Neoplasia Flashcards
What two components are all tumours composed of?
Neoplastic cells that constitute tumour parenchyma and reactive stroma made up of connective tissue, blood vessels and cells of the adaptive and innate immune system
Define hamartoma
Disorganised mass composed of cells indigenous to the involved tissue. (As in other neoplasms most have clonal chromosomal aberrations that are aquired through somatic mutation)
Define Choristoma
Is the term applied to at heterotopic (misplaced) rest of cells. Is not a neoplasm e.g. normally organised pancreatic tissue in the submucosa of the stomach.
What are six morphological changes that cancer cells can exhibit?
(Remembering there is a spectrum and not all show all)
- Anaplasia
- Pleomorphism (note tumour giant cells)
- Abnormal nuclear morphology (e.g. disproportionately large)
- Mitoses (most importantly atypical, bizarre mitotic figures)
- Loss of polarity
- Other changes (e.g. areas of ischemic necrosis)
Explain the differences between metaplasia, dysplasia and carcinoma in situ
- Metaplasia is the replacement of one cell type to another. Usually in association with tissue damage, repair and regeneration. Prone to malignant transformation
- Dysplasia is disordered growth with the affected area showing changes like those of cancer. It is a precursor to malignant transformation but does not always progress to cancer. With removal of inciting causes it may be completely reversible.
- Carcinoma in situ is when dysplasia is severe and involves the full thickness of epithelium but does not penetrate the basement membrane. Unless treated have a high probability of progression to invasive cancers.
Next to the development of metastases, what is the most reliable discriminator of malignant and benign tumours?
Invasiveness
Why do most benign tumours develop a capsule?
Because they grow and expand slowly. Stromal cells and fibroblasts deposit ECM following activation by hypoxic damage due to the expanding tumour.
What three pathways can dissemination of cancers occur through?
- Seeding of body cavities and surfaces
- Lymphatic spread (common with carcinomas)
- Hematogenous spread (common with sarcomas)
List seven of the best established environmental factors affecting cancer risk
- Infectious agents
- Smoking
- Alcohol consumption
- Diet
- Obesity
- Reproductive history
- Environmental carcinogens
What are three types of acquired predisposing conditions to developing cancer?
- Chronic inflammation
- Precursor lesions (hyperplasia, metaplasia, dysplasia and some benign neoplasms)
- Immunodeficiency
What four epidemiological factors are thought to contribute to the development of cancer?
- Environmental factors
- Age
- Acquired predisposing conditions
- Genetic predisposition
What are the four classes of genes that are the principal targets for cancer causing mutations?
- Proto-oncogenes
- Tumour suppressor genes
- Genes that regulate programmed cell death
- Genes that are responsible for DNA repair
What are the eight hallmarks of cancer?
- Self-sufficiency in growth signals
- Insensitivity to growth-inhibitory signals
- Altered cellular metabolism (aerobic glycolysis)
- Evasion of apoptosis
- Limitless replicative potential
- Sustained angiogenesis
- Ability to invade and metastasise
- Ability to evade host immune response
What are oncogenes?
Mutated genes that cause excessive cell growth, even in the absence of growth factors and other growth-promoting external cues
For the following three receptor tyrosine kinase genes, describe the effect of the mutation that tends to occur allowing constitutive activity in certain tumours:
1. ERBB1
2. ERBB2
3. ALK
- Point mutations in lung adenocarcinomas produce constitutive activation of EGF
- Gene Amplification leading to over-expression of HER2
- Constitutively active form created through gene rearrangement e.g. a deletion on ch 5 can lead to EML4-ALK fusion gene
What kind of mutation involving what family of genes is the most common type of abnormality involving proto-oncogenes in human tumours?
Point mutations of RAS (HRAS, KRAS, NRAS)
In the receptor tyrosine kinase receptor signalling pathway, what two kinase families downstream of RAS can also frequently be involved in oncogenic gain of function mutations?
- RAF e.g. BRAF in hairy cell leukemias
- PI3K e.g. in 30% of breast carcinomas
What is the classic example of an oncogenic mutation in nonreceptor tyrosine kinases (they activate same signalling pathways as RTKs)?
Translocation of ABL gene (for ABL TK) from ch 9 to ch22 where it fuses with BCR, BCR drives self association, resulting in CML
What is oncogene addiction?
When tumour cells are highly dependent on the activity of one oncoprotein. e.g. in CML BCR-ABL inhibitors work very well (but do not cure as some CML “stem cells” persist).
MYC is a transcription factor regularly involved in cancers. It’s activation is common to most growth signalling pathways, it can also be directly affected by mutation as in Burkitt lymphoma where it is translocated from ch 8 to 14 where is fuses with an IG gene, leading to the enhancers instead enhancing MYC.
What are three activities of MYC that show how it contributes to multiple hallmarks of cancer?
- Activated expression of many genes involved in cell growth e.g D cyclins, rRNA and those that lead to metabolic reprogramming
- In some contexts upregulates expression of telomerase
- Can act together with a handful of other transcription factors to reprogram somatic cells into pluripotent stem cells
What are the four main groups of proto-oncogenes?
Growth factors, growth factor receptors and subsequent pathway protiens, transcription factors, and cyclins and cyclin-dependent kinases
In the cell cycle the G1/S checkpoint is more important in cancer because as well as leading to dysregulated growth it can impair DNA repair. What are the most frequently occurring oncogenes for this stage?
D cyclin and CDK4
Loss of normal cell cycle control is central to malignant transformation and at least one of the four key regulators of the cell cycle is dysregulated in the vast majority of human cancers (whether via direct mutation or upstream mutation).
What are the four key regulators?
p16/INK4a, cyclin D, CDK4, RB
RB is a key negative regulator of the G1/S cell cycle transition. In quiescent cells it exists in an active hypophosphorylated state in complex with E2F transcription factors, preventing them from activating transcription of S-phase genes. In what two ways can its function be compromised?
- Loss of function mutations involving both RB alleles (or viral oncoproteins that bind and inhibit RB)
- A shift to the inactive hyperphosphorylated state caused by gain of function mutations upregulating CDK/cyclin D activity or by loss of function mutations of CDK inhibitors (p16/INK4a)
What is the most frequently mutated gene in human cancers and what is its general role?
TP53 - regulates cell cycle progression, DNA repair, cellular senescence and apoptosis
MDM2 is an enzyme that ubiquitinates p53 in the normal cell, making it virtually non-existent. What are the two major mechanisms by which p53 is released from this inhibition?
- Through phosphorylation of MDM2 and p53 stimulated by one of the protein kinases ATM or ATR in response to DNA damage and hypoxia
- Binding of p14/ARF to MDM2 displacing p53 due to increased expression triggered by signalling from oncoproteins
- How does p53 induce transient cell cycle arrest and 2. assist in facilitating DNA repair?
- By inducing transcription of CDKN1A, producing p21 which inhibits CDK4/D cyclin complexes
- By inducing proteins such as GADD45 (growth arrest and dna damage) that enhance DNA repair
