Cancer Biology

Neoplasm+Tumor

neoplasm→mx name for tumor

tumor

• abnormal mass of tissue

• forms when cells grow+divide more than necessary

• cells→serve no physiologic purpose

benign or malignant (cancerous)

Benign Tumor

retain recognizable tissue structure

well-organized+well-differentiated

encapsulated by connective tissue

do not invade other tissues/doesn’t spread to other sites

grow very large→cause sx
over produce hormones
can turn malignant

Benign Tumor Nomenclature

named after tissue type

ex:
adenoma→ (made from) glands
lipoma→fat
hemangioma→blood vessels
neuroma→nerve tissue

polyp: benign tumor from the lining of the bowel (GI tract)

fibroid: benign tumor that grows from muscle layer of the uterus (leiomyoma)

Adenoma vs Leiomyoma vs Lipoma

adenoma: a tumor from glands
small
organized
integrated into GI tract

leiomyoma: a tumor from muscle layer of the uterus (aka fibroid)
contained
organized
symmetric

lipoma: a tumor made from fat
subcutaneous (under the skin)
free movement

Malignant Tumor Nomenclature

named after cell type

carcinoma→epithelial cells
-glands→adrenocarcinoma (ex: pancreas)
-ducts→ ductal carcinoma
-squamous cells→squamous cell carcinoma (ex: skin)

sarcoma→mesenchymal cells

lymphomas→lymphocytes

leukemias→bone marrow cells

other: melanoma
multiple myeloma
neuroendocrine
etc.

Colon Carcinoma vs Endometrial Carcinoma vs Sarcoma

colon carcinoma: in colon

endometrial carcinoma:
irregular
can’t define normal from cancerous tissue

sarcoma:
subcutaneous (under skin)
inflammation

Malignant Tumor

composed of undifferentiated (anaplastic) cells

lose recognizable tissue structure

disorganized

grow into+invade other structures/spreads to distant sites (metastasis)

untx→death

Precancerous Lesions+Carcinoma In Situ

tissue growth patterns:

1. hyperplasia: increased cell number→cellular division increases too frequently

2. dysplasia: abnormal growth

3. carcinoma in situ: cells that look like cancer under microscope but haven’t growth beyond their capsules+don’t invade other structures (can metastasize)

TNM Cancer Staging System

T: tumor size

N: lymph node status (# of lymph nodes affected)

M: metastasis (to other organ systems)
-m1→stage 4→incurable

Cancer Connection to Genetics

cancer→genetically caused→cancer cells preferred over normal cells→unchecked cell division

accumulate genetic changes→selective advantage over surrounding cells

DNA mutations+epigenetic changes→alter gene expressions

somatic: mutations during lifetime (through events after birth)

germline: mutations genetically inherited

Cancer Hallmarks List

genomic instability

enabling replicative immortality

deregulating cellular energetics

inducing angiogenesis

resisting cell death

avoiding immune destruction

tumor promoting inflammation

active invasion+metastasis

sustaining proliferative signaling

evading growth suppression

Proliferative Signaling

normal: cells enter proliferative phase (G1) in response to growth factors→bind to receptors on cell surface

proto-oncogenes: genes that encode receptors

mutation of proto-oncogenes→over-expression (oncogenes)

Evading Growth Suppressors

inactivation of tumor suppressor genes→uncontrolled growth

tumor suppression→inhibits cell proliferation

mutations in tumor suppression genes→unrestrained growth

TP53 gene:
regulates DNA repair+cell division
TP53 gene mutations→50-60% of gene mutations

Genomic Instability

snowball effect: cancer cells accumulate genetic changes→greater genomic instability→more mutations→more chances for pro-cancer features to develop

mutations in caretaker genes+epigenetic changes→modifications/silencing gene expression

ex:
PP: BRCA1/BRCA2 mutations
mx: PARP inhibitors

Reprogramming Energy Metabolism

cancer cells need more energy then normal cells

gene mutations→alter metabolism processes→cancer cells able to utilize energy in a different way

ex:
warburg effect
cancer cells develop ability to do aerobic glycolysis→requires high amonut of glucose→advantageous ability to make macromolecules

Inducing Angiogenesis

cancer cells need blood supply to promote growth

angiogenesis:
the creation of new blood vessels
controlled by balancing pro-angiogenic factors and inhibitors

normal cells:
hypoxia→hypoxia inducible factor-1alpha (HIF-1a) activation→increase expression of vascular endothelial growth factor (VEGF)→promotes angiogenesis

cancer cells:
mutations in TP-53 gene→HIF-1a upregulated/increased activity+thrombospondin-1/angiogenesis inhibitors downregulated/decreased activity→unchecked angiogenesis→increase in amount of blood cells

