Cancer Flashcards

Question

What is involved in the tumour microenvironment?

Answer 1

Non-cancer cells: Resident cells, Infiltrating immune cells, Nerves (support & conceal, or suppress), Exosomes from cancer/other cells. Structural: Interstitial fluid (pressure, shear), Extracellular matrix (mechanosignalling, porosity), Fibroblasts/myofibroblasts. Irrigation: Blood vessels and lymphatics. Soluble: nutrients, metabolites, cytokines (IL-1, IL-17), plasma proteins, DAMP.

Answer 2

Cancer depths have poor perfusion and diffusion from surroundings: high interstitial fluid pressure (~10x), solid stress from tumour growth. This produces a core environment of ischaemia and pressure stress due to: Sluggish blood flow (leaky angiogenesis increases viscosity), Few/compressed intra-tumoural lymphatics so no drainage, Acidic (pH6.7-7), hypoxic, low glucose, DAMP, autolytic enzymes. Interstitial fluid flows radially from core, past tumour margins then to nearest lymphatics. Steers cell migration toward peri-tumour lymphatics/vessels and impedes drug diffusion within cancer.

Answer 3

Diffusion limits produce perivascular gradients of nutrients: Critical ischaemia at 100-180μ from capillaries; Peri-capillary sleeve of proliferating cells - more distant quiescence and survival - cell cycle-based therapy misses the more distant quiescent cells, hypoxia reduces efficacy of X-rays to generate lethal oxidative radicals, hypoxia-induced transcription regulators (HIF) change the phenotype of cancer cells; Produces strong selection pressure for angiogenesis in growing cancers - hypoxia-driven gene expression (HIF), angiogenic factors (VEGF, angiopoietins).

Answer 4

Cancer angiogenesis creates chaotic blood flow. Cancer cell competition for blood resources leads to uncoordinated angiogenesis: haphazard, immature vascular geometry; not hierarchical, unstable haemodynamics - pooling, eddies, flow reversals. So pO2 varies in “waves & tides” (sec/min)-(hrs), causing fluctuating ischaemia, pH, hormone levels, reperfusion injuries, ‘dry streambed’ vessels surrounded by dead cancer cells.

Answer 5

A cancer is an ecosystem of malignant and non-malignant cell types, interacting with each other and surrounding matrix structure. Growing cancers have selection pressure for an angiogenic switch; but cancer angiogenesis is haphazard, with regional and unpredictable variations in blood flow; so cancer masses have poorly perfused and drained cores, with radial fluid flow into the adjacent tissue and lymph that affects invasive spread and drug access. These characteristics tend to produce regional differences within a cancer, and shape how sizeable cancers evolve.

Answer 6

The causal impact in human cancer: most human cancers have 2-8 mutant drivers [581 genes (solid evidence), 162 genes (strong indication)]. Half of early clonal driver mutations occur in just 9 genes (e.g. TP53, KRAS, TERT). Later clonally mutated driver genes are more diverse between cancer types: mutation distribution often mirrors the accessible chromatin of the normal cell; suggests cell of origin influences what could be a cancer driver (via available transcriptional landscape). The typical cancer driver gene affects multiple cancer hallmarks, suppressing some and promoting others [e.g. RAC1: promotes angiogenesis, proliferation and metastasis; but protects from uv-induced skin cancer]. Has opposing roles (or no role) in different cancers, i.e. other factors matter. Role depends on gene defect, cell type, cancer stage [e.g. BRCA1 inactivations: DNA mutations increased (early); metastasis enhanced (late); proliferation may benefit positive selection early, but limit metastasis capacity later].

Answer 7

Cancer cells are mutationally more similar than random normal cells, due to early clonal sweeps. Key driver mutations are often ubiquitous in untreated cancer and its metastases; new mutations often have no selective impact - neutral passenger mutations in subclones. Treatment pressures unmask previously neutral or minority but resistant subclones; rapidly relapsed small cell lung cancer after apparently successful cisplatin chemotherapy as it can survive different apparently successful treatments before emerging (ancestral clones from treatment-naïve cancer: not ‘cancer progression’). Other important genetic changes include: Chromosome defects (losses often precede gains); Whole genome duplication is common (30%) and bad news; Oncogene copies (amplified in >50% cancers), eg glioblastoma; most copies are outside chromosomes in circular extrachromosomal DNA; different inheritance pattern so unequal segregation at mitosis, allows fast (weeks) change in oncogene copy number to new selective pressure - drivers, drug-resistance, immunomodulatory, etc.

Answer 8

Genome instability and mutation, Inducing angiogenesis, Activating invasion and metastisis, Tumour-promoting inflammation, Resisting cell death, Reprogramming energy metabolism, Enabling replicative immortality, Avoiding immune distrction, Evading growth suppressors, Sustaining proliferative signalling.

