → brain stem signals body to breathe faster

    • ex. exercise: ↑ metabolism → ↑ CO2, → ↑ breathing

  • lower levels → brain stem signals body to breathe slower

    • ex. sleep: ↓ metabolism → ↓ CO2 in blood, → ↓ breathing rate

Types of Lung Cancer discussed in class

mesothelioma - cancer of lung lining and largely connected to asbestos exposure

• asbestos - naturally occurring chemical compound; used as building insulation (illegal since 80s)

  • in walls, doesn’t cause harm (still safe there) unless disrupted

  • ex. tear-down; airborne if protocols aren’t followed [if airborne, this is what can cause mesothelioma]

SCLC - “oat cell” - begins in bronchi

• very aggressive

• classified under microscope

NSCLC - most common

• have different subtypes

• named after cell type it derives from

• “lung carcinoma”

  • carcinogens - chemicals known to cause cancer

What carcinogens do

cause mutations in DNA

• typically, you can’t isolate what is making the change occur

• lots of heterogeneity - understand impact on cellular behavior

Differential gene expression

comparing cancer cell(s) to normal cell(s)

What tools are used to compare (in differential g.e.)

• microarray - used to see what expression changes are caused

Microarray steps (5)

1. mRNA is isolated from tumor and normal cells

2. Synthesize: cDNA-complements DNA sequences; sourced from mRNA

3. Hybridize cDNA to existing DNA on chip

   1. nucleotide sequence in probe connects → complementary

4. Analysis

   1. how much color stuck

      1. green = normal expression

      2. red = cancerous expression

      3. yellow = both have expression

      4. black/clear = not expressed in either

5. Use of data

   1. green → lower expression of this gene in tumor tissue compared to normal tissue

   2. red → higher expression of this gene in tumor tissue compared to normal tissue

   3. yellow → expression of this gene is the same in tumor and normal tissues

Sputum Cytology

study of cells from a sample

thorascopy

removing a sample of a tumor

adenocarcinoma

cancer from lung’s epithelial tissue

three common areas of the body affected by metastasis

brain, bones, lungs

wedge resection

surgical removal of a lung tumor and surrounding tissue

cisplatin function

binds to DNA, preventing replication

pacitaxol function

halts cells in M phase; prevents mitosis

carboplatin

derivative of cisplatin

• “non-cell cycle specific drug”

• damage cells at different stages

Taxol (paclitaxol)

used to treat cancer of ovaries, breast, NSCLC

what system the skin is considered to have

integumentary system

layers of the skin from surface → inward

epidermis - surface layer of skin

• dead keratinocytes

• melanocytes

• living keratinocytes

basal layer - layer between epidermis and dermis

dermis - secondary layer of skin

• nerve endings

• blood vessels

• hair follicles

• sweat ducts and glands

sub-Q (fatty layer)

• ends with a barrier before the blood

compositions of skin layers

• dead keratinocytes - dead skin cells on the epidermis; shed over time

• melanocytes - produce melanin

  • melanin - dark product made in the body; absorbs UV light

  • more UV exposure → increased gene expression of melanin

• living keratinocytes - take the melanin produced by the melanocytes to protect themselves from UV

Types of UV light

A - reaches dermal and sub-Q → connected to premature aging and wrinkles; cancer-causal

B - reaches epidermis → less associated with aging; cancer-causal

C - stops at Earth’s ozone layer (layer is gradually shrinking)

what UV can do to the body (DNA)

causes DNA changes → creating thymine dimers

thymine dimers

caused by H2 bonds being broken down between double-stranded DNA

• DNA “bubbles” → affects transcription and ultimate protein produced

• though we have proteins (enzymes) to remove them, some people may have too many for the system to catch up or some may never be detected → possible cancer in long-term

Cause of a sunburn

• UV rays causing too much damage

  • → tissue damage: blood rushes to area (red appearance)

• feeling hot with sunburn → inflammatory response

• if bad enough: sunburnt cells/UV → triggers cell death → dead cells peel off

sun poisoning

extreme tissue damage → even stronger immune response

• scrape-like patches where skin has died off

Types of Sunburns

First-degree - only impacts epidermal layer

Second-degree - impacts epidermal and dermal layer

Third-degree - all layers (epidermal, dermal, sub-Q)