Carcinogenesis Flashcards
New growth (aka tumour)
Neoplasia:
Neoplasm is an abnormal mass of tissue
-Uncoordinated & excessive growth
-Continues beyond cessation of growth
stimuli.
Tumours can be classified as malignant or benign.
Benign
remain localized at their site of origin
Malignant
invade and destroy adjacent structures and spread to distant sites.
-oma
Often denotes a benign tumour
ex) Lipoma, osteochondroma, adenoma
Some notable exceptions: lymphoma, melanoma, mesothelioma (all malignant)
Carcinoma
Malignant tumour of epithelial cell origin
Sarcoma
Malignant tumour of mesodermal/mesenchymal origin
ex) muscle, cartilage, bone
Differentiation
Extent to which neoplastic parenchymal cells resemble corresponding normal parenchymal cells both morphologically and functionally.
tumour cells resemble normal cells
Well-differentiated
Characteristic of benign tumors
tumor cells do not resemble normal cells
Poorly-differentiated (aka anaplastic)
Characteristic of malignant tumor
Pleomorphism: cells vary in size and shape
-may include the presence of tumor giant
cells.
Abnormal nuclear morphology
-Nuclei containing abundant chromatic will
stain darker than normal (aka
hyperchromatic)
-Disproportionally large nuclei & nucleoli
-Presence of large numbers and abnormal
mitosis.
ex) Tripolar or quadripolar
Loss of cell polarity
Anaplasia (poorly differentiated)
In addition to anaplasia, malignant tumors will often show:
Ischemic necrosis
Areas of hemorrhage
Local invasion:
-Benign tumors are frequently encapsulated and do not demonstrate local invasion.
-Malignant tumors typically lack a capsule and do extend into adjacent normal tissue
Metastasis:
-migration to distant tissues via lymphatics or blood vessels
Chart of tumor characteristics:
visual:
What are the two factors that can contribute to cancer risk?
genetic and environmental
Best established environmental risk factors include:
-Infectious agent
-Smoking
-Alcohol
-Diet
-Obesity
-Reproductive history
-Environmental carcinogens
Cancer can occur at any age, but most carcinomas occur in adults older than ______
55
-Likely explained by accumulations of somatic mutations that accompany the aging of cells.
-A decline in immune competence may also play a role.
Some acquired conditions increase the risk of cancer:
-Chronic inflammatory disorders
-Precursor lesions
-Immunodeficiency states
Cancer risk is increased in individuals with a wide variety of chronic inflammatory diseases. Why?
Chronic inflammatory diseases is accompanied by tissue damage.
-Cell proliferation must occur to repair the
damage.
Activated immune cells produce reactive oxygen species that can damage DNA.
Inflammatory mediators produced can promote cell survival.
Localized morphologic changes in epithelial tissue that increase the risk of malignant transformation.
ex) could be hyperplasia, metaplasia, or dysplasia
Precursor lesions
Increase in number of normal cells
ex) endometrial hyperplasia increases risk of endometrial cancer.
Hyperplasia
Metaplasia
replacement of one differentiated somatic cells with another
Presence of abnormal cells
ex) cervical dysplasia increases risk of cervical cancer
Dysplasia
Metaplasia is the ________ of one differentiated somatic cells with another.
Replacement
When does metaplasia occur?
In response to chronic irritation so that cells can better withstand the stress.
-Occurs due to the reprogramming of stem
cells
or undifferentiated mesenchymal cells
found in connective tissue.
ex) Transformation of columnar epithelium of squamous epithelium in trachea of cigarette smokers.
Immunodeficient patients are at an increased risk for cancer. Why?
They have a higher than-normal incidence of chronic infection from viruses.
Thus, higher risk of getting oncogenic virus.
Increased cellular replication creates a “fertile ground” for the development of malignant tumors:
Repeated rounds of cell division-> higher likelihood of accumulating mutations resulting in malignancy
(Mutations frequently involve dysregulation of start transition)
__________ a multistep process resulting from the accumulation of multiple mutations.
Carcinogenesis
Mutations that results in the attributes of malignant cells-excessive growth, local invasion, distant metastasis
Found in all progeny, begins the process towards malignant transformation.