Answer 9

Several common cancers share 3-5 distinct gene expression programmes. Different clinical associations but these ‘cancer task’ archetypes incorporate the cancer hallmarks; gene drivers of a task can differ between cancer types. Cancer tasks: Cell division (early stage) - cancer hallmark is replicative immortality, growth suppressor escape, proliferation; Biomass/energy (early stage) - cancer hallmark is metabolic reprogramming (electron transport, glycolysis); Lipogenesis (early stage) - cancer hallmark is metabolic reprogramming (peroxisome lipid metabolism); Immune interaction (late stage) - cancer hallmark is immune tolerance, resist cell death, tumour-promoting inflammation; Invasion and tissue remodelling (late stage) - cancer hallmark is migration, matrix degradation, angiogenesis.

Answer 10

Diversity emerges under pressure to perform several tasks, when you can’t be optimal at everything because of trade-offs between them. Cells adapting within the range of options will better tolerate change (resources, threats). Plasticity allows cancers to alter trade-offs between tasks. Proliferation – Survival: metabolically different strategies, trade-off depends on stress level (drug, nutrient); Proliferation – Invasion. Driver genes push cells towards a specialisation [p53 in breast cancer: cell division archetype, NRAS in thyroid cancer: biomass/energy archetype]; Cancer cells close to an archetype are sensitive to drugs that disrupt that task [cell division: mitosis inhibitors; biomass/energy: mTOR inhibitors (growth regulator)]; Cells re-prioritise between key tasks by transcriptional adaptation (plasticity) so responses that seem to be cancer ‘evolution’ are cancer cell ‘adaptation’ to circumstance.

Answer 11

Allows for the plasticity of cancer cells. Many cancer cells move in and out of stemness states, this means: They can repopulate depleted ‘cancer stem cells’; Have proximity to niche signals - self-renewing undifferentiated state (WNT factors) e.g. HGF from cancer-associated fibroblasts, blocked differentiation (NOTCH ligands from adjacent cells), proliferation signals (EGFR ligands); Cancer progression reduces dependence on external niche signals, so easier switch to stemness state when beneficial, stem cell programmes can be activated epigenetically [NOTCH1 in breast & pancreas carcinoma, WNT in leukaemia].

Answer 12

Epithelial-mesenchymal plasticity (EMP) is reversible mesenchymal properties; development, wound healing program [minority of cancer cells (1-10%), cycling between EMT-MET]. Response to stress: hypoxia, acidity, dense matrix; at invasive front (stromal contact), around necrosis; factors from cancer-associated fibroblasts/macrophages (e.g. TGFb). Motility (invasiveness)/angiogenesis helps enter the circulation (most circulating solitary cancer cells), doesn’t help establish metastasis, for which epithelial differentiation is important. Less proliferation resists therapy that targets proliferating cells - metformin reverses EMT: improved survival among diabetic breast cancer patients.

Answer 13

Cancer metabolism is adaptable between anabolic and survival states. Anabolic (aerobic glycolysis) depletes nutrients (oxygen, glucose, essential amino acids), toxic metabolites accumulate (H+ , lactate acidity, adenosine). Gains from non-cancer cells; e.g. cancer cell ammonia (from glutamine metabolism) triggers fibroblast autophagy, yielding protein breakdown products like glutamine to support the cancer cell. Metastasis requires anti-oxidant strategies; circulation - oxidative stress (pO2 & iron) hinders survival; skeletal muscle is very hostile (++ H2O2).

Answer 14

Anabolic cancer cells and chaotic vasculature produce metabolic stress, which depleted oxygen and nutrients, and metabolites accumulate. Metabolic stress causes immune dysfunction; antigen signalling under metabolic stress causes CD8 T cell exhaustion, which impairs innate immune cell activation and function. Metabolic competition induces effector T cell senescence; cancer cells and Treg competitively ‘steal’ limited glucose from effector T cells, triggering senescence, senescent T cell products suppress other immune cells. Sentinels: NK, Tc, innate T cells delete new immunogenic clones (immunoediting); Virus antigen (oncogenic virus e.g. HPV, EBV); Neoantigens - driver or passenger mutation alters protein, dysregulated enzyme alters carbohydrate side chains (glycoprotein/glycolipid); NK cells eliminate most circulating cancer cells, but platelets, NET coatings conceal and facilitate metastasis. Cancer cells subvert immune activation, release immunosuppressive factors [TGFb, IL-10, PG], repress antigen processing and presentation (small cell lung cancer), reduce MHC I and display immune inhibitors (PDL1, CTLA4).

