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Y1 TP2 Pathological Processes (topic 3 Onwards) > 10. Neoplasia 3 > Flashcards

10. Neoplasia 3 Flashcards

1
Q

Hallmarks of cancer

A
  • Self-sufficiency in growth signals – don’t need anything extra to aid growth
    • Insensitivity to antigrowth signals
    • Sustained angiogenesis
    • Tissues invasion and metastasis
    • Limitless replicative potential
    • Evasion of apoptosis – avoid cell death
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2
Q

THE CAUSE OF NEOPLASIA IS MULTIFACTORIAL

A

—> Combination of extrinsic and intrinsic factors – something within the cell and something within cellular environment

A critical combination of intrinsic host factors (such as heredity, age and sex (especially hormonal), and extrinsic factors related to the environment and behaviour account for cancer risk.

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3
Q

Intrinsic factors

A
  • Hereditary
    • Age
    • Sex
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4
Q

Extrinsic factors

A
  • Environment

* Lifestyle

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5
Q

• Modifiable (by the individual)

Factors for cancer

A 
○ Diet 
		○ Smoking 
		○ Uv exposure 
		○ Alcohol 
= 75% of cancer deaths due to our own behaviour
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6
Q

• Non modifiable factors for cancer

A

○ Ionizing radiation

○ Medical procedure

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7
Q

How do we link environmental factors to carcinogenesis (causing cancer)?

A

Observation
—> First do an observation to identify link between factor and causing cancer

Epidemiology:
—> clusters of many cases of a specific type – e.g. cluster of cancer cases = it is a scaled up normal observation with a larger sample

Experiment:
- sometimes with animals

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8
Q

TESTING OF CHEMICAL CARCINOGENS

Problem

A

—> It has not been economically feasible to test all the compounds to which people may be exposed.
Not enough money provided by government to do testing and not enough pressure put on to t

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9
Q

Criteria for testing selection include:

Testing chemical carcinogens

A
  • Compounds related to known carcinogens
  • New compounds that are to be placed in the environment
  • Compounds that are indicated by surveys to be associated with an increased incidence of cancer
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10
Q

IN VITRO TESTING OF CHEMICAL CARCINOGENS

A

Testing for them in animals

  • The high cost of animal screening has driven the search for short-term in vitro tests.
  • Because many carcinogens require metabolic activation, the bacteria are incubated with a rat liver S9 fraction.
  • The theoretical basis for tests of this type is the good but not perfect correlation between mutagenic and carcinogenic activity.
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11
Q

The Ames Test for Mutagenicity

A

—> done in bacteria

1. Test compound 
2. Mix test compound with homogenised liver – e.g. homogenised rat liver
• This is done to activate the test compound in the liver = metabolic activation
3. But metabolically activated compound on bacteria on the disc 
• Add it to salmonella bacteria that is unable to grow without added histidine 
• If compound is metabollically activate it will reverse the point mutation – allows the bacteria to grow without the added histidine 
4. Identify the number of bacteria colonies have grown
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12
Q

The Diversity of Chemical Carcinogens

A

—> The number of known carcinogens in experimental animals is large. It is suspected that most of these are potentially carcinogenic in humans but documentation is lacking in most cases.

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13
Q

Carcinogens and targets

A

• Carcinogens are related to certain targets e.g. asbestos acts on and impact the lung and pleura

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14
Q

Carcinogen Metabolism

A
  • Chemical carcinogenesis appears to be associated with reaction with cellular nucleophiles (electron donor).
  • Many carcinogens must be metabolized to form electrophilic species (electron acceptor).
  • Organic compounds with double bonds may be metabolized to form reactive epoxides e.g. with benzo(a)pyrene, vinyl chloride and aflatoxin.
  • Nitrosamines can be metabolized to form carbonium ions that react with guanine to give an O6 -methyl derivative.
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15
Q

Carcinogen activation

A

When you are exposed to a chemical agent it is normally harmless an must be activated through chemical and metabollic changes to form a chemical species that likes to accept electrons = metabolites
• Occurs in the liver

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16
Q

Benzo(a)pyrene Activation

A

—> most potent carcinogen in tobacco smoke

When you smoke not all of it is converted into active form
• Most of it is deactivated – by adding additional functional groups
• Addition of reactive oxygen groups – causes it to react with DNA by sticking to nucleotide and intercalating into nucleus structure to disrupt and kink the helix in a permanent form

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17
Q

Different Steps of Carcinogenesis

A

Initiation
Promotion
Progression

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18
Q

Different Steps of Carcinogenesis

Initiation

A

• Initiation is the induction of a mutation in a critical gene involved in the control of cell proliferation and/or apoptosis
initiation requires one or more rounds of cell division for the “fixation” of the process.

