Cancer test 4

Catabolic reactions vs anabolic

break things down, anabolic build things up

What do cells need for metabolism

ATP (energy), reducing power (in the form of electron carriers such as NADPH), and Building blocks for biosynthesis (organic carbon and nitrogen, micronutrients, etc

Reprogramming metabolism

• Proliferating cancer cells need more of EVERYTHING; more organic molecules (building blocks of macromolecules and cells) and more ATP and electron carriers (energy to synthesize and function)

What do cancer cells need for the increased need for fuel of reprogrammed metabolism

more input of Glucose (to make ATP) and Glutamine (reduced Nitrogen for nucleotides)

What is normal metabolism in a cell look like

Occurs in normal cells and balance depends on cell’s needs and availability of O2.

• Aerobic respiration

• Fermentation

• Various biosynthetic (anabolic) pathways will use intermediates from glycolysis as the precursors for nucleotides, amino acids and lipids. This reduces ATP production but allows cells to maintain themselves and/or to grow.

Aerobic respiration

maximizes ATP production and uses oxygen and loses CO2 as organic carbon. (Glucose makes ATP and pyruvate through glycolysis. Pyruvate turns Acetyl-CoA into the krebs cycle. Eventually sends e- carriers through oxidative phosphorylation to make more ATP. 

Fermentation

makes less ATP and more building blocks. It works if Oxygen is limiting and carbon stays as organic carbon (lactate)

Warburg effect

observed that tumor cells take in more glucose than normal cells, produce more lactate (40x more) than normal cells, and the effect is seen even when oxygen is available to cells 

Why does warburg effect make PET scans useful diagnostic tool

Radioactive glucose accumulates in cells, and shows doctors where the cancer is with PET scans because it shows where all the glucose goes. Useful for identifying metastatic colonies and monitoring them.

How is metabolism altered in cancer cells?

• changes the balances of metabolism; oxidative phosphorylation still makes ATP, fermentation and lactate is upregulated, and more glycolysis intermediates are diverted

Effects of metabolism reprogramming on cancer cells

• more glucose import, synthetic precursors of nucleic acids, proteins, lipids, etc, ATP production is maintained and improved invasion on cancer cells.

• nearby cells increase VEGF expression and angiogenesis

How can metabolic reprogramming change the tumor microenvironment

• suppresses nearby cytotoxic T cells

• alter systemic metabolic regulation; such as by influencing insulin signaling to reduce glucose uptake by other cells and make it more available for itself.

• Uses lactate production to acidify the tumor microenvironment and activate the matrix metalloproteinases and promote invasion. Extracellular lactate triggers VEGF and promotes angiogenesis.

How do changes in HIF activity influence metabolic reprogramming

HIF1 causes increased activity.

More HIF1 activity in: hypoxic conditions, loss of function VHL mutations, or Src or Ras oncogenes

How do changes in Myc activity influence metabolic reprogramming

Myc activity increased by promoter mutations (cause overexpression) or Ras/MAPK pathway mutations increase Myc stability

• also increase glutamine uptake and subsequent nucleotide synthesis

How do changes in p53 activity influence metabolic reprogramming

• Normal job is to repress GLUT1 transcription, but when p53 has a loss of function mutation it causes increased GLUT1 expression

• P53 can also have a gain of function mutation that makes more GLUT1 get translocated to the membrane from intracellular vesicles.

• increase glutamine uptake and nucleotide synthesis

Oncometabolite

mutation in a metabolic enzyme that causes it to catalyze a new reaction that creates a metabolite not present in normal cells.. The presence contributes to cancer development

How does oncometabolite 2-hydroxyglutarate made and how does it effect cell behavior

• Step in TCA (krebs) cycle is messed up, which has isocitrate dehydrogenase using alpha-ketoglutarate to make 2-hydroxyglutarate. 

  • Promotes cancer by inhibiting differentiation and changing epigenetic regulation. Increases HIF1 activity to change metabolism and increase angiogenesis. 

Why is most metabolic reprogramming difficult to target therapeutically, and why do oncometabolites often get targeted

• Highly specific inhibitors are used to target the mutant enzymes that make oncometabolites. 

