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principles of disease > tumour pathology > Flashcards

tumour pathology Flashcards

1
Q

what are the properties of cancer cells

A
  • loss of tumour suppressor genes
  • gain of function of oncogenes
  • Altered cellular function
  • Abnormal morphology - key for evaluating tumour and making diagnosis of type and likely behaviour
  • Cells capable of independent growth - one of the defining factors of tumours
  • No single feature is unique to cancer cells
  • Tumour biomarkers - specific genes/proteins which are used to make an assessment of a tumour in a clinic for a particular purpose
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2
Q

give 3 examples of tumour suppressor genes

A

exist in normal cells and keep them under regulatory control
• Adenomatous polyposis (APC) - colon, benign which can turn into cancer
• Retinoblastoma (Rb) - tumour suppressor gene

BRCA1 - breast cancer tumour suppressor gene

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3
Q

give 6 examples of oncogenes

A

normally silent in cells

* B-raf 
* Cyclin D1
* ErbB2
* C-Myc
* K-ras, N-ras
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4
Q

cellular function in cancer cells

A
  • Loss of cell to cell adhesion - normal cells stick together, cancer cells are less likely to stick together making them more likely to spread to other sites in the body
  • Altered cell to matrix adhesion
  • Production of tumour related proteins
    Tumour biomarkers
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5
Q

what are tumour biomarkers

A

protein/gene expressed in a specific type of tumour which can be exploited clinically to aid diagnosis, treatment and prognosis

  • Onco-foetal proteins - present in normal foetal life, switched off post-natally, switched on in tumours
  • Oncogenes
  • Growth factors and receptors
  • Immune checkpoint inhibitors - used in treatment of cancer
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6
Q

what is the clinical utility of tumour biomarkers

A
  • Screening (of asymptomatic patients for specific types of cancer, allows early detection)
  • Diagnosis
  • Prognostic - Identifying patients with a specific outcome (good or bad)
  • Predictive - Identifying patients who will respond/won’t respond to a particular therapy (means treatment can be avoided if it will only cause side effects and wont have any clinical effect)
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7
Q

clinical use of alpha-fetoprotein

A

equivalent to albumin, produced in the liver, switched off following birth, switched on in tumours, can be measured in the blood
• Teratoma of testis
Hepatocellular carcinoma

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8
Q

clinical use of carcino-embryonic antigen

A

onco-foetal protein, useful to monitor patients following diagnosis, increased level indicates onset of metastatic disease
• Colorectal cancer

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9
Q

clinical use of oestrogen receptor

A

high proportion of breast cancer tumours express oestrogen receptors
Breast cancer

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10
Q

clinical use of prostate specific antigen

A
  • found in prostate gland, useful in diagnosis and response to treatment
    Prostate cancer
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11
Q

give 5 clinically useful predictive tumour biomarkers

A

Kras = Colorectal cancer
Braf = Melanoma
EGFR (epidermal growth factor receptor), PD-L1 (molecule in the immune system)= Lung cancer
Her2 = Breast cancer, gastric cancer

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12
Q

Morphology of cancer cells

A
  • Cellular and nuclear pleomorphism
    • Marked variation in size and shape
    Mitoses present and often abnormal - as cancer is a growing tissue
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13
Q

tumour growth

A
  • Tumour growth is balance between cell growth and cell death
    Angiogenesis - New blood vessel formation by tumours
    apoptosis - mechanism of programmed cell death
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14
Q

angiogenesis in tumour growth

A

○ Required to sustain tumour growth (nutrients into the tumour), need own blood supply once bigger than 1mm
○ Provides route for release of tumour cells into circulation
○ More blood vessels in a tumour = poorer prognosis - tumour cells are more likely to be released into the blood vessels and into the circulation, higher chance of metastases forming

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15
Q

apoptosis in tumour growth

A

○ Active cell process
○ Regulates tumour growth
○ Involved in response to chemotherapy and radiotherapy - higher rate of apoptosis are more likely to be responsive to therapy and more likely to be destroyed

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16
Q

spread of cancer

A

fundamental property of cancer, invasion and metastases

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17
Q

invasion and metastases

A
  • Multi-step process
    • Increased matrix degradation by proteolytic enzymes - creates a track through which the tumour can move
    • Altered cell to cell and cell to matrix adhesion - allows the tumour to move
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18
Q

what is the clinical significance of cancer spreading

A
  • Major clinical problem is formation of metastatic (2y) tumours - look identical to the 1y tumours
    • Prognosis depends on extent of cancer spread
    • Patients can present with metastatic disease
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19
Q

modes of spread of cancer

A

• Local - invasion
○ Trans-coelomic - special form of local spread, spread of tumour cells across body cavities e.g. pleural or peritoneal cavities (potential space). Tumours of lung, stomach, colon and ovary show trans-coelomic spread. Can lead to multiple tumour deposits quite rapidly
• Lymphatic - to regional lymph nodes
• Blood - to many different tissue types throughout the body