• Initiation is irreversible although the initiated cell may eventually die during the development of the neoplasm.

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19
Q

Different Steps of Carcinogenesis

Promotion

A

• Selective growth enhancement induced in the initiated cell and its progeny by the continuous exposure to a promoting agent.

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20
Q

Different Steps of Carcinogenesis

Progression

A

• Results from continuing evolution of unstable chromosomes; further mutations from genetic instability during promotion - results in further degrees of independence, invasiveness, metastasis, etc. Progression covered in Neoplasia 2 lecture

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21
Q

Mutational Targets of Initiation

A
  • Mutational activation of oncogenic (proliferative) pathways (e.g. growth factor receptors and downstream signaling proteins, proteins involved in cell cycle checkpoints.
  • Mutational inactivation of apoptotic (cell death) pathways (e.g. growth inhibitory receptors, proteins involved in apoptosis, tumor suppressors).
  • Mutational inactivation of DNA repair mechanisms (e.g. BER, NER, etc).
  • Mutational inactivation of antioxidant response (e.g. Super Oxide Dismutase) - reactive oxidative species cause oxidative stress
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22
Q

p53 protein – the Guardian of the Genome

A
  • p53 is mutated in most cancers
  • p53 is a transcriptional factor that controls cell cycle, apoptosis, DNA repair mechanisms. - regulates transcription and critical physiological pathways involved in initiation of acner
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23
Q

Mdm2

A
  • Mdm2 is a negative regulator of p53 that functions both as an E3 ubiquitin ligase and an inhibitor of p53 transcriptional activation.
    • When Mdm2 binds to p53 it binds to it and inactivates it
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24
Q

Carcinogens and p53

A

• Carcinogens often inactivate p53 as well as proteins that control p53 function (e.g. Mdm2, p14)

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25
Q

p53 signalling

• Normal unstressed cell
A

○ P53 binds to Mdm2
○ P53 is not active
○ Binding of p53 to Mdm2 causes it be chucked out of nucleus and degraded by proteosome

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26
Q

p53 signalling

• Dna damage cell damage
A

○ Activate kinases
○ Increased polymerise p53 – phosphorylation means Mdm2 can’t bind to p53
○ So proliferation is not regulated as p53 can’t be inactivated

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27
Q

Ras gene and protein

A
  • RAS gene is mutated in approximately a third of all human malignant neoplasias
  • The RAS gene encodes a small G protein that relays growth promoting signals into the cell that release the cell cycle restriction points – GTP–> GDP
  • Mutant Ras protein is always active = doesn’t respond to growth signals and constantly makes cells grow
  • As for p53, carcinogens often inactivate RAS itself as well as proteins that control Ras function.
28
Q

K-Ras and p53 are the two oncogenes most frequently mutated in smoking-related lung cancers

A
  • Benzo(a)pyrene leads to mutations in K-Ras and p53 in the genomic loci found to be mutated in smoking-induced lung cancer
  • If not corrected by the cell’s DNA repair mechanism, this guanine “adduct” is misread as a thymine by the DNA polymerase that copies chromosomes during replication
  • Ultimately, the original G-C base pair may be replaced by a T-A base pair, a mutation called a transversion
  • Cells treated with Benzo(a)pyrene show the same spectrum of G-T transversions as found in the K-RAS and p53 of smokers.
29
Q

Tumour suppressor genes and oncogenes

examples

A
  • TP53 a tumor suppressor gene

* RAS an oncogene

30
Q

Tumour suppresor genes

A

• Tumour suppresor genes = inhibit neoplastic growth

○ Autosomal recessive - both alleles must be inactivated

31
Q

Oncogenes

A

• Oncogenes = enhance neoplastic growth once it has already started, it is an abnorally activated version of normal proto oncogenes
○ Only one allele of each proto-oncogene needs to be activated to favour neoplastic growth. - autodomal dominiant

32
Q

Proto oncogenes can encode

A

• Proto-oncogenes can encode growth factors (e.g. PDGF), growth factor receptors (e.g. HER2), plasma membrane signal transducers (e.g. RAS), intracellular kinases (e.g. BRAF), transcription factors (e.g. MYC), cell cycle regulators (e.g. CYCLIN D1) or apoptosis regulators (e.g. BCL2).