Other metabolic reprogramming can be difficult to target just in cancer cells without disrupting normal cells.

How does diet influence cancer development

• PCBs (polychlorinated biphenyls): old carcinogen that was banned but still around and very long-lived in environment. 

• Aspergillus flavus has procarcinogen aflatoxin that’s really bad, and can get to humans through what we eat or what the things we eat end up eating. Aflatoxin is bad because it’s xenobiotics that can turn into carcinogens. After phase 1 it turns into APB-9,0-epoxide which is the ultimate carcinogen that causes DNA mutations.

  • Xenobiotic = chemical in organism that isn’t natural in organism

How does alc influence cancer development

• ANY amount of alc increases cancer in women

• Alc has gotta go once we drink it, it turns into acetaldehyde before excreting as Acetate. Acetaldehyde is a mutagen. The enzyme to detoxify alc is present in the liver and in bacteria in your mouth, which is why alc leads to higher chance of liver, oral, or esophageal cancer. Breast cancer risk increases with Alc (even just a bit) because alc increases aromatase activity (higher estrogen) and estrogen is closely correlated to breast cancer.

How does obesity influence cancer development

• Increases colon, breast, endometrium, kidney, pancrease, liver, and esophageal cancer. Multiple mechanisms to contribute to canc, such as

  •  increased estrogen receptor activation for breast cancer. The aromatase in fat tissue makes more estrogen, and cholesterol derivatives can activate the estrogen receptor. 

  • Chronic system inflammation from hypertrophic adipocytes that release inflammatory molecules. They also recruit and activate macrophages. 

  • Free fatty acids cause insulin resistance that leads to high blood insulin levels. Insulin and the related GFs change the cell behavior systematically, causing proliferation and inhibiting apoptosis. 

What comes out of foods in general

HCAs, PAHs, Nitrosamines and nitrosamides

How do enzymes that process xenobiotics for excretion convert procarcinogens into their carcinogenic form

N-acetyltransferase converts heterocylic aromatic amines into the ultimate carcinogen. If you have less active allele you have less high cancer risk because there’s less ultimate carcinogen. Opposite for more active allele, which increases cancer risk and makes more ultimate carcinogen

How do genetic polymorphisms in enzymes influence cancer risk

Genetic polymorphisms influence risk: they change how parts of your diet are metabolized and broken down. Aldehyde dehydrogenase alleles can have different efficiency leading to buildup of carcinogen Acetaldehyde. Similar issue with meat consumption

How does folate deficiency contribute to carcinogenesis

Folate includes folic acid and its derivatives. Folate and its nucleotides are needed to make DNA. It's also used with other precursors to allow DNA methylation. Low folate causes nucleotide synthesis to be disrupted, so DNA repair makes double strand breaks and mutations. It also disrupts SAM synthesis causing oncogene overexpression due to disrupted epigenetic regulation.

How does vitamin C have cancer preventative effects

can neutralize reactive oxygen species and give electrons to the oxidizing agent to make Ascorbyl radical which is safer. It can also regenerate Vitamin E. Can also be regenerated or safely degrade the ascorbyl radical (safe, not unstable)

How does vitamin E have cancer preventative effects

reusable antioxidant that neutralizes Reactive oxygen species and becomes radical. 

How does vitamin D have cancer preventative effects

has a protective effect when present, deficiency increases cancer risks. Can be acquired through diet or made by skin. Vit D is inactive until its processed. Inhibits EGF and wnt signaling, which limits proliferation and tumor growth. It also upregulates tumor suppressor expression. P21 inhibits Cyclin/Cdk and BRCA1 has multiple effects. Vit D also promotes apoptosis by decreasing expression of anti-apoptotic genes

How does diet influence normal NRF2 activity to decrease cancer risk?

Broccoli and greens have chemicals that interact w/ KEAP1 in a similar way to electrophiles. They make your cell constantly express detoxifying enzymes. Instead of waiting for an issue after it starts, things like broccoli and green tea act proactively and keep detoxifying enzymes always on.

How does mis regulation of NRF2 during cancer progression make cancer more dangerous?

In sub cancer cells if there’s overactivation of NRF2 then it can have worse prognosis and be more aggressive.

