13. cancer biology

benign = abnormal growth with no important physiological functions

- non-invasive, non-metastatic, well differentiated

- small, well demarcated, slow growing

malignant = cancer

- locally invasive, metastatic, poorly differentiated

- large, poorly demarcated, rapidly growing with hemorrhage and necrosis

cell tissue + "-oma"

cell tissue + "- carcinoma"

- ex: adenoma vs adenocarcinoma

cell tissue + -"sarcoma"

cell tissue + "-blastoma"

cell tissue + "-carcinoma"

leukemias and lymphomas

Hodgkin lymphoma; Kaposi Sarcoma

through anaplasia = loss of normal tissue structure and function

proteins, hormones, genes

screening + prevention

molecular classification + treatment choice

monitoring treatment success + progression

false positives/negatives (ex: PSA (a lot of males just naturally have high PSA)/silent tumors)

paraneoplastic syndrome (ex: thyroid cancer (tumor hidden by hyperthyroidism), pheochromocytoma)

transformation: a normal healthy cell becomes a malignant cancer cell (healthy phenotype to a malignant one)

differentiation: cell acquires functions (immature cell becomes mature)

if a healthy cell gets transformed into a cancer cell but it cannot perform its function anymore, and looks very different morphologically and anatomically -> cell is now transformed and undifferentiated

immortality = divides indefinitely (usually cells have a finite #, - explains aging)

uncontrolled proliferation = proliferation = rapid increase in #

altered metabolism = doesn't rely on optimal metabolism process

anaplasia = looks anatomically different from normal cell

no contact inhibition = usually when cells are in contact with other cells, it inhibits their growth but NOT cancer cells, they divide on top of one another.

Anchorage independence = usually for cells to divide they need to be anchored to something (if its just floating in your blood it won't divide), but cancer cells can divide without anchorage

most cells will rely on oxidative phosphorylation = 36mol ATP/ 1mol glucose (oxygen necessary)

if oxygen absent, rely on anaerobic glycolysis = 2mol ATP/1mol glucose

cancer cells rely on aerobic glycolysis REGARDLESS if oxygen is there = 4 mol/1mol glucose.

a lot of lactate waste product

- explains why cancer cells are so energy consuming, and why those with cancer are losing a lot of weight

one cancer stem cell which became cancerous and acquired ability to divide and multiply

in a tumor there would only be a few stem cells

for treatment you would want to target these stem cells to stop tumor growth

mutations occur over time either randomly or via exposure to different chemicals

- mutation = DNA changes or epigenetic modifications

1 mutation won't cause cancer, but once we reach 4-7 mutations = cancer

- certain mutations are more likely to produce cancers than others

tumor suppressor genes and oncogenes

- part of what determines if a cell will grow, divide or not

they are like the gas pedal of cancer -> promote growth

accelerate proliferation

promote growth

gain of function mutations

they are like the brake pedal of cancer -> suppress growth

inhibit proliferation

decreased mutation

increased DNA repair

loss-of-function mutations of both alleles

they are like the gas pedal, they promote growth and dividing

gain of function mutation = more risk of cancer

loss of function mutation = protected from cancer

only need ONE gene from either mom or dad

an proto-oncogene

normally inactive, but when there's a growth factor that binds to receptor, it activates RAS and it allows for cell growth to proceed

often mutated in tumours, so it does not need to be activated by growth factor (gain of function mutation) -> cell growth just goes on all the time

is not promoting cancer, but has the potential

point mutation

gene amplification = more of them

chromosomal translocation

- overexpression (translocated promoter)= read more often

- chimeric protein (translocated gene fragment)= fused with another protein that stimulates its action more frequently

they are like the brake pedal, they stop growth and cell dividing

major example = TP53

whenever there is DNA damage, either triggers apoptosis pathway or state of senescence (cell ages out and dies)

loss of function mutation = more risk of cancer

gain of function mutation = low risk of cancer

need BOTH genes

miRNA that increases cancer risk

- small segments of RNA that code for a specific part of an miRNA

- they behave differently and increase cancer risk

oncomir turns on oncogene (NOT epigenetic modification)

oncomir working too much on a tumor suppressor gene (turns off tumor suppressor gene)(epigenetic modification)

- damage or inhibit ribosome unit, so gene not produced and is turned off -> cancer risk

when they infect our cells, they inject their DNA material into our own, and then they use our own DNA polymerase and RNA polymerase proteins to multiply + create their own proteins, multiply + divide

- this could lead to mutations

- could activate the oncogenes, suppress tumor suppressors -> leads to cancer promoting lesions

HBV and HCV -> hepatocellular carcinoma

Epstein Barr, HHV8, immunodeficiency -> Burkitt lymphoma, Kaposi Sarcoma

HPV16, 18, 31, 33 -> cervical + anogenital cancers

human t-cell, lymphotropic virus-1 -> adult T-cell lymphoma/leukemia

evading immune destruction

evading growth suppressors

enabling replicative immortality

tumor promoting inflammation

activating invasion and metastasis

genomic instability

inducing angiogenesis

resisting cell death

deregulating cellular energetics

sustained proliferative signaling

no longer express molecules that our immune cells use to detect them

- called immunodetecting -> our immune cells cannot recognize them

they also express molecules that attract our immune cells but then deactivates them

- called immune checkpoint

can attract immune cells that suppress the activity of other immune cells

- ex: regulatory T cells, macrophages -> helps tumor grow

normally, ligands inside cells tell them when to start/stop growing.