33
Q

Promoters

A
  • Reactive Oxygen Species (ROS) and redox active xenobiotics and metals.
  • Phorbol esters (e.g. TPA).
  • Polycyclic aromatic compounds (e.g. Dioxin).
  • Peroxisome Proliferators (oxidized fats).
  • Endocrine Disruptors (estradiol, DES). - important
    • Structurally look similar to normal signalling and regulatory molecules
    • Mode of action - mimicry
34
Q

Endocrine disruptors

A

—> specific compounds that look like hormones that are produced in the body
• Fools cells into thinking that they are bound to and interacting with normal hormone – so cells trigger a normal hormone response but under abnormal circumstances

35
Q

Endocrine Receptors and Carcinogenesis

A

–> compound that mimics oestrogen will push cells into growth

Endocrine disruptors are involved in breast, ovarian, colon, prostate cancers.

  • ERβ/ERα (estrogen receptors) ratio is decreased in cancers (ligands include estradiol); ERs are transcription factors.
  • ERβ inhibits ERα
  • ERα-ERα dimerization (homodimer) leads to mitogenic activation.
  • ERβ-ERα dimerization (heterodimer) leads to an inactivation.
  • Androgen Receptor (prostate) (AR) can also homodimerize with AR leading to mitogenic activation; AR can heterodimerize with ERβ to cause growth arrest (prostate also dependent on estrogenic signals)
36
Q

Initiation promotion relationship

A
  1. Initiator
    1. Promoter
    2. Progression

Timing is important and the initiator and promotor relationship is specific to different compound

Some carcinogens can act as both initiators and promotors

37
Q

Inflammation as a carcinogen

A
  • Inflammation acts at all stages of tumorigenesis
  • It may contribute to tumor initiation through mutations, genomic instability
  • Inflammation activates tissue repair responses, induces proliferation of premalignant cells, and enhances their survival
  • Inflammation also stimulates angiogenesis, causes localized immunosuppression, and promotes the formation hospitable microenvironment in which premalignant cells can survive, expand, and accumulate additional mutations
  • Inflammation also promotes metastatic spread.

—> due to repeated damage and stress that inflammation causes to cells and then in the healing processes the presence of proliferating cells is the perfect environment for carcinogenesis

38
Q

Infection as a carcinogen

A

• Some infections directly affect genes that control cell growth.

Others do so indirectly by causing chronic tissue injury, where the resulting regeneration acts either as a promoter for any pre-existing mutations or else causes new mutations from DNA replication errors.

39
Q

HPV and cervical carcinoma

A

direct carcinogen because it expresses the E6 and E7 proteins that inhibit p53 and pRB protein function respectively, both of which are important in cell proliferation.
• HPV infects cell pushes cell to produce E6 and E7 which inhibits p53 – so cells pass through cycle without regulation = direct viral carcinogen as the products of HPV interact with genes directly

40
Q

Hep b and C

A

indirect carcinogens that cause chronic liver cell injury and regeneration. Bacteria and parasites can also indirectly lead to neoplasms. Helicobacter pylori causes chronic gastric inflammation and parasitic flukes cause inflammation in bile ducts and bladder mucosa, increasing the risk for gastric, cholangio- and bladder carcinomas respectively.
• Non direct – as they don’t interact with cell directly but create a suitable environment for carcinogenesis

41
Q

Direct carcinogen

A

Product of infection interacts directly with genes

42
Q

Indirect carcinogen

A

• Non direct – as they don’t interact with cell directly but create a suitable environment for carcinogenesis

43
Q

HIV

A

• Human Immunodeficiency virus (HIV) acts indirectly by lowering immunity and allowing other potentially carcinogenic infections to occur.

44
Q

Sporadic cancer

A
  • Sporadic – no links to other family members

* People with sporadic cancer typically do not have relatives with the same type of cancer.

45
Q

Familial Cancer

A

• Familial Cancer – Cancer likely caused by a combination of genetic and environmental risk factors. Cancer that occurs in families more often than would be expected by chance. These cancers often occur at an early age, and may indicate the presence of a gene mutation that increases the risk of cancer. They may also be a sign of shared environmental or lifestyle factors.

46
Q

Hereditary Cancer

A

• Hereditary Cancer – Cancer occurs when an altered gene (gene change) is passed down in the family from parent to child.