• NRF2 promotes metabolic reprogramming and increased proliferation, also helps cells resist chemotherapy

What’re the current recommendations for diet and dietary supplements to reduce cancer risk?

• The Mediterranean diet decreases cancer rates. Diets high in fruits/vegetables decrease cancer risk. Some dietary deficiencies increase cancer risk. 

• Beta-carotene supplements aint it. Supplements increased cancer rates in high risk populations. Veggies still help, micronutrients help and are more important than an easy fix supplement. Vit E increased cancer long term as well.

• Current recommendations are regular good stuff: limit alcohol, stay good weight, eat good, stay active. Eat food but mostly veggies.  

What’re the DNA VIRUS cancer-causing infectious agents

• Epstein Barr virus

• Kaposi’s Sarcoma associated herpesvirus

• Human papillomavirus

• Hepatitis B virus

Epstein barr virus

DNA virus; infects lymphoid cells and usually found in people with nasopharyngeal or burkitt lymphoma cancer

Kaposi’s sarcoma associated herpesvirus

DNA virus; mostly asymptomatic. Causes kaposi’s sarcoma and primary effusion lymphoma. The virus makes viral oncogenes that promote cell division, survival, and p53 and Rb degradation

• more cell division, less death

Human papillomavirus

DNA Virus; most infections cleared by immune system resulting in no cancer. Has 2 oncogenes that determine carcinogenity of HPV strains.

• viral protein E6 targets p53 and degrades it.

• Viral protein E7 targets Rb for degradation to increase proliferation. Both increase genetic instability

Hepatitis B virus

DNA virus; causes liver cancer. Chronic infection and inflammation causes necrosis and proliferation/regeneration for a loop. 

• Viral enhancers cause misexpression of host genes

• Viral oncoprotein HBx regulates ghost cells, disrupting epigenetic repression, leading to random mutagenesis

Human T-cell lymphotropic virus type 1

ONLY RNA VIRUS; carcinogenesis depends on 2 viral proteins; TAX and HBZ. Regulates over a hundred host proteins

Helicobacter Pylori

Only Bacteria infectious agent; found with gastric stomach cancer

What is the classic Koch’s postulates?

1. Agent is found in all diseased organisms, but not in healthy ones

2. Isolate the agent and grow microbe culture from host

3. stick agent back in a healthy mouse and see if it infects it

4. Isolate same agent in this new host

What are the issues with classic Koch’s postulates

Not everyone w/ the infection may develop cancer. Some strains of the pathogen may be more carcinogenic than others. It may also be hard to culture the viruses. Final issue is that many human viruses won’t infect mice, so you can’t do this experiment on humans. Cancer also usually takes a long time to develop.

What factors influence gastric cancer risk in people w/ H. Pylori?

Helicobacter pylori can cause chronic inflammation in the stomach and is linked to gastric cancer. Only a few people develop the cancer, it just depends on the strain of bacteria (if it has CagA)

Why does CagA make H pylori worse 

CagA is a bacterial protein that activates the Ras/MAPK pathway to promote proliferation and inhibit the E-cadherins in epithelial cells, to lose their epithelial behavior. 

Examples of vaccines that decrease cancer risk

Vaccines for HPV and hepatitis B

Examples of antivirals that decrease cancer risk

Antivirals for HepB

Examples of antibiotics that decrease cancer risk

Antibiotics for H. Pylori

Chronic inflammation

Starts the same as acute; recognize damage, call everything in, and cells start to proliferate and become motile. The difference is that response isn’t enough and doesn’t fix the issue

Acute inflammation

Well regulated and short lived promotion of proliferation and immune cell recruitment. Important for immune response. It's the innate immune response to infectious agents and injuries/wounds. The immune cells brought in fill in and remove the bad stuff, clean it out, and then promote healing and shut down inflammation.

How do external agents contribute to inflammation?

• Infectious agents; acute inflammation resolves if infection is cleared. Chronic inflammation occurs if infection can’t be cleared. 

• Tobacco smoke; can trigger activation of inflammatory path through Ras overactivation

• Asbestos: non-degradable initiator of inflammatory response.