-Essentially the first driver mutation
-Often include loss-of-function mutations in genes that maintain genomic integrity.
-leading to genomic instability
Initiating Mutation
mutation that increases malignant potential of the cell.
Driver Mutation
Mutation with low malignant effect
Passenger Mutation
What are the 4 main categories of mutated genes:
Proto-oncogenes: gain of function mutations=>oncogenes
Tumor suppressor genes: Generally loss-of-function mutations
Genes regulating apoptosis: can be gain- or loss-of function
Genes responsible for DNA repair: Generally loss of function, affected cells acquire mutations at an accelerated rate (aka genomic instability)
Once established, tumors evolve genetically based on _____________ of the fittest.
survival/selection
-Mutations are acquired at random.
-Resulting in tumor cells being genetically
heterogeneous.
Tumor ________ compete for access to nutrients with fittest _________ dominating tumor mass.
As a result, the tumor will become more aggressive over time. (tumor progression)
This also explains changes in tumor behaviors following therapy.
-Tumors that recur after therapy are almost always resistant to initial treatment.
subclones; subclones
Oncogenes:
Promote excessive cell growth, even in the absence of normal growth-promoting signals.
-created by mutations in proto-oncogenes
(unmutated cellular counterparts)
-Encode oncoproteins that participate in
signaling pathways driving cell proliferation.
Can include: growth factors or their receptors, signal transductors, transcription factors, or cell cycle components.
Proto-oncogenes:
-Ras
-PI3 K
-Myc
-Cyclins and cdks
-Downstream component of receptor tyrosine kinases signaling pathways.
-Point mutation of RAS family genes is the single most common abnormality of proto-oncogenes in human tumors.
-Approx. 15& to 20% of all human tumors
contain mutated versions of RAS
ex) 90% of pancreatic adenocarcinomas
and cholangiocarcinomas
-50% of colon, endometrial, and thyroid
cancer
-30% of lung adenocarcinomas and
myeloid leukemia -Important downstream signaler for lots of growth factors: EGF, PDGF, and CSF-1
Ras (oncogenes)
Very common in certain cancers
ex) 30% of breast carcinomas have PI3K gain-of-function mutations
PI3K (oncogenes)
-Immediate early response gene
Induced by Ras/MAPK signaling
when activated:
-Increases cell proliferation and growth
-Contributes of other hallmarks of cancer
Warburg effect (can upregulate glycolytic
enzymes)
Increased telomerase activity (contribute
to endless replicative activity)
May also allow more terminal
differentiated cells to gain
characteristics of stem cells.
-Implicated in cancers of breast, colon, lung
MYC (transcription factor): onconogene
Which of the two cell cycle checkpoints regulated by cdk-cyclin complexes do you suppose is more important in cancer?
G1 & G2
cdks & cyclins (onconogenes)
Gain-of-function mutations in cyclin D and Cdk4:
How would this affect progression through the G1/S checkpoint?
Cells may enter the S phase without appropriate control mechanisms, potentially leading to uncontrolled proliferation and an increased risk of accumulating DNA damage and mutations.
FYI: implicated in melanomas, sarcomas, glioblastomas
Products of ____________ apply brakes to cell proliferation.
-Abnormalities lead to failure of growth inhibition
-Many, such as RB and p53 recognize genotoxic stress.
Responds by shutting down proliferation.
Activation of oncogenes aren’t enough for cancer induction usually requires loss of tumor suppressor genes as well.
Types:
-RB
-P53
-CKI’s
Tumor suppressor
RB: (tumor suppressor)
Functions as a key regulator of the G1/S checkpoints
Directly or indirectly inactivated in most human cancers.
Directly- loss of function mutation upregulating CDK4/ cyclin D
Loss of function mutation of CKI’s
What form do we normally find RB in a quiescent cell?
Rb is primarily found in its hypophosphorylated state, where it acts to maintain cell cycle arrest.
What form is RB in to facilitate passing through the G1/S checkpoint?
Phosphorylation of Rb is a key regulatory event that enables cell cycle progression when the cell receives appropriate signals for growth and division.