47
Q

Inherited predisposition to neoplasia

A

—>2 hit hypothesis = knock out both alleles – so both alleles are unable to act in the normal way
• In the 1970s Knudson postulated a two hit hypothesis to explain the differences between tumours occurring in families and those occurring in the general population I

48
Q

Knudson 2 hit hypothesis

A

• For familial cancers, the first hit is delivered through the germline and affected all cells in the body. The second hit is a somatic mutation. In the case of retinoblastoma this was in one of the 10 million+ retinal cells already carrying the first hit.

49
Q

Left ventricular hypertrophy

A
  • Lumina of left ventriclesis abnormally thick
    • Lumina of right ventricles
    • Normal left ventricular wall thickness
    • Thickened (hypertrophied) left ventricle = harder to pump blood
50
Q

Skeletal muscle atrophy

A

• Atrophied muscle fibres – reduction in muscle fibre diameter can also be associated with reduction in function

51
Q

Metaplasia

A

• Metaplasia = transformation of cells

52
Q

Severe dysplasia

A

• Severe dysplasia – more mitosis change to nucleus all within the epithelium does not extend beyond basement layer

53
Q

Breast fibroadenoma – benign tissue

A
  • Smooth edge of fibroadenoma (benign tumour of the breast)
    • Fibroadenoma
    • Most common breast tumour – no risk of cancer
    • Well defined edge of tumour
    • Differentiatiate between benign and malaignant tumour – malignant tumours invade surounding tissue
54
Q

Anaplasia

A
  • Sheets of undifferentiated pleomorphic cells
    • Mitotic figures – abnormal appearances
    • Blood vessel
    • Poor cell differentiate- can’t distinguish mature cancerous cell
    • High grade of peomorphism – variation in shape and size
    • Dark stained nuclei
    • Giant cells

—> can’t determine the original cell that they are differentating from

55
Q

Pleomorphism

A
  • Malignant cells showing significant pleomorphism

* Varying shapes and size

56
Q

Nuclear hyperchromasia

A
  • Malignant cells showing significant nuclear hyperchromasia

* Darkly stained chromatin

57
Q

High nuclear to cytoplasmic ratio

A
  • Cytology preparation showing high nuclear:cytoplasmic ratio in malignant epithelial cells
    • Inflammatory cells like neutrophils
58
Q

Abnormal mitotic figure in malignant tumour

A
  • Abnormal mitotic figure with four poles - quadpolar

* Normal mitotic figure = 2 poles

59
Q

Squamous cell carcinoma

A

• Islands of malignant cells containing ‘whorls’ of keratin
○ Keratin in squamous cell carcinoma as it arises from epithelium of skin
○ Extend from epidermis to dermis
○ Larger nucleus
• Stroma

—> malignant tumour of epithelium tissue

60
Q

Adenocarcinoma

A
  • Glandular lumen surrounded by malignant epithelial cells
    • Adenocarcinoma = tumour of glandular epithelium
    • Bizarre shaped cells, high nuclear to cytoplasm ratio, can differentiate origin of the cell

Tumour of gland – adenoma

61
Q

Malignant melanoma

A
  • Epidermis
    • Nodules of malignant cells within dermis
    • Melanin pigment
    • Large cells, granular cytoplast, large nuclei, brown melanin pigment scattered
62
Q

In situ and invasive malignancy

A
  • Epithelial basement membrane – broken basement memebrane at a certain point due to invasive malignancy
    • Invasive malignancy (has broken through the basement membrane)
63
Q

Cervical intraepithelial neoplasia

A

• Cervical intraepithelial neoplasia(is a precancerous condition in which abnormal cells grow on the surface of the cervix) - neoplasm in epithelium

64
Q

Transcoelomic spread

A
  • Blue arrow indicates peritoneal deposit of carcinoma
    • Small tumours within peritoneum
    • Under microscope = malignant tumours infiltrating peritoneum
    • Abdomen and pelvic cavity – transcolemic spread
65
Q

Malignant mesothelioma

A

• Malignant mesothelioma involving pleura – cancer of covering of lung – pleura
○ Due to asbestos exposure

66
Q

Schistosome eggs in bladder wall

A

• Transitional epithelium
• Inflamed bladder wall – dark purple inflammatory cells
• Schistosome eggs = disease due to parasite infection
○ Affect urinary tract and intestine
○ Extensive inflammation
○ Abdominal pain, bladder stool, blood in urine

Y1 TP2 Pathological Processes (topic 3 Onwards) (9 decks)

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