Disorders of Cell Growth

Question 1

What is a tumour

Answer 1

• Swelling or mass
• Two general types of tumours
• Benign (non-cancerous)
• Malignant (cancerous)

Question 2

What is a neoplasm

Answer 2

• An abnormal mass of tissue
• Growth of which exceeds and is uncoordinated with that of normal tissues
• Persists in same excessive manner after cessation of stimuli which evoked change

Question 3

What is neoplasia and dysplasia

Answer 3

Neoplasia:
- Cancer, new growths of cells in the body
- Mutated proto-oncogenes / tumour suppressor genes
Dysplasia:
- Irreversible
- Replacement of one mature cell type with a less mature cell type
- Mutations in genome, epigenetic changes, principally in epithelia

Question 4

What are the features of a benign tumour

Answer 4

• Nomenclature (-oma)
• Localised
• Non-invasive, slow growth
• Resemble tissue of origin
• Encapsulated / circumscribed edge, intact surface
• Exophytic growth
• Homogenous cut surface
• No metastases

Question 5

What are the features of a malignant tumour

Answer 5

• Nomenclature (-carcinoma or -sarcoma)
• Non-localised
• Invasive, rapid growth
• Poor resemble of tissue of origin
• Poorly defined and irregular border, ulcerated, vascular permeation
• Endophytic growth
• Heterogenous cut surface / necrosis
• Metastases common

Question 6

What are the common causes of cancer

Answer 6

• Sporadic (non-familial) cancers caused by DNA damage and genomic instability
• Oncogenic viruses carry genes that can lead to cancer (HPV / EBV)
• Inheritance of one defective copy of a tumour suppressor gene / cancer susceptibility gene
• Li-Fraumeni Syndrome - Mutant TP53
• Hereditary Breast / Ovarian Cancer (HBOC) - Mutant BCRA1 / BRCA2
• Lynch Syndrome - Abnormal DNA mismatch repair

Question 7

What are some genetic mutations found in cancer

Answer 7

• Gene Deletion / Inactivation: Loss-of-function, tumour suppressor genes (TP53)
• Gene Amplification: Copy number changes, hyper-activity of proto-oncogenes, oncogenes (MYC, EGFR)
• Protein Activating Mutation: Gain-of-function, BRAF V600E, IDH1 R132
• Translocations: BCR-ABL
• Epigenetic Alterations: Histone H3

Question 8

What are proto-oncogenes

Answer 8

• Encode proteins that normally control cell growth / proliferation
• When mutated become oncogenes that cause self-sufficiency
• Extracellular signalling, hormones, GFs, signal transduction and nuclear proteins

Question 9

What are oncogenes

Answer 9

• Jammed accelerator
• Genes / proteins that activate normal cell proliferation
• These genes are mutated in cancer resulting in uncontrolled proliferation
• Gain-of-function mutation (dominant)
• MYC, RAS, EGFR/ERBB1, HER2/ERBB2

Question 10

What are tumour suppressor genes

Answer 10

• Defective brakes
• Genes / proteins that normally prevent cell proliferation are mutated in cancer resulting in uncontrolled proliferation
• Loss of function mutation (recessive) or loss of heterozygosity
• TP53, RB, CDKN2A (Ink4a / Arf), CDKN2B (Ink4b)

Question 11

What is the p53 tumour suppressor gene (loss of function mutation)

Answer 11

p53
- Tetramer DNA complex containing TFs (can bind DNA), - When mutated multiple cellular processes are disrupted
Activated By:
- Lack of nucleotides
- UV / ionising radiation
- Oncogene signalling
- Hypoxia
- Blockage of transcription
Effect:
- Cell cycle arrest and senescence or return to proliferation
- DNA repair
- Block of angiogenesis 
- Apoptosis

Question 12

What are gain of function mutations

Answer 12

• Results in constitutive kinase activity, increased stimulation
• Cause of melanoma (BRAF V600E), lung cancer, colorectal cancer, thyroid carcinoma, paediatric low grade glioma and craniopharyngioma

Question 13

List the 6 hallmarks of cancer

Answer 13

• Sustained proliferative signalling
• Resistance to anti-growth signals
• Immortality
• Resistance to apoptosis
• Sustained angiogenesis
• Invasion / metastasis

Question 14

What is sustained proliferative signalling (1)

Answer 14

• Constitutively activated growth signalling

- Often driven by oncogenes

Question 15

What is resistance to anti-growth signals (2)

Answer 15

• Unregulated cell cycle progression (mutated CDKs, kinases and cyclins)
• Inactivated cell cycle checkpoints (inactivation of tumour suppressors)
• Leads to cells with aneuploidy, DNA damage and incomplete DNA replication

Question 16

What is immortality (3)