Answer 15

Many cancer treatments leave behind residual cells - ‘minimal residual disease’, ancestral sub-clones from pre-treatment, reservoir for relapse. Resister cells due to poor drug access into tumour microenvironment (TME) and resistance. Genetic resistance: New clone develops under treatment pressure - mutation, gene amplification/deletion, chromosome translocation; More often, pre-existing subclones expand, selective advantage for previously neutral mutations, extrachromosomal DNA. Non-genetic resistance: Often there is no clear new genetic explanation for acquired drug resistance, which is then explained by adaptation within a genotype; this can be reversible and even heritable (e.g. methylation); In this scenario the evolutionary path can be explained by non-genetic adaptation to the various pressures, and no new driving genetic mutations arise. Plasticity in melanoma minimal residual disease: Targeted treatment eliminates most cells; MRD contains 4 non-proliferating resistant cell states in clusters (proportions vary among patients); Transcriptional reprogramming - catabolic (survival), differentiated (pigment-making), EMT (invasive)* Stemness (neural crest stem cell - reversible, can restart proliferation {relapse}). Plasticity allows drug resistance from enhancer switching: cancer cells borrow from other available cell type identities [stable, heritable but reversible (epigenetic)]; EMP/stemness opens access to developmental epigenetic reprogramming. Lineages use different enhancers to coordinate transcription of the same core survival genes (e.g. Myc) so different routes to the same end. Under pressure from targeted therapy residual cancer cells switch to another enhancer set by opening up chromatin, repertoire is shaped by the tissue/cell of origin - transdifferentiation is typical; cells now differentiate along this new trajectory (lineage switching) [neuroendocrine transdifferentiation of prostate & lung adenocarcinoma].

Answer 16

In many organs we can see changes in the architecture of the epithelium and cytological morphology of the cells that precede invasion and metastasis. In the squamous epithelium of the cervix, skin, anus,vulva and other organs pre-invasive stages are seen. These are described as intra-epithelial neoplasms, or intra-epithelial lesions (also called dysplasia or carcinoma in situ); not invasive – therefore benign.

Answer 17

In the cervix there is a spectrum – low grade to high grade of Cervical Intra-epithelial Neoplasm - CIN (UK); or Squamous Intra-epithelial Lesion - SIL (USA). High grade intraepithelial neoplasms can have other descriptors such as severe dysplasia or carcinoma in situ. High grade intra-epithelial neoplasms have a proliferating epithelium which has the cytological features of neoplasia: abnormal nuclei (big, pleomorphic, hyperchromatic), abnormal mitoses, loss of nuclear polarity, loss of differentiation. These abnormal cells have not invaded; they stay on the epithelial side of the basement membrane – intra-epithelial (benign). Suggest a sequential progression to cervical cancer: normal –> low grade CIN –> high grade CIN –> cancer.

Answer 18

There is a single layer epithelium in normal breast ducts. In Breast Ductal Carcinoma In Situ (DCIS) precedes breast cancer and is present for many years in most cases. “In Situ” = Non-Invasive. There is an excess number of neoplastic epithelial cells that fill the duct lumen.

Answer 19

This is the second commonest site of invasive cancer in either sex in the UK. It is a site where a sequence of changes can be traced. Normal epithelium -> Adenoma Low grade dysplasia -> High grade Dysplasia -> Carcinoma Adenomas of the colon (commonly described as polyps) are not uncommon, particularly in older age groups. Often invasive cancer develops from an adenoma, as a result of progression from dysplasia to cancer, called adenoma-adenocarcinoma sequence or colorectal “adenoma-carcinoma” sequence.

Answer 20

Tumour cells escape from normal homeostatic controls of tissue architecture and cell numbers. The process involves changes/mutations to key genetic controls – direct damage to DNA (mutations); targets for mutations are genes controlling proliferation, cell death and genomic stability. The transition from a normal growth controlled cell through precursors to malignant cancer requires several mutations.

Answer 21

Carcinogens are agents which induce cancer in man or animals. Carcinogenesis is the process of cancer induction. There are 3 Types of carcinogen: chemical (natural or synthetic), physical (UV or ionising radiation), and biological (bacteria, viruses, parasites). Carcinogen dose affects tumour number/size and latent period. Dose response: a linear relationship between the amount of carcinogen delivered in a single dose and the number of tumours which develop. Latent period: time lag between the administration of a carcinogen and appearance of macroscopic tumours; the length of this time lag is dose dependent, as high doses reduce it, low doses extend it. Threshold dose: there is a threshold dose of carcinogen, below which no tumours form.