“Guardian of the genome”
TP53
TP53 codes for:
P53
What is P53?
Regulates cell cycle progression, DNA repair, cellular senescence, and apoptosis.
Most frequently mutated gene in human cancer
Loss of function mutation found in more than 50% of cancers including:
-Lung
-colon
-breast
(three leading causes of cancer death)
Can include mutations in P53 of Mdm2
How can mutated P53 contribute to carcinogenesis?
It allows cells to bypass critical control mechanisms, leading to uncontrolled growth, genomic instability, resistance to apoptosis, and other features that promote cancer development and progression. The loss of functional p53 is a significant factor in many types of cancer.
P53 functions in the presence of DNA damage:
Arrests the cell cycle until DNA can be repaired.
P53 stimulates DNA reair:
If DNA repair is successful=> cell cycle can resume
If DNA repair fails => P53 will activate pro-apoptotic pathways
True or False: P53 mutations are commonly responsible for genomic instability, driving tumor progression.
True
With loss of ______, DNA damage goes unrepaired & driver mutations accumulate in oncogenes & other cancer genes-> malignant transformations
P53
_______ are frequently mutated or otherwise silenced in many human malignancies.
CDKI’s
-Inherited mutations implicated in familial forms of melanoma.
-Acquired mutations detected in many cancers
ex) bladder cancers, head and neck tumors, all, cholangiocarcinoma
-________ can also be silenced by hypermethylation rather than mutation (epigenetic change)
-Occurs in some cervical cancers
P16; P16 (CDKI)
P16 function:
Inhibits Cdk4-Cyclin D complex (G1-cdk complex)
needed for progression through the cell cycle
What do you notice about the common oncogenes and tumor suppressor genes we have discussed? Where do they all affect the cell cycle?
Loss of normal cell cycle control is a major contributor to malignant transformation.
At least 1 of the 4 key regulators of the cell cycle is dysregulated in the significant majority of all human cancers.
p16, cyclin D, Cdk4, RB
G1/S checkpoint & phases
β-Catenin:
APC:
-Very commonly mutated in colorectal cancers
-Part of Wnt-B-catenin pathway
E-Cadherin:
-Loss of function mutations can contribute to loss of contact-inhibition in tumors and metastasis
Hallmarks of cancer:
1) Self-sufficiency in growth signals
2) Insensitivity to growth-inhibitory signals
3) Altered cellular metabolism
4) Evasion of apoptosis
5) Limitless replicative potential
6) Sustained angiogenesis
7) Ability to invade and metastasize
8) Ability to invade the host immune system
Cancer cells take up high levels of glucose and demonstrate increased conversion of glucose to lactate.
-Even in the presence of ample oxygen
-Also called aerobic glycolysis
Warburg effect
Why do you suppose a cancer cell is relying on glycolysis alone for ATP production?
Provides rapidly dividing tumor cells with metabolic intermediates needed for synthesis of cellular components.
-Mitochondrial oxidative phosphorylation does not!
Normal human cells divide _______ times and then become senescent.
60-70
Cell permanently exits the cell cycle & never divides again
Senescent
Cancer cells can evade senescene:
-Likely due to loss of functions mutations in p53
and p16
-Allows cell to pass through G1/S checkpoint
Cancer cells have also demonstrated the ability to express ___________
telomerase
-Very minimally expressed in most somatic cells
-Allows cancer cells to continue replicating indefinetly
Radiation is ____________ and _____________
Mutagenic; carcinogenic
UV Radiation:
Associated with squamous cell carcinoma, basal cell carcinoma, and melanoma of the skin
Ionizing radiation:
-Medical X-Rays
-Occupational exposure
-Nuclear plant accidents
Many ___ and ___ viruses have been proven to be oncogenic.
RNA & DNA
RNA Viruses:
Human T-cell leukemia virus type 1 (HTLV-1)
-Associated w/ leukemia
DNA viruses:
-HPV: Human Papillomavirus
-EBV: Epstein Barr virus
-HBV(&HCV): Hepatitis B virus
-Merkel cell Polyomavirus
-HHV8: Human herpesvirus 8
