Carcinogenesis

Question 1

New growth (aka tumour)

Answer 1

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.

Question 2

Benign

Answer 2

remain localized at their site of origin

Question 3

Malignant

Answer 3

invade and destroy adjacent structures and spread to distant sites.

Question 4

-oma

Answer 4

Often denotes a benign tumour
ex) Lipoma, osteochondroma, adenoma

Some notable exceptions: lymphoma, melanoma, mesothelioma (all malignant)

Question 5

Carcinoma

Answer 5

Malignant tumour of epithelial cell origin

Question 6

Sarcoma

Answer 6

Malignant tumour of mesodermal/mesenchymal origin

ex) muscle, cartilage, bone

Question 7

Differentiation

Answer 7

Extent to which neoplastic parenchymal cells resemble corresponding normal parenchymal cells both morphologically and functionally.

Question 8

tumour cells resemble normal cells

Answer 8

Well-differentiated
Characteristic of benign tumors

Question 9

tumor cells do not resemble normal cells

Answer 9

Poorly-differentiated (aka anaplastic)
Characteristic of malignant tumor

Question 10

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

Answer 10

Anaplasia (poorly differentiated)

Question 11

In addition to anaplasia, malignant tumors will often show:

Answer 11

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

Question 12

Chart of tumor characteristics:

Answer 12

visual:

Question 13

What are the two factors that can contribute to cancer risk?

Answer 13

genetic and environmental

Question 14

Best established environmental risk factors include:

Answer 14

-Infectious agent
-Smoking
-Alcohol
-Diet
-Obesity
-Reproductive history
-Environmental carcinogens

Question 15

Cancer can occur at any age, but most carcinomas occur in adults older than ______

Answer 15

55

-Likely explained by accumulations of somatic mutations that accompany the aging of cells.
-A decline in immune competence may also play a role.

Question 16

Some acquired conditions increase the risk of cancer:

Answer 16

-Chronic inflammatory disorders
-Precursor lesions
-Immunodeficiency states

Question 17

Cancer risk is increased in individuals with a wide variety of chronic inflammatory diseases. Why?

Answer 17

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.

Question 18

Localized morphologic changes in epithelial tissue that increase the risk of malignant transformation.

ex) could be hyperplasia, metaplasia, or dysplasia

Answer 18

Precursor lesions

Question 19

Increase in number of normal cells
ex) endometrial hyperplasia increases risk of endometrial cancer.

Answer 19

Hyperplasia

Question 20

Metaplasia

Answer 20

replacement of one differentiated somatic cells with another

Question 21

Presence of abnormal cells

ex) cervical dysplasia increases risk of cervical cancer

Answer 21

Dysplasia

Question 22

Metaplasia is the ________ of one differentiated somatic cells with another.

Answer 22

Replacement

Question 23

When does metaplasia occur?

Answer 23

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.

Question 24

Immunodeficient patients are at an increased risk for cancer. Why?

Answer 24

They have a higher than-normal incidence of chronic infection from viruses.

Thus, higher risk of getting oncogenic virus.

Question 25

Increased cellular replication creates a "fertile ground" for the development of malignant tumors:

Answer 25

Repeated rounds of cell division-> higher likelihood of accumulating mutations resulting in malignancy (Mutations frequently involve dysregulation of start transition)

Question 26

__________ a multistep process resulting from the accumulation of multiple mutations.

Answer 26

Carcinogenesis Mutations that results in the attributes of malignant cells-excessive growth, local invasion, distant metastasis

Question 27

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

Answer 27

Initiating Mutation

Question 28

mutation that increases malignant potential of the cell.

Answer 28

Driver Mutation

Question 29

Mutation with low malignant effect

Answer 29

Passenger Mutation

Question 30

What are the 4 main categories of mutated genes:

Answer 30

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)

Question 31

Once established, tumors evolve genetically based on _____________ of the fittest.

Answer 31

survival/selection -Mutations are acquired at random. -Resulting in tumor cells being genetically heterogeneous.

Question 32

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.