Answer 16

• No limit to cell divisions
• Telomere length extension by telomerase, infinite replicative ability
• Inactivated cell death pathways
• Hayflick Limit: Number of times cell can divide before telomeres shorten and inhibit duplication

Question 17

What is resistance to apoptosis (4)

Answer 17

• Resistance to programmed cell death
• Activation of survival signalling pathways (AKT)
• BCL2 over-expression in cancer prevents induction of apoptosis

Question 18

What is sustained angiogenesis (5)

Answer 18

• Formation of blood vessels
• Activated vascular endothelial GF signalling
• Tumour: Transformed or neoplastic cells, proliferating
• Stroma: Normal cells (normal DNA), connective tissue, BV and host immune/inflammatory cells, provides support to enable tumour growth

Question 19

What is invasion / metastasis (6)

Answer 19

• Loss of cell-to-cell interactions
• Loss of contact inhibition
• Loss of anchorage dependence
• Cells in culture and in vivo exhibit contact-inhibition
• Cancer cells lack contact inhibition feedback mechanisms, clumps or foci develop

Question 20

Describe how molecular understanding of cancer can be used in research

Answer 20

Discovery:
- Elucidation of oncogenic mechanisms
- Identification of therapeutic targets
- Identification of cancer biomarkers
Validation:
- Validation of candidate therapeutic targets and biomarker signatures
Clinical Utility:
- Classification of patients based on disease prognosis
- Stratification of patients based on predicted therapeutic response

Question 21

What is multistep carcinogenesis

Answer 21

• Carcinogenesis is a multistep process resulting from accumulation of multiple genetic alterations
• Collectively give rise to transformed phenotype and associated hallmarks
• Most cancers have at least 6-9 different mutations

Question 22

What are common translocations / genetic changes in cancer

Answer 22

Translocations:

• Burkitt’s Lymphoma: Affects antibody rearrangement (T cells)
• Acute Promyelocytic Leukaemia (APL): Stalls myeloid differentiation
• Acute Lymphoblastic Leukaemia (ALL): Constitutive ABL kinase activity
• Ewing’s Sarcoma: Inhibits differentiation, solid tumour
• Deletions: Loss of tumour suppressor genes
• microRNAs (miRNA): Increase expression of oncogenes, decrease expression of tumour suppressor genes
• Epigenetic Changes: Post-translational modification of histones, abnormal DNA methylation

Question 23

What is grading and staging of cancers

Answer 23

• Staging: Progression or spread through the body

- Grading: Cell differentiation and rate of cell growth

Question 24

What are common characteristics of cancer

Answer 24

• Genetic origin – DNA damage / change and epigenetic changes (histone modifications)
• Accumulation of specific mutations promoting cancer
• Cell division without growth control
• Parasitic in nature
• Require endocrine support of host
• Dependent on host blood supply and nutrition
• Heritable changes which get passed on to daughter cells
• Usually clonal, derived from one single cell

Question 25

What are the 4 fundamental features to distinguish and characterise benign vs malignant neoplasms

Answer 25

- Differentiation and anaplasia - Rate of growth - Local invasion - Metastasis

Question 26

Describe differentiation and anaplasia in benign vs malignant

Answer 26

- Benign: In parenchyma fairly normal, well differentiated cells, still fulfil tissue function, mitosis rare but normal - Malignant: In parenchyma differentiated to completely undifferentiated cells with loss of tissue function, nuclei hyper chromatic and large, several nuclei possible, anaplasia

Question 27

Describe rate of growth in benign vs malignant

Answer 27

- Benign: Slow growth (months to years) and mitosis is rare but normal - Malignant: Fast growth, atypical, numerous mitosis, growth rate usually inversely proportional to level of differentiation

Question 28

Describe local invasion in benign vs malignant

Answer 28

- Benign: Remains localised at site of origin, most are encapsulated but not all - Malignant: Progressive growth, infiltration, invasion, destruction and penetration of surrounding tissue, no development of well defined capsules

Question 29

What is metastasis

Answer 29

- Metastasis: Spreading of malignant neoplasms - Metastases: Secondary implants, originating from a primary lesion, of a different cellular origin (different morphology, colour, cell to cell signalling)

Question 30

Describe metastasis in benign vs malignant

Answer 30

- Benign: Never - Malignant: Pathways of dissemination, seeding within body cavities, lymphatic / hematogenious to liver, lungs, veins and arteries (less)

Question 31

Describe the process of metastasis

Answer 31

- Detachment at tumour site invasion of surrounding connective tissues - Intravasation into blood / lymph / body cavities, evasion of host defence (immune escape) - Extravasation from blood vessel into secondary sites - Proliferation and angioneogenesis (VEGF)