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20
Q

tumour invasion process

A

malignant tumour –> invasion into connective tissue –> invasion into lymph/blood vessles

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21
Q

tumour metastasis via lymphatics

A

adherence of tumour cells to lymph vessels –> invasion from lymphatics –> invasion into lymph node –> formation of metastasis in lymph node –> clinical evidence of metastasis

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22
Q

tumour metastasis via blood

A

ASSUMES CANCER CELLS ARE WITHIN THE BLOOD VESSEL
adherence of tumour cells to blood vessels –> invasion from blood vessels –> invasion into tissue –> formation of metastasis –> clinical evidence of metastasis

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23
Q

sites of tumour metastases are not related to …

A

tissue blood flow

formation depends on tumour and tissue related factors

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24
Q

common sites of metastasis

A
  • Liver
    • Lung
    • Brain
    • Bone (axial skeleton) - limb bones are much
      less likely to develop metastases
    • Adrenal gland
    • Omentum (fat found within the abdominal cavity)/peritoneum
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25
Q

uncommon sites of metastasis

A
  • Spleen
    • Kidney
    • Skeletal muscle
      Heart
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26
Q

tumours which commonly metastasise to specific sites

A

breast –> bone
prostate –> bone
colorectal –> liver
ovary –> omentum/peritoneum

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27
Q

local effects of benign tumours

A
  • Pressure - mass of tissue growing against an anatomical structure
    Obstruction - if the mass if adjacent to or within a hollow structure
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28
Q

local effects of maligant tumours

A
  • Pressure
  • Obstruction
    Tissue destruction
  • bleeding
  • pain
  • Effects of treatments - local and systemic effect, killing off the tumour can result in setting off inflammatory reaction - swelling and obstruction
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29
Q

tissue destruction as an effect of malignant tumours

A

Ulceration/infection

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30
Q

bleeding as a result of malignant tumours

A

ulceration exposes the underlying blood vessels
• Anaemia - slow loss of blood, common with tumours in the GI tract
• Haemorrhage - tumour hits a large blood vessel, large and sudden loss of blood

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31
Q

pain as a result of malignant tumours

A
  • Pressure on nerves
    • Perineural infiltration - tumour grows along the nerve
    • Bone pain from pathological fractures - fractures of weakened bone as a result of being destroyed and replaced by metastatic tumours
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32
Q

systemic effects of malignant tumours

A
  • Weight loss-cancer cachexia
  • secretion of hormones
  • paraneoplastic syndromes
  • effects of treatment
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33
Q

weight loss cancer cachexia

A

characteristic of any sort of cancer irrespective of site and spread, weight loss not related to lack of food intake

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34
Q

secretion of hormones a a result of malignant tumuors

A

patients can present with symptoms of the hormone imbalance, not the underlying malignancy
• Normal: produced by tumours of an endocrine organ
• But abnormal control of hormone production/secretion
• Abnormal/inappropriate: produced by tumour from an organ that doesn’t normally produce hormone
• E.g. ACTH, ADH - lung cancer
Patients present with signs and symptoms of the abnormal hormone production

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35
Q

paraneoplastic syndromes

A 
muscle pain and weakness
	• Cannot be explained by local or metastatic effects if tumours e.g. neuropathy, myopathy 
		• Hard to explain and treat
	• Immune mechanism 
Production of hormone/growth factor
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36
Q

early detection of cancer

A
  • Important to detect cancer at early stage
  • Reduce/prevent morbidity/mortality
  • Detection at pre-invasive stage (pre-malignant state)
    • Identification of dysplasia/intraepithelial neoplasia
  • Requires effective test: sensitive/specific, acceptable
  • E.g. Cervical cancer screening
    • Established NHS programme, aims to reduce incidence of squamous carcinoma of cervix, detection of dysplastic cells from squamous epithelium of cervix
  • E.g. breast cancer screening
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37
Q

dysplasia

A
  • Pre-malignant change
  • Earliest change in the process of malignancy that can be visualised
  • Identified in epithelium
  • No invasion - if it has invaded it is a cancer
  • But can progress to cancer
38
Q

features of dysplasia

A

• Disorganisation of cells: increased nu size, increased mitotic activity, abnormal mitoses
• Grading of dysplasia: high grade/low grade (how abnormal the cells are, higher grade - higher degree of abnormality and higher risk)
No invasion