Answer 22

There is a threshold dose of carcinogen below which a single dose will not result in tumour formation. However if some secondary non carcinogenic stimulus (wounding, chemicals such as phorbol esters) is applied to the site after this subthreshold dose of carcinogen tumours develop. carcinogen -> promoter -> papilloma

Answer 23

Normally 2 stages, can be 3. 1. Initiation: The alteration of a normal cell to a potentially cancerous cell; carcinogens cause this and it is irreversible; carcinogens are mutagens. 2. Promotion: A process which permits the clonal amplification of the initiated cell; promoters are not mutagens, they induce proliferation (fix the mutation = make permanent). 3. Progression: Sometimes a third stage is added; acquisition of further mutations within the neoplastic clone drive progression to a malignant neoplasm.

Answer 24

Primary diploid cells in tissue culture exhibit the phenomenon of replicative senescence: Primary cells only undergo a defined number of cell divisions – the Hayflick number. This is because chromosome ends (telomeres with repetitive sequences) shorten with each division. Undergo cell cycle arrest and are held in G0, eventually dying by apoptosis (Replicative Senescence). At low frequency they may escape from senescence and become immortal (no limit on growth in culture). Telomerase maintains chromosome telomere ends to overcome replicative senescence, allowing for immortality. Telomerase is usually only expressed in germ and stem cells, but is abnormally upregulated in cancers.

Answer 25

Retinoblastoma is a rare childhood cancer of retinoblasts, with a peak incidence at 3-4 years of age. It can be both inherited and sporadic (no family history). In retinoblastoma the mutations affect the 2 alleles of the gene Rb the mutations result in loss of the wt Rb gene product. The tumour cells show loss of heterozygosity (LOH); in familial the parent and child both have Rb/RB alleles but the retinoblastoma cells are Rb/Rb, in sporadic the parent and child both have RB/RB alleles but retinoblastoma cells have Rb/Rb. Inherited: (1) pre-zygotic mutation, (2) post-zygotic mutation Sporadic: (1) & (2) both steps post-zygotic or acquired.

Answer 26

Heterozygotes: The affected individual (proband) has the genotype wt/mutant, autosomal dominant inheritance (inherit 1st hit). The tumour cells acquire 2nd hit and have the genotype mutant/mutant. Homozygous: The proband has the genotype mutant/mutant. They are homozygous for the mutant gene, inheriting 2 mutant alleles, one from each parent. Autosomal recessive inheritance (inherit 1st & 2nd hits).

Answer 27

They are mutagens. Most are metabolically inactive pro-carcinogens need to be activated to an active form – the ultimate carcinogen. Ultimate carcinogen is a highly reactive electrophilic molecule that directly damages DNA. Many show tissue specificity, and probably stage specificity of action. Many show species specificity. Carcinogens include both synthetic and naturally occurring chemicals. Synthetic (require in vivo activation): Polycyclic hydrocarbons – e.g. benzpyrene, benzanthracene, methylcholanthrene; Aromatic amines and Azo dyes – e.g. beta-naphthylamine, activated in liver by addition of -OH then solubilised by addition of glucuronyl, but glucuronyl removed in bladder -> activated -> bladder cancer (so aniline and aminobenzene in dyes cause increased incidence bladder cancer). Naturally Occurring: Nitrosamines – e.g. dimethyl nitrosamine (amines + nitrites + acid in stomach -> nitrosamines); Aflatoxin – peanut contaminent from Aspergillus flavens activated to epoxide by MFO in liver (causes liver cancer).

Answer 28

2 types: Ionising Radiation: x-rays, Gamma-rays, neutrons, Beta-particles, Alpha-particles; radiation exposure measured as energy absorbed per unit of tissue – 1 Gray = 100 rads; Damages DNA by making tracks of free radicals and ions as pass through; Alpha – dense track, Gamma – scattered ions. Ultra-violet light: Photo-activates adjacent pyrimidines -> pyrimidine dimers (NER repair).

Answer 29

Parasites: Schistosoma haematobium infection and carcinoma of the bladder - probably acts as a promoting agent by inducing chronic irritation. Bacteria: Infection with Helicobacter pylori is a major risk factor for the development of gastric carcinoma and gastric lymphoma. Virus: HPV - human papilloma virus types 16, 18 cause carcinoma cervix; HPV infection is present in 99.7% of invasive cervical carcinomas; HPV 16 and 18 are transforming viruses that immortalise primary genital keratinocytes by activating telemorase. Hepatitis B virus (HBV), hepatitis C virus (HCV) causes Hepatocellular carcinoma. Epstein Barr virus (EBV) causes Nasopharyngeal carcinoma, Burkitt’s lymphoma, post-transplant lymphoproliferative disorder/lymphoma, Hodgkins lymphoma. Human T cell lymphotropic virus type 1 (HTLV 1) causes Adult T cell leukaemia. Human herpesvirus type 8 (HHV8) causes Kaposi’s sarcoma.