Resisting Cell Death

apoptosis:
programmed cell death
highly regulated
elimination of damaged cells+tumorigenesis prevention

mutation in oncogenes+epigenetic effects→alter pro/anti-apoptotic factor balance→tips balance towards more anti-apoptosis→cancer cells avoid cell death

ex: Bcl-2 family proteins increased→inhibit apoptosis→greater cell survival

Enabling Replicative Immortality

normal cells: restricted in number of times for division

telomeres:
protective caps of ends of each chromosome
shorten with each replication→too short to continue replication

telomerase: enzyme that restores the size of telomeres→continued replication

cancer cells: telomerase gene activated→continued cell division

Evading Immune Destruction

cancer cells present unusual antigens on cell surfaces→finds ways to avoid body’s immune system surveillance

checkpoints: cell receptors that when bound to corresponding receptors on cancer cells are blocked from destroying them

ex:
-PD1
-PDL1
CTLA4

checkpoint inhibitors: block checkpoints+help immune system kill cancer cells

ex: keytruda/pembrolizumab

DNA Methylation

addition of methyl group on DNA→blocks ribosome transcription of DNA

methylation→turns genes off

demethylation→turns genes on

Histone Modification

DNA is wrapped around histones

histones tightly packed→proteins can’t open gene→gene turned off

Non-Coding MRNA

helps control gene expression

can be influenced by epigenetic chemical additions

ROS (Free Radicals)+Oxidative Stress

generated by metabolic processes

small amounts→important for many bio processes

oxidative stress: too much ROS→direct tissue damage+DNA mutagenesis

E:
pollutants
chronic inflammation
radiation

Tumor Promoting Inflammation

chronic inflammatory response

• promotes tumor development

• overproduction of pro-proliferative cytokines+ORS→increase cancer cell development+mutagenesis

• causes epigenetic changes

cancer cells:
use chronic inflammatory pathways→increase survival+promote proliferation

ex: tumor recruit macrophages (TAM) lock immune system killing tumor cells+secrete pro-cancer cytokines+growth patterns

Cancer Associated Pathogens

chronic inflammation→increases risk of specific cancers→cancer:

H. Pylori infections→inflammation→direct DNA changes+epigenetic effects (methylation of genes)

HPV→incorporated into cervical cell DNA→increased number of dysplastic cells→cancer formation

Invasion+Metastasis

cancer cell travel/metastasis→epithelial mesenchymal transition (EMT)

EMT: cell dedifferentiation+suppression of adhesion molecule expression (including E-cahedrin)+digestion of the connective tissue capsule

normal: EMT→apoptosis
cancer: cells skip apoptosis cell→move to other parts of body+may lay dormant

Carcinogens List

tobacco

diet+nutrition

obesity

alcohol use

lack of exercise

air pollution

occupational

ionizing radiation

non-ionizing+electromagnetic radiation

ultraviolet radiation

Carcinogens: Tobacco

causes of cancer:
direct mutagenesis
inflammation+production of reactive oxygen species (ROS)
epigenetic alterations (including DNA methylation)

e-cigarrettes: contain small particles→carcinogenic

marijuana smoke: increases risk of chronic bronchitis

Carcinogens: Diet+Nutrition

anti-carcinogenic:
-mediterranean diet
-nutrients+herbs
act as antioxidants→scavenge+bind free radicals
create beneficial epigenetic effects

carcinogenic:
-processed foods
-preservatives
-saturated fats
-grilled red meat

pt recommendations:
much is still not known
lots of vegetables
more fish
low fat
less red meat
more whole grains

Carcinogens: Obesity

causes of cancer:

insulin-like growth factor effects:
alters expression of insulin growth factor 1 (IGF-1)+related receptors→cancer-promoting features

adipocyte-derived cytokines:
lipolysis of saturated fats→pro-inflammatory effects (macrophage activation+cytokine release)

sex hormone production:
estrogen→aromatase enzyme production

Carcinogens: Alcohol

well established as carcinogen

no safe limit of consumption

causes of cancer:
increasing oxidative stress
increased DNA methylation
histone modifications
aberrant microRNA expression

pt recommendation: drink as little as possible

Carcinogens: Exercise

proved to reduce the risk of cancer

methods of reducing cancer:
positive influence on insulin-like growth factors
reduces obesity
decreases circulating sex hormones
improves immune system function+reduces inflammation
enhancing cytochrome P-450 activity
decreases insulin growth factor

Carcinogens: Air Pollution

made up of numerous acids/organic/in-organic chemicals/metals/dust particles

all smoke is carcinogenic

causes of cancer:
oxidative stress
DNA damage
inflammation

E:
combustion from inefficient indoor cooking
volatile organic compounds (VOCs) from cleaning supplies/paint/air conditioners
formaldehyde from furniture and glues
building materials

Occupational Carcinogens Examples

asbestos→mesothelioma

benzenes→leukemia

O-Toluidine+aniline→bladder cancer

pesticides→lyphomas

Ionizing radiation

higher energy radiation that alters electrons in substances it passes through→can directly damage DNA

causes of cancer:
pro-cancer inflammation
oxidative stress

Non-Ionizing+Electromagnetic Radiation

E:
radiowaves
microwaves
wifi
cell phones
electronic devices

link between non-ionizing+electromagnetic radiation→cancer has been hard to establish+controversial

pt recommendations: don’t worry

Ultraviolet Radiation

exposure→increases both squamous cell+basal cell carcinomas

acute sunburns→melanoma

lighter skin→higher risk

causes of cancer:
induction of gene mutations
DNA methylation+histone modifications
increased inflammation+oxidative stress
reduced immune surveillance

pt recommendations: use sun protection methods

Two Hit Theory

cancer isn’t the result of just one problem→a combination of multiple problems

need two copies of a mutated tumor suppressor gene to cause cancer

cancer benefits from a combination of the hallmarks we discussed→not all hallmarks need to be present for a cancer to take root+thrive