Disorders of Cell Growth Flashcards
What is neoplasia?
- Neoplasia: neo- = new, -plasia = growth”
- Tumor = swelling
- Clinically, Tumor = Neoplasm
- “A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change.“ Willis , 1952
Neoplasms Nomenclature:
- Oma = Tumour
- Carcin-oma = Hard-Tumour
- Sarc-oma = Soft Tumour
What is grading and staging?
What is dysplasia?
- Occurs principally in the epithelial tissues
- Caused by mutations in genome, altered differentiation or epigenetic changes
Mild-to-moderate dysplasia is often reversible following the removal of causative stimuli
- Disorderly but non-neoplastic cell proliferation
- Some similarity with cancer -> pre-neoplasia
- Severe dysplasia becomes irreversible and may be considered a premalignant lesion due to its ability to progress to carcinoma
What are the morphological changes in dysplasia?
- Loss of single cells uniformity and architectural orientation
- Dysplastic cells are highly pleomorphic (variation in size and shape)
- Often exhibit hyperchromatic nuclei and increase in the nucleus/cytoplasm ratio
Different distribution of mitotic figures
- Expected that stem cells in basal lamina produce
cells -> differentiation from the basal to the superficial layers
- In dysplasia often mitotic figures within epithelium
What are the characteristics of cancers?
- Genetic origin – DNA damage/change and epigenetic changes (e.g. histone modifications)
- Accumulation of specific mutations promoting cancer
- Cell division without growth control
- Require endocrine support, blood and nutrition of host
- Usually clonal, derived from one single cell -> heritable changes get passed on to daughter cells
What is the gross difference between benign and malignant neoplasms and the fundamental features?
Four fundamental features:
- Differentiation and anaplasia
- Rate of growth
- Local Invasion
- Metastasis
What is the difference between benign and malignant neoplasms in differentiation and anaplasia?
What is the difference between benign and malignant neoplasms in rate of growth?
What is the difference between benign and malignant neoplasms in local invasion?
What is the difference between benign and malignant neoplasms in metastasis?
- Metastasis = spreading of malignant neoplasms
- Metastases = secondary implants of a tumor, located in remote tissue, originating form a primary lesion
What is the process of metastasis?
- 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 & angioneogenesis (VEGF)
Metastases are often of a different cellular origin than the cells in the organ they invade -> different morphology, colour, cell to cell signalling
What are the causes of cancer?
- No single mutation is sufficient to transform a normal cell into a cancer cell.
- Thus carcinogenesis is a multistep process resulting from the accumulation of multiple genetic alterations that collectively give rise to the transformed phenotype and all of its associated hallmarks
- Cause is DNA damage and genomic instability
- Oncogenic viruses: Viruses carrying genes that can lead to cancer (e.g. HPV, EBV)
- Environment: Increase in mutation rate (eg. diet, radiation, smoking, UV)
- Hereditability: Cancer predisposition syndromes – inherit ONE defective copy of a tumour suppressor gene / cancer susceptibility gene
Cancer is a genetic disease:
- Cancer arises from the accumulation of genetic changes
- Most cancers have at least 6-9 different mutations
- Not a hereditary disease
- Many genes mutated in cancer are involved in cell cycle regulation and DNA repair
What is Knudson’s “two hit” theory of carciogenesis?
- Initiation of carcinogenesis needs ‘loss-of-function’ in both alleles of tumor suppressor
What are the different genetic mutations found in cancer and examples?
- Gene deletion / inactivation = ”Loss-of-function”
e.g. tumour suppressor genes (TP53, RB, PTEN) - Protein activating mutation = “Gain-of-function”
e.g. BRAF V600E, IDH1 R132 - Copy number changes / gene amplification
e.g. oncogenes (MYC, EGFR)
- Activating mutations and/or gene amplification can result in hyper-activity of proto-oncogenes - Translocations
e.g. BCR-ABL
- Translocations: Chromosomes have exchanged chromosome tips altering the position and thus expression of many different genes.