Answer 30

Bladder cancer – workers exposed to naphthylamine (dye industry). Pleural Malignant Mesothelioma – exposed to asbestos. Bronchus Squamous Cell Carcinoma – cigarette smokers. Tongue Squamous Cell Carcinoma – pipe smokers. Head & Neck Squamous Cell Carcinoma – tobacco chewers.

Answer 31

Genes that regulate cell proliferation, cell death, and signalling to/from cells and matrix; Monitor and maintain genetic stability/genomic integrity; Regulate and maintain tissue architecture - movement and adhesion. In cancer 2 classes of genes are altered: Oncogenes (Onc), and Tumour Suppressor Genes (TSG).

Answer 32

Alleles which if mutated are said to act in a “dominant” or positive (gain-of-function) fashion. Mutations affect one allele only. They are not special cancer genes but normal genes important in growth control that can be activated in several ways. First identified in the genome of oncogenic retroviruses.

Answer 33

Retroviruses can carry oncogenes: Normal cellular genes recombined into the retroviral genome and are inappropriately expressed under the powerful viral promoters (in Long Terminal Repeats). Around 40 oncogenic retroviruses are known; they produce tumours quickly after infection. Normal = proto-oncogenes, Activated = oncogenes. Retrovirus Promoter Insertion: Some retroviruses are oncogenic but do not carry oncogenes; the provirus integrates beside a cellular proto-oncogene which is then under the control of the viral promoters and is inappropriately expressed. This is known as insertional mutagenesis. Point Mutation: RAS proto-oncogene in codons 11, 12, 13; e.g. GCT GGT GGC (alanine-glycine-glycine) gets point mutation to become GCT GTT GGC (alanine-valine-glycine) . Normal K-RAS proto-oncogene -> mutation (at codon 12) -> activated K-RASVal12 c-oncogene (c-onc). Amplification and Truncation: The epidermal growth factor receptor (EGF-R) can become overactive in at least 2 ways, so multiple copies inserted rather than one: (1) In squamous cell carcinomas the gene for the EGF-R can be amplified to many 100s of copies the cell is much more sensitive to EGF stimulation; (2) Truncation of the extracellular domain of the EGF-R constitutively activates it so the cell constantly receives EGF like signals. C-ERB-B2 (HER2) is amplified in breast cancer. N-MYC is amplified in neuroblastoma. Inappropriate Regulation: MYC is activated by inappropriate regulation of its expression, following chromosome translocation, with deletion of regulatory sequences for the promoter or use of an inappropriate promoter. Inappropriate translocation of C-MYC from 8/14.

Answer 34

Growth factors: SIS (Simian sarcoma virus) platelet derived growth factor Receptor: ERB-B (Avian erythroblastosis virus) epidermal growth factor receptor Signalling protein: ABL (Abelson mouse leukaemia virus) tyrosine kinase or RAS (Rat sarcoma virus) nucleotide binding molecular switch Transcription factor: MYC (Myelocytomatosis virus) binds DNA which stimulates proliferation and regulates apoptosis

Answer 35

Alleles which must be inactivated (loss-of-function). Both alleles must be mutated/lost/silenced; TSGs are said to be “recessive” in mechanism to wild type. They are critical control and regulatory genes, many of which restrain cell proliferation.

Answer 36

Responds to DNA damage so arrest the cell cycle. p53 is a protein with a very short half life present, in the normal situation, in very low concentrations in cells. When DNA is damaged, p53 is stabilised and its concentration increases, p53 then acts as a transcription factor inducing the expression of a cdk inhibitor p21CIP, which inhibits almost all cdk/cyclin complexes. This leads to cell cycle arrest in both G1 and G2. If the DNA damage is severe pro-apoptotic genes (e.g. Bax) are activated and the cell dies by apoptosis.

Answer 37

Deregulation of the pathways controlling Rb and p53 occurs in most cancers but can involve different players in the specific pathway in individual cancers. Rb pathway: Inactivate Rb or p16INK4a, Activate cyclinD or cdk4/6 p53 pathway: Inactivate p53 or ARF, Activate mdm2 Mutating p53 makes the cell genetically unstable. Deregulation of both Rb and p53 allows telomerase to overcome replicative senescence.

Answer 38

Genetic Instability. Transition from a growth regulated cell to a malignant cancer cell requires several mutations (>6 probably many more in solid cancers); probability of this occurring would demand a huge lifespan. The mutation rate has to be sped up; this is achieved by the acquisition of genetic instability – increased mutation rate.