39
Q

what is the cell cycle

A

cell cycle = ordered series of events between mitotic divisions
Nuclear division plus cytokinesis produces 2 genetically identical diploid daughter cells

40
Q

what are the 3 periods of the cell cycle

A
  • INTERPHASE: (G1, S, G2)during which the cell grows and accumulates nutrients needed for mitosis; the cell is synthesizing RNA, producing protein and growing in size. The molecular events that regulate the cycle are ordered and directional- it is impossible to reverse the cycle
  • MITOSIS: phase during which the cell splits itself into two distinct cells
  • CYTOKINESIS: new cell is completely divided
    Each phase of the cycle has a distinct set of specialised biochemical processes that prepare the cell for division.
41
Q

cell cycle control

A
  • Cycle phases must be in correct sequence
    • DNA synthesis and mitosis must occur sequentially
    • Quality control: Each daughter cell must receive a full chromosome complement; genetic damage must be detected and repaired
  • Division is coordinated and tightly controlled and ensures the correct type of cells grow in the correct environment - prevents uncontrolled cell division and genetic damage passing on

The genome is replicated only once; daughter cells missing all or part of crucial genes die. Errors in mitosis can either kill a cell or cause mutations. Possession of extra copies of certain genes also deleterious.

42
Q

checkpoints in the cell cycle

A
  • Monitor and regulate progress and achieve control
    • Prevent progression at specific points
      G1/S checkpoint and the G2/M checkpoint.
43
Q

what is the rate-limiting step in the cell cycle

A

G1/S transition

known as restriction point

44
Q

G1/S restriction point

A

signals cells with inadequate nutrients or DNA damage to stop growing

45
Q

where would the cycle be stopped if cells had inadequate nutrient supply or external stimulus was lacking

A

G1 arrest

46
Q

if the cell was an abnormal size or DNA damage was detected where would be cycle be stopped

A

G1 or G2 arrest

47
Q

if DNA wasnt replicated where would the cycle be stopped

A

S arrest

48
Q

if chromosomes were misaligned where would the cycle be stopped

A

M phase arrest

49
Q

what external factors may influence the cell cycle

A

hormones, growth factors, cytokines

50
Q

what are cell cycle checkpoint activators

A
  • System of cyclically active and inactive enzyme switches
  • Catalytic subunit CDKs activated by a regulatory subunit cyclins
  • The active enzyme complex = cdk/cyclin complex
51
Q

what are the 2 key classes of regulatory molecules

A

cyclins and cyclin dependent kinases
- Different CDK/cyclin complexes operate at sequential stages of the cycle
- Active CDK/cyclin complexes phosphorylate target proteins which results in the proteins being activated/inactivated
Substrates regulate events in the next cycle phase

52
Q

action of CDKs

A

When activated by a bound cyclin, CDKs perform phosphorylation that activates or inactivates target proteins –> coordinated entry into the next phase of the cell cycle.

Different cyclin-CDK combinations determine the downstream proteins targeted.

A pro-mitotic extracellular signal, induces G1 cyclin-CDK complexes- become active and prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication.

53
Q

cell cycle inhibitors

A
  • CDK inhibitors (CKIs) - inhibitor molecules that bind to cyclin/CDK complexes
  • INK4A gene family - p16 (act at a very specific point of the cell cycle)
  • CIP/KIP gene family - p21, p27 (act at different points in the cell cycle)
    Multiple ways of inhibiting the cell cycle means they can respond to more than one stimulus
54
Q

what prevents cell cycle progression and how? (cell cycle inhibitors)

A

Two families of genes, the cip/kip family and the INK4a prevent cell cycle progression
The INK4a family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14 which prevents p53 degradation
The cip/kip family includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53

55
Q

the retinoblastoma gene

A
  • Encodes a 110 kDa phosphoprotein (pRb) expressed in almost every human cell
  • Hypophosphorylated pRb is active i.e. not phosphorylated
    • cells remain in G1 phase (puts a brake on the cell cycle)
  • Active cyclin D/CDK complexes phosphorylate pRb as the cell cycle progresses
    • Rb gene mutations favour cell proliferation - brake in cell cycle is removed

• Mutations in other genes controlling pRb
phosphorylation mimic the effect of pRb loss
• Mutational activation of cyclin D or CDK4
• Mutational inactivation of CDKIs also drive proliferation