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cancer behaves a lot like certain pathogens - they replicate at a faster rate, have the capacity to invade other tissues, they express certain antigens

- a good immune response is associated with a decline in certain forms of cancer

cancer cells are very similar to our healthy cells, so hard for our immunity to make the difference between

acute inflammation is protective against cancer

chronic inflammation promotes cancer development and metastasis because its an environment that promotes the onset of mutations

- particularly GI cancers are susceptible to this

increase in inflammation is associate with an increase in cell division because it stimulates cell division and the release of a lot of ROS species that are damaging to the DNA.

- signals for angiogenesis (provide nutrients and O2)= growth promoting tumor microenvironment

tumors can "highjack" immune cells

- gain ability to secrete cytokines, stimulate wound healing mechanisms (angiogenesis, tissue remodelling),

- promote recruitment of lymphocytes and macrophages = tumor associated macrophages and tumor infiltrating lymphocytes

hair loss = due to cytotoxic drugs (because hair cells are rapidly dividing)

increased risk of infections = due to loss of inflammatory mediators (they are rapid dividing)

nausea + vomiting = GI epithelium cells are sensitive to chemo

fatigue = tumor using up a lot of energy (aerobic glycolysis)

chronic bleeding = tumor compressing on blood vessels + tumor recruits and form new blood vessels, but they are very leaky + less platelets

pain = tumor compressing

symptom complex triggered by cancer = mimic symptoms of other diseases but are caused by cancer

- common ex: if you have tumor on anterior pituitary, high amounts of ACTH, Cushing syndrome

- excessive secretion of EPO -> polycythemia

- excessive secretion of immune mediators -> formation of immune complexes -> nephrotic syndrome

defined as body wasting

- anorexia due to altered pattern of hypothalamic mediators (loss of appetite)

- thermogenesis due to energetic insufficiency for brown adipose tissue

- cardiac dysfunction due to atrophy, increase E consumption

- malabsorption due to gut-barrier dysfunction, release of inflammatory mediators

- acute-phase response due to release of acute-phase proteins, reduced albumin synthesis

moves from origin tissue and starts to grow elsewhere

lung cancer

- brain = headaches, seizures, vertigo

GI cancer

- respiratory = cough, dyspnea, hemoptysis

- lymph nodes = lymphadenopathy

- liver = jaundice, hepatomegaly

breast + prostate cancer

- skeletal = pain, fractures, spinal cord compression

T = tumor

- 1 = hasn't reached epidermis or hypodermis, 2 = same place but larger, 3 = started invading nearby tissue

N= nodes

- 0 = no nodes, 1 = proximal node, 2 = multiple nodes

M = metastases

- 0 = none, 1 = yes

stage 1 = cancer in origin tissue

stage 2 = cancer locally invasive

stage 3 = local lymph node invasion

stage 4 = distant organ metastasis

anything that promotes mutation

- mutation - causing agent

- DNA alterations + mutations

- targets: any gene

cancer causing agent

DNA or epigenetic or protein alterations

targets: cell growth + cancer hallmarks

by definition is a mutagen as well, but needs to have impact on cancer development

sun exposure, tobacco, alcohol consumption, lack of fruit/vegetables, lack of PA, infections

it is a result of genetics + epigenetic alterations

- these alterations are produced because of exposure to carcinogens or just simply bad luck

- remember exposure in the womb happens too

- if dad was exposed to chemicals his sperm could have been altered

- cancer is a long-term disease

no, it is also about how the DNA is read

- influenced by lifestyle, carcinogen exposure, occupational exposure

- these can change the epigenetic marks increasing their susceptibility to cancer

lung, bladder, larynx, esophagus, pancreatic kidney, stomach, mouth, leukaemia, cervix

they contain 1000+ carcinogens

- nicotine, polycyclic aromatic hydrocarbons (PAH)

interaction with asbestos increases lung cancer risk greatly (synergistic action)

has in utero epigenetics effects -> decreased birth weight, increased stillborns

also associated with respiratory + coronary diseases deaths

- happens faster, cancer is a long term process

no, if you stop smoking, it can decrease your risk

bowel, liver, breast, oesophagus, larynx, mouth and upper throat

because the mechanisms through which alcohol can induce carcinogenesis are quite generic, meaning that it could apply to many different types of tissue and tumor cells.