Answer 39

There is a loop of misincorporated nucleotides within one side of the DNA strand. MMR corrects mismatched bases (e.g. C-T instead of C-G). MMR corrects insertion/deletion loops that most commonly occur where short sequences are repeated e.g. AAAAAAA or CACACACA (microsatellite sequences – such repeats are common in the human genome). In absence of mismatch repair, mutation rate increases 100-1000x. If mutations occur in a coding region -> mutant protein. Mutations in mismatch repair genes (MLH1, MSH2) occur in Lynch syndrome/Hereditary Non-Polyposis Colorectal Cancer (HNPCC) [~3-4% of all colorectal cancers]. Sporadic: MLH1 silencing (promoter methylation) [~15% colorectal cancer].

Answer 40

Adjacent thymines are Crosslinked by UV, creating a thymidine-dimer; the carcinogen attaches to the base. Excision of damaged or altered bases. Defects in excision repair occur in Xeroderma Pigmentosum (skin tumours)

Answer 41

Double- and single- strand breaks can occur. BRCA1 and BRCA2 are involved in double-strand break repair induced by ionising radiation, chemical carcinogens, sometimes seen in virally infected cells. Failure of repair systems leads to genetic instability and tumour progression.

Answer 42

Translocation of 9 and 22 is a signature of chronic myeloid leukaemia (CML). t(9;22) -> BCR/ABL fusion is the initiating mutation in CML. After a latent period of about 3-4 years other genetic events occur - p53 deletion/mutation, RAS activation, duplication of the Ph+; so disease transforms to acute myeloid leukaemia (multi-step carcinogenesis).

Answer 43

Chromosomal rearrangements in solid tumours, particularly carcinomas, are extensive, but not characteristic of a specific cancer type. The rearrangements often involve tumour suppressor genes (deletion). How aneuploidy arises is not fully understood, but deregulation of p53 is usually involved.

Answer 44

Cancers make active efforts to prevent the apoptotic response: p53 inactivation, Telomerase activation, BCL2 overexpression Radiation and Chemotherapy induce cancer apoptosis. In tumours at least one death pathway seems to remain intact. Apoptosis evasion mutations are targeted (not the caspases) but to genes encoding the receptors (Fas, TNFR) or activation of anti-apoptotic proteins such as BCL-2 or downregulation of pro-apoptotic proteins (BAX), as well as p53 inactivation (-> BAX, PUMA, NOXA).

Answer 45

Invasion is cells moving through 3D space, creating destruction of tissue or widening tissue spaces by oedema. Invasion requires 3 repeated steps: Change and/or loss in cell-cell and cell-matrix adhesion (changes in adhesion are essential for motility), Focal proteolysis of the matrix, Movement to occupy the space.

Answer 46

Cadherins are central to adhesion, they establish cell polarity and cell-cell differentiation. Integrins are essential for cell-matrix adhesion and signaling for cell survival and proliferation. In a stationary normal cell, integrin receptors are clustered and attach to the assembled matrix; In a motile malignant cell the intergrin receptors are dispersed and its secreted matrix is not assembled - tumour cells lose the apoptotic response to changes in matrix signals, after changing distribution and stability of integrin receptors.

Answer 47

Cancer cells switch on synthesis and secretion of matrix proteases, which signals to stromal fibroblasts to turn on secretion of matrix proteases. These proteases include Matrix Metallo-Proteases (MMPs), collagenases, hyaluronidases. They also down regulate expression of Tissue Inhibitors of Metallo-Proteases (TIMPs). In effect, a tissue remodelling process which recruits many of the players in wound healing.

Answer 48

Detachment and invasion into surrounding tissues, neo-vascularisation; Penetration of body cavities and vessels (lymph and blood); Release of tumour cells for transport to other sites in vessels; Evasion of host defences, avoiding immune destruction; Adherence and re-invasion or extravasation at the site of arrest; Manipulation of the new environment to promote tumour cell survival, vascularisation and growthin new site (metastasis).

Answer 49

Metastatic spread is not random. It is determined by: Nature of lymphatic and venous drainage, e.g. breast cancer to local axilla nodes, colorectal cancer to local mesenteric nodes and liver; Organ specificity since some cancer cells express adhesion molecules that permit preferential attachment to different capillary beds, and/or chemokine receptors to chemokines highly expressed on different capillary beds. Common metastatic sites: liver, lung, bone, brain.