56
Q

what is the role of hypophosphorylated retinoblastoma

A

pRb is active and carries out its role as tumor suppressor by inhibiting cell cycle progression.
- ACTIVE pRb applies a brake to the cell cycle

57
Q

how is pRb inactivated

A

phosphorylated

58
Q

failure of cell cycle control

A

carcinogenesis

  • Balance between proliferation and apoptosis disrupted
  • Mutations in genes regulating cell division, apoptosis, and DNA repair cause a cell to lose control of proliferation
  • Uncontrolled proliferation of cells forms tumours
59
Q

what are the 2 frequently disrupted regulatory pathways in the cell cycle

A
  1. The cyclin D-pRb-E2F pathway

2. p53 pathway

60
Q

p53 regulatory pathway and its role in the cell cycle

A

P53 maintains the integrity of the genome.
Cells with mutated p53 don’t G1 arrest or repair damaged DNA.
Genetically damaged cells proliferate and from malignant neoplasms - the mutant cells inherit the damaged DNA and mutations continue. Normally the p53 is activated and binds to the damaged DNA and the cell is either repaired (cell cycle stops at G1 or the repair fails and the cell undergoes apoptosis.

61
Q

balance between proliferation and apoptosis - carcinogenesis

A

Cell division normally balances proliferation and apoptosis,
Carcinogenesis is caused by mutations that upsetting this normal balance resulting in uncontrolled cell division, rapid proliferation leading to tumours.

62
Q

gene mutations - carcinogenesis

A

More than one mutation is necessary for carcinogenesis: a series of several mutations to certain classes of genes is usually required
Only mutations in those certain types of genes which play vital roles in cell division, apoptosis (cell death), and DNA repair will cause a cell to lose control of its cell proliferation.
Virutally all canders are dysregulated at G1-S. Mutated cell cycle regulating genes: cyclin D, CDK4, p16, Rb
cells with mutated p53 proliferate and form malignant neoplasms

63
Q

what factors can cause carcinogenesis

A

• Environmental agents
○ Chemicals
○ Radiation
○ Oncogenic viruses
• Inherited factors (passed on from parents to offspring)
Genotoxins cause irreversible genetic damage or mutations by binding to DNA.
Genotoxins include chemical agents like N-nitroso-N-methylurea (MNU) or non-chemical agents such as ultraviolet light and ionizing radiation.
Certain viruses can also act as carcinogens by interacting with DNA.

64
Q

two hit hypothesis of oncogenesis

A

Retinoblastoma - tumour of the light detecting cells in the eye, usually in children, tumour arises from retinal tissue in the eye. There are 2 forms of retinoblastoma (inherited - multiple tumours in both eyes, younger children. Sporadic - tumour in one eye, older children)
Retinoblastoma cells are growing very rapidly following birth
Inherited - mutation inherited from parents which explains early age of development
Sporadically accumulating mutations in both alleles - develops at a later age
Gene function is recessive

65
Q

tumour suppressor genes (anti-oncogenes)

A
  • Normal regulatory genes that protect a cell from forming cancers
  • Generally follow the “two-hit hypothesis”
  • Tumour suppressor alleles are usually recessive
  • Loss of both normal allelic copies gives rise to cancer
  • Mutation causes ‘loss of function’
  • Normal regulatory genes

• Mutation causes loss of function - removing the brake which leads to proliferation

66
Q

normal regulatory genes

A

○ Normal growth-inhibiting genes
□ Genes negatively regulating mitosis – Rb, INK4A family
□ Genes regulating apoptosis – p53
○ Genes regulating DNA repair

67
Q

inherited cancer syndromes

A

• Cancer is a molecular disease but can be hereditary
• account for 5-10% of all cancers
• genetic predisposition to develop cancer
early onset of multiple tumours in established familial cancers - cancers at an early age, multiple cancers

68
Q

inherited predisposition to cancer

A
  • Familial retinoblastoma
  • Familial adenomatous polyposis.(FAP) of colon
  • Hereditary Breast & Ovarian Cancer Syndrome (BRCA)
  • Hereditary Non-polyposis Colorectal Cancer Syndrome
  • Li-Fraumeni Syndrome
  • multiple endocrine neoplasia
  • Von Hippel- Lindau syndrome
69
Q

familial retinoblastoma

A

Carriers have 10 000x risk of bilateral retinoblastoma (both eyes)
Increased risk of second cancers e.g. bone sarcomas (which are relatively rare sporadically)