Answer 32

subclones; subclones

Question 33

Oncogenes:

Answer 33

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

Question 34

-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

Answer 34

Ras (oncogenes)

Question 35

Very common in certain cancers ex) 30% of breast carcinomas have PI3K gain-of-function mutations

Answer 35

PI3K (oncogenes)

Question 36

-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

Answer 36

MYC (transcription factor): onconogene

Question 37

Which of the two cell cycle checkpoints regulated by cdk-cyclin complexes do you suppose is more important in cancer?

Answer 37

G1 & G2 cdks & cyclins (onconogenes)

Question 38

Gain-of-function mutations in cyclin D and Cdk4: How would this affect progression through the G1/S checkpoint?

Answer 38

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

Question 39

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

Answer 39

Tumor suppressor

Question 40

RB: (tumor suppressor)

Answer 40

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

Question 41

What form do we normally find RB in a quiescent cell?

Answer 41

Rb is primarily found in its hypophosphorylated state, where it acts to maintain cell cycle arrest.

Question 42

What form is RB in to facilitate passing through the G1/S checkpoint?

Answer 42

Phosphorylation of Rb is a key regulatory event that enables cell cycle progression when the cell receives appropriate signals for growth and division.

Question 43

"Guardian of the genome"

Answer 43

TP53

Question 44

TP53 codes for:

Answer 44

P53

Question 45

What is P53?

Answer 45

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

Question 46

How can mutated P53 contribute to carcinogenesis?

Answer 46

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.

Question 47

P53 functions in the presence of DNA damage:

Answer 47

Arrests the cell cycle until DNA can be repaired.

Question 48

P53 stimulates DNA reair:

Answer 48

If DNA repair is successful=> cell cycle can resume If DNA repair fails => P53 will activate pro-apoptotic pathways

Question 49

True or False: P53 mutations are commonly responsible for genomic instability, driving tumor progression.

Answer 49

True

Question 50

With loss of ______, DNA damage goes unrepaired & driver mutations accumulate in oncogenes & other cancer genes-> malignant transformations

Answer 50

P53

Question 51

_______ are frequently mutated or otherwise silenced in many human malignancies.

Answer 51

CDKI's

Question 52

-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

Answer 52

P16; P16 (CDKI)

Question 53

P16 function:

Answer 53

Inhibits Cdk4-Cyclin D complex (G1-cdk complex) needed for progression through the cell cycle

Question 54

What do you notice about the common oncogenes and tumor suppressor genes we have discussed? Where do they all affect the cell cycle?

Answer 54

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

Question 55

β-Catenin:

Answer 55

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

Question 56

Hallmarks of cancer:

Answer 56

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

Question 57

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

Answer 57

Warburg effect

Question 58

Why do you suppose a cancer cell is relying on glycolysis alone for ATP production?

Answer 58

Provides rapidly dividing tumor cells with metabolic intermediates needed for synthesis of cellular components. -Mitochondrial oxidative phosphorylation does not!

Question 59

Normal human cells divide _______ times and then become senescent.

Answer 59

60-70

Question 60

Cell permanently exits the cell cycle & never divides again

Answer 60

Senescent

Question 61

Cancer cells can evade senescene:

Answer 61

-Likely due to loss of functions mutations in p53 and p16 -Allows cell to pass through G1/S checkpoint

Question 62

Cancer cells have also demonstrated the ability to express ___________

Answer 62

telomerase -Very minimally expressed in most somatic cells -Allows cancer cells to continue replicating indefinetly

Question 63

Radiation is ____________ and _____________

Answer 63

Mutagenic; carcinogenic

Question 64

UV Radiation:

Answer 64

Associated with squamous cell carcinoma, basal cell carcinoma, and melanoma of the skin

Question 65

Ionizing radiation:

Answer 65

-Medical X-Rays -Occupational exposure -Nuclear plant accidents

Question 66

Many ___ and ___ viruses have been proven to be oncogenic.

Answer 66

RNA & DNA

Question 67

RNA Viruses:

Answer 67

Human T-cell leukemia virus type 1 (HTLV-1) -Associated w/ leukemia

Question 68

DNA viruses:

Answer 68

-HPV: Human Papillomavirus -EBV: Epstein Barr virus -HBV(&HCV): Hepatitis B virus -Merkel cell Polyomavirus -HHV8: Human herpesvirus 8