Answer 50

Clinical, radiological, biochemical findings contribute to working towards a cancer diagnosis. Final cancer diagnosis almost always involves tissue diagnosis by microscopy. Tissue samples include excisional biopsy, incisional biopsy, needle biopsy (or aspirated cells for cytology). Morphological features for cancer diagnosis: Nuclear enlargement, pleomorphism, hyperchromasia Mitotic activity, (tumour necrosis). Can use immunohistochemistry (IHC) for biomarkers identifying cell type (e.g. cytokeratins, desmin, CD markers, oestrogen receptor), proliferation (Ki-67/MIB-1), hormones (thyroglobulin), others. Tumour DNA/RNA may be extracted for molecular pathology tests (e.g. RAS, EGFR mutations or HPV detection).

Answer 51

Grading – degree of differentiation (G1-3). Staging – invasion and metastasis; guides treatment

Answer 52

Blood concentration of tumour marker is used in cancer monitoring. Hepatocellular carcinoma: Alpha Fetoprotein (AFP), Gut Adenocarcinoma: Carcinoembryonic Antigen (CEA), Choriocarcinoma: human chorionic gonadotrophin (hCG), Malignant Teratocarcinoma: AFP & hCG, Potential: cell-free DNA in blood (tumour mutations).

Answer 53

Validated blood tests that measure a protein in the blood that rises and falls in proportion to the volume of cancer present. Can be used to assess treatment response or to assess detect recurrence. Frequently the higher the value the greater the volume of disease. PSA: Prostate Cancer, CA 125: Ovarian Cancer, CEA: Colorectal Cancer, AFP: Hepatocellular Cancer, CA-15-3: Breast Cancer, CA19-9: Pancreatic Cancer.

Answer 54

Late presentation with advanced disease, A disease of the elderly, Extensive co-morbidities; especially cardiac and respiratory.

Answer 55

Smoking (>95%) - Passive smoking (effects difficult to quantify); Occupational exposures - Uranium mining, Asbestos exposure; Environmental exposures - Radon gas; Genetic - Li-Fraumeni Sydrome (mutated p53 gene); (Viral infection - Retroviral infection in sheep leads to lung adenocarcinomas).

Answer 56

The vast majority (>90%) of primary tumours in the lung are carcinomas (i.e. malignant tumours of epithelial origin). Primary lymphomas, sarcomas and melanomas may be seen but are rare. The lung is a common site of metastasis of carcinomas arising at other sites (e.g. breast, colon, kidney). Lung carcinomas are very heterogeneous and are not a single clinical/pathological entity, but they may be classified as: Squamous carcinoma (30-40% and decreasing) - the tumour cells show squamous differentiation and keratin production or ‘prickles’ (desmosomes); Adenocarcinoma (40-50% and increasing) - evidence of glandular growth pattern or mucin production; Small cell (undifferentiated) carcinoma (20%) - very poorly differentiated carcinoma with variable degrees of neuroendocrine differentiation; Others (5%) - Carcinoid tumours - sheets of bland epithelial cells which can be shown to have neurosecretory granules in their cytoplasm, so classified as ‘neuroendocrine’ tumours..

Answer 57

Relatively rare tumours (<5%) which may be slow growing and frequently present with haemoptysis or symptoms of airway obstruction (e.g. pneumonia). Can occur in younger adults and in children. These are malignant but generally have a better prognosis than other types of primary lung carcinomas. Sheets of bland epithelial cells which can be shown to have neurosecretory granules in their cytoplasm, so classified as ‘neuroendocrine’ tumours. Classification: Typical (classical) carcinoid - < 2 mitoses per 2mm^2, no necrosis, 5 year survival 90-98%; Atypical carcinoid - > 2 but < 10 mitoses per 2mm^2, focal necrosis (may be very focal, commedo-like), 5 year survival 61-73%.

Answer 58

Development of a malignant tumour is a multi-step genetic process and requires the accumulation of mutated genes. The ‘adenoma carcinoma’ theory is often applied. Genetics: Oncogenes – mutated genes encoding growth-promoting proteins, these are over expressed in neoplasia (e.g. k-Ras, cylinD1); Oncosuppressor genes – mutated genes encoding growth-inhibitory proteins, decreased expression can result in neoplasia (e.g. retinoblastoma gene [Rb]); Genes regulating apoptosis may also be mutated (e.g. p53); Genes regulating DNA repair may be mutated.

Answer 59

DNA damaging agents (chemicals, radiation, etc.) leads to DNA damage, which would normally be repaired by DNA repair mechanisms; But if there are inherited mutations in genes affecting DNA repair mechanisms/growth/apoptosis, then these can fail to repair damaged DNA, leading to mutations in somatic cell genomes. Mutations in somatic cell genomes can lead to activation of growth promoting oncogenes, alteration of genes regulating apoptosis, and inactivation of oncosuppressor genes; These lead to expression of altered gene products and loss of regulatory gene products; Subsequent clonal expansions, additional mutations (progression), and heterogeneity can lead to a malignant neoplasm.