70
Q

Familial adenomatous polyposis.(FAP) of colon

A

□ Thousands of polyps on the colon
□ 100% risk of colon cancer by age 50 years
Colon is removed before polyps become cancerous

71
Q

Hereditary Non-polyposis Colorectal Cancer Syndrome

A

□ Germline mutations in DNA mismatch repair genes are inherited
hMSH2, hMLH1, MSH6

72
Q

Li-Fraumeni Syndrome

A

p53 abnormality, one copy inherited from parents

73
Q

Multiple Endocrine Neoplasia

A

tumours of endocrine organs, present with multiple tumours at multiple sites

74
Q

Von Hippel-Lindau Syndrome

A

hemangioblastoma, renal tumours

75
Q

inherited mutations of tumour suppressor genes

A

APC - Signal transduction - FAP colon cancer

p53 - Cell cycle/apoptosis after DNA damage - Li-Fraumeni syndrome; multiple carcinomas, sarcomeres

Rb - Cell cycle regulation - Retinoblastoma, osteosarcoma

P16 (INK4a) - Inhibits CDKs - Malignant melanoma

76
Q

proto-oncogenes

A

• Normal genes coding for normal growth regulating proteins
• Growth factors
• Growth factor receptors
Signal transduction

77
Q

oncogenes

A

cancer causing genes
Derived from proto-oncogenes with ‘gain of function’ (i.e. normal genes with a gain of function mutation)
Activated by –
Alteration of proto-oncogene structure
Dysregulation of proto-oncogene expression
• HER2 and breast cancer - these genes can multiply and be amplified in breast cancer, tend to cause very aggressive breast cancer
Oncoproteins are diagnostically and therapeutically important

78
Q

Alteration of proto-oncogene structure

A
  • point mutation
  • chromosome rearrangements + translocations
    ○ Overexpression: Burkitt lymphoma (malignancy of B cells in blood); Mantle cell lymphoma - cyclin D1 gene-IgH
    ○ Recombination to form chimeric proteins
    Chronic myeloid leukaemia
79
Q

Dysregulation of proto-oncogene expression

A
  • gene amplification

- over-expression

80
Q

chemical carcinogenesis

A

helps explain non-inherited cancer presentations
• Purine and pyrimidine bases in DNA are critically damaged by oxidizing and alkylating agents
• Chemical carcinogens react with DNA forming covalently bound products (DNA adducts)
• Cell machinery can no longer detach the strands from each other - causes jumps and problems in DNA replication e.g. loss of anti-oncogene function
• Adduct formation can lead to activation of oncogenes and loss of anti-oncogenes

81
Q

radiation carcinogenesis

A

• Purine and pyrimidine bases in DNA are critical targets for radiation damage
• High-energy radiation is carcinogenic if received in sufficient doses
• ultraviolet radiation (UV-B present in sunlight)
• X-rays (e.g. diagnostic CT scan)
Gamma radiation

82
Q

viral carcinogenesis

A

• ONCOVIRUSES
• virus genome inserts near a host proto-oncogene
○ viral promoter causes proto-oncogene over-expression
• virus directly inserts an oncogene into host DNA causing cell division
• Viruses known to cause cancer in humans
• HPV (genital, throat and anal cancers) - higher risk ones are HPV 16 and HPV 18
○ HPV AND CERVICAL CANCER: High oncogenic HPV types –> integration –> viral sequences act as oncogenes –> E6 - p53 / E7 - RB binding (bind to important molecules which are involved in centrally controlling the cell cycle)
• Hepatitis B (liver cancer)
• EBV (lymphoma) - Epstein Barr virus

83
Q

multistep carcinogenesis

A

• All sporadic cancers harbour multiple genetic aberrations
• Mutations accumulate with time
Activation of several oncogenes and loss of two or more anti-oncogenes occurs in most cancers

84
Q

what is the highest risk factor for cancer

A

age

85
Q

over expression of growth factor PGDF (sis) causes

A

astrocytoma, osteosarcoma

86
Q

amplification of growth factors receptors - EGF family (her2/neu) causes

A

breast
ovarian
lung
stomach cancers

87
Q

point mutation of signal transducers - GTP binding (ras) causes

A

lung
colon
pancreas cancer
leukaemia

88
Q

translocation of nuclear regulatory proteins - transcriptional activators (myc) causes

A

burkitt lymphoma

89
Q

translocation/amplification of cell cycle regulators (cyclin D) causes

A

mantle cell lymphoma

90
Q

amplification of CDK 4 causes

A

melanoma

sarcoma

principles of disease (40 decks)

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