interaction with smoking -> increased procarcinogen activation

can activate the different epidemic epigenetic mechanism through DNA methylation and micro–RNA is to promote oncogenes or suppress tumor suppressor genes

Ethanol metabolism is also involved in the synthesis of many reactive oxygen species that can trigger more inflammation.

linked to nutritional deficiencies which can also trigger some methylation changes favoring oncogenes

known to induce cirrhosis and then cirrhosis is an often a prerequisite for liver cancer

food or nutrition, obesity and physical activity are associated with multiple processes that have a role in cancer, apoptosis, DNA repair, inflammation, hormone regulation proliferation

minimizing red meat

avoid drugs, alcohol, smoking

exercise daily (60+ mins)

eat lots of different fruits and vegetables

drink water or tea, avoid sugary drinks

avoid specific and weight-loss targeted diets

sleep 7-9h/day

mediation/mindfulness training

moderation and variety are your best friends!

healthy diet decreased your risk

unhealthy diet increased weight gain + inflammation increases risk

physical activity decreases risk (decreased stress + inflammation)

weight gain increases risk (chronic low grade inflammation)

vit A + folate -> deficiency decreases p53 expression (tumor suppressor gene)

polyphenols -> decreases DNA methylation

these are just some studies being done

a lot of data suggesting that there is a link between higher BMI and increased incidence and lower survival to cancer -> could also be comorbidities that can explain this (hypertension, diabetes...)

- more cells = more risk of tumor

- children with high BMI = increased risk (remember cancer is a long term process)

night shift insomnia can dysregulate the circadian rhythm and this can lead to altered glucose and lipid metabolism which can lead to both weight gain and inflammation, which then can lead to cancer which makes it look like the weight gain correlates with it.

•Insulin Resistance (T2DM)

•Low-Grade inflammation & Oxidative Stress

•Adipokines Dysregulation (Leptin & Adiponectin)

•↑ GH Signalling (IGF-1 + Estrogen & Testosterone)

exercise

- evidence convincing for colon cancer

- evidence probable for breast + endometrial

- evidence limited for lung and pancreas

no benefits still apply

- reduce inflammation, reduce amount of ROS, restore food and sleep homeostasis, increase sensitivity to insulin, reducing levels of IGF 1, stabilizing and estrogen/testosterone

30-60mins daily of moderate or +

infrared + visible light spectrum: heat + colors = no risks

UV rays (sun rays + tanning salons)= increases ROS + skin cancer risks

radio + microwave (wifi + cell phones) = limited evidence, more research needed

X and gamma rays (nuclear weapons + cosmic backgrounds) = ionic radiations

limited evidence in humans

- can penetrate skull 4-6cm deep

- possibly carcinogenic/group 2B carcinogen

easy precautions:

- limit cell phone use

- avoid direct contact to head

- keep away from children

- pregnancy: keep away from abdomen

x-rays + gamma rays

- strongest form of waves + have enough energy to displace electrons within molecules and promote radio ROS and breaks the DNA strands

increases cancer risks (leukemias, thyroids, GI, gonads...)

risk highest in children and elderly

- U-shape relationship: immediate direct DNA damage (children) vs indirect bystander + progeny effects later (elderly)

atomic bomb survivors = 1st link between IR and cancer

radiotherapy can increase risk of 2nd cancer: require risk-benefit analysis

- a lottttttt more CT scans nowadays

carcinogen actions:

- express the expression of oncogenes

- decrease the tumor suppressor genes

lead to progeny and bystander effects

- chromosomal aberrations via direct strand breaks or oxidative stress

1- kill tumor cell

- look at drawing

2 - increase tumor aggressiveness via more mutations

- look at drawing

progeny effect = daughter cells from those exposed to IR many cells cycle ago can have an increased propensity for mutations

bystander effect = cells not DIRECTLY exposed to IR but living nearby other who can receive damage or ROS via Gap junctions

both have overall increased mutation rate from past exposure

adult cancer >>> children cancer

leukemia, CNS, lymphoma most common

slight increase in incidence since 1990s

- possibly Dx improvement

death rates decrease since 1970s

- 80% cured

genetic changes > environment

anabolic steroids -> hepatocellular carcinoma

chemotherapy, pesticides -> leukemia

immunosuppressive Tx -> lymphoma

HIV (AIDS) -> kaposi sarcoma

Epstein Barr Virus -> Burkitt Lymphoma

CT scans (2 before 22 years) -> brain cancer 2-3x increase

BUT they barely have exposure because they are so young

genetic predisposition

ex: philadelphia chromosome (swap between chromosome 9 and 22) = chronic myeloid leukemia

Down syndrome has 10-20x increased risk of leukemias

Li-Fraumeni syndrome = familial TP53 mutation increases risk of cancer