Burkitt’s Lymphoma:
- Translocation t(8;14)
, Aberrant expression of MYC by placing next to highly active promotor (IGH)
Acute Myeloid Leukemia (AML):
- Translocation t(15/17) or t(8/21)
Acute Lymphoblastic Leukemia (ALL):
- Translocation t(9;22) = Philadelphia chromosome
- BCR-ABL = constitutive ABL kinase activity
Ewing’s Sarcoma:
- Translocation t(11;22)
- EWS-FLI1 = abnormal expression of FLI1 stops differentiation
5. Epigenetic alterations (other changes observed in cancer)
e.g. Histone H3
- Deletions: i.e. loss of tumor suppressor genes
microRNAs (miRNA):
- Increase expression of oncogenes, decrease expression of
tumor suppressor genes
Epigenetic changes:
- reversible heritable changes in gene expression
- DNA methylation
- Post-translational modification of histones
What genes are responsible for neoplastic growth?
- Proto-oncogenes
- Oncogenese
- Tumor suppressor genes
What are proto-oncogenes and oncogenes?
Proto-Oncogenes:
- Genes that activate normal cell proliferation, but if mutated/activated are turned into oncogenes -> uncontrolled proliferation
- Encode proteins that normally control cell growth/proliferation, but when mutated they become oncogene
Examples:
- Extracellular signaling – eg. EGFR in glioblastoma
- Hormones – eg. Estrogen receptor in breast cancer
- Growth factors – eg. PDGF in paediatric glioma
- Signal transduction – eg. BRAF mutn in melanoma
- Nuclear proteins – eg. MYC amplification
- Often “gain-of-function” mutation = dominant
Oncogenes:
- Genes that have the potential to cause cancer due to becoming self sufficient
What are tumor suppressor genes?
- Growth inhibiting genes/proteins that normally prevent cell proliferation, but if both alleles mutated/inactivated leads to uncontrolled proliferation
Examples:
- TP53 (encodes p53), RB, CDKN2A, CDKN2B
- Often “loss-of-function” mutation = recessive
What are loss of function and gain of function mutations?
Loss of function mutation:
- result in an inactive or less active protein,
- recessive
- more common
Gain of function mutation:
- more active protein or acquisition of a different function
- dominant
What is p53 and why is it important?
Hint: Tumor Suppressor
Tumor Suppressor gene TP53:
- p53 can bind DNA = transcription factor
- Normally causes cell cycle arrest following DNA damage to allow for DNA repair
- When mutated in cancer multiple cellular processes are disrupted
- Guardian of the genome
What are the six hallmarks of cancer?
- Sustained proliferative signalling
- Resistance to anti-growth signals (evading growth suppressors)
- Immortality - no limit to cell divisions
- Resistance to cell death through apoptosis (programmed cell death)
- Sustained angiogenesis (formation of blood vessels)
- Invasion and metastasis
What is sustained proliferative signalling in cancer?
- Constitutively activated growth signalling
- Often driven by oncogenes e.g. Ras, Akt
What is the cell cycle?
The mammalian cell cycle can be divided into 4 phases
- G1 , S, G2 , M (prophase, metaphase, anaphase, telophase)
- G0: non-proliferating state of cells = resting cells, cells that have withdrawn from the cell cycle
- FOUR cell cycle checkpoints regulate cellular proliferation
- Cell cycle must proceed in a sequential manner - Cell cannot proceed to next phase until checkpoint requirements have been met
Explain the regulation of the cell cycle
Regulation of the cell cycle:
- Tightly regulated
- Detection and repair of genetic damage
- Prevention of uncontrolled cell division
Molecules regulating cell cycle:
- Cyclin dependent kinases (CDK)
- Kinases are inactive unless bound to a cyclin molecule
- Kinases = catalytic subunits
- Different Cyclins and varying concentrations during the cell cycle
How do the cancer genes impact regulation of the cell cycle?
Tumour suppressors (e.g. p53, Rb) control the cell cycle checkpoints
-> prevent progression of the cell cycle if errors
Loss of function of two tumor-suppressors
-> over-proliferation of cells
Image: Involvement of tumor suppressor genes and proto-oncogenes in the regulation of the cell cycle