Answer 60

Central tumours may arise in a similar manner to squamous carcinoma. Pre-malignant states not really recognised. Peripheral tumours believed to arise through a sequence of step-wise changes. Normal alveolar walls -> Atypical adenomatous hyperplasia -> Adenocarcinoma 'in-situ' -> Invasive adenocarcinoma

Answer 61

Normal respiratory epithelium -> Metaplastic squamous epithelium (common finding in smokers; reversible) Metaplastic squamous epithelium -> Squamous dysplasia -> Squamous carcinoma 'in-situ' -> Invasive squamous carcinoma

Answer 62

Intrapulmonary growth: Obstructive pneumonia, Lymphangitis carcinomatosis Invasion of adjacent structures: Pleura (with associated effusion), Chest wall, Mediastinum (SVC, phrenic nerve, recurrent laryngeal nerve, atrium, aorta, oesophagus), Diaphragm Distant spread via lymphatics and blood: Hilar and mediastinal nodes, Liver, Bones, Adrenals, Brain

Answer 63

Cough, Dyspnoea, Haemoptysis, Weight loss, Chest/shoulder pain, Hoarseness, Fatigue; Slow to clear pneumonia, Finger clubbing, Cervical lymphadenopathy, Liver/bone/brain metastases, Pleural effusion Radiology: Chest x-ray (shows lesions), CT scan (cross sectional imaging can confirm the location of the lesion and provide further evidence about whether it is likely to be a malignancy or another cause of a mass lesion, e.g. TB); Blood tests: High Ca, Abnormal liver function tests, Low serum Na

Answer 64

Diagnosis and classification require tissue sampling for microscopic examination. Biopsies: Bronchial biopsies, CT guided lung biopsies, Biopsies of distant metastases (e.g. pleura, liver, lymph node) Cytology: Bronchial brushings and washings, Sputum, Pleural fluid aspiration, Fine needle aspirates of metastases; (malignant cells have large pleomorphic nuclei and form irregular clusters and balls)

Answer 65

Staging is assessing the extent of tumour growth and spread is essential as it will dictate treatment options. Allows patients to be grouped together for treatment schedules/trials and is a predictor of prognosis. TNM system: ‘T’ - a measure of the growth of the primary tumour, ‘N’ - indication of the extent of local nodal disease (mediastinal = N2 as outside lung, hilar = N1), ‘M’ - presence or absence of distant metastases Staging for more distant disease: Cross sectional imaging by CT, PET (positron-emission tomography)

Answer 66

Used to assist with tumour classification since morphology limits our ability to accurately classify tumours. Squamous markers: CK5, CK14, p40, 34βE12 Adenocarcinoma markers: CK7, TTF1 (~70−80% of primary lung tumours) [CK = cytokeratin; TTF = thyroid transcription factor]

Answer 67

Oncogenic drivers in pulmonary adenocarcinoma are largely unknown but include KRAS and EGFR mutations, EML4-ALK translocations, etc. Knowing molecular pathology allows for development of ‘designer drugs’ like Tyrosine kinase inhibitors. EGFR mutation and ALK fusion testing are the first of a growing list of mutation/genetic factors that are potential targets. Concept of ‘personalised cancer therapy’ is treatment not based on a generic diagnosis of ‘lung cancer’, but on specific characteristics of the patient’s tumour.

Answer 68

Immune check point regulation: Lung carcinomas may be associated with an inflammatory infiltrate, Suggested for decades that a lymphoid infiltrate within tumours may be associated with a better outcome (not just lung cancer). PD-L1 in tumour−T cell interactions: PD-L1 overexpressed by tumour cells binds T-cell-expressed PD-1 receptor, PD-1 checkpoint pathway activation à leads to downregulation of T-cell effector functions leading to immune response inhibition.

Answer 69

The personalised therapies used routinely include: Epidermal growth factor receptor (EGFR) mutations, Anaplastic lymphoma kinase (ALK) fusion, Reactive oxygen species (ROS)-1 translocation, Programmed death ligand (PDL)-1 expression. In reality, 20% lung cancers are small cell carcinomas and 30% squamous carcinomas, both of which there is no licenced target therapy for; Adenocarcinoma/other non-squamous carcinomas make up the other 50%, of which 13% have EGFR mutation (6.5% all lung cancers), 2% have ALK translocation (1% of lung cancers), and 1% have ROS1 translocation (0.5% lung cancers). So only around 8 cases per 100 that we diagnose are suitable for specific targeted therapies.

Answer 70

A disease of cells; Normally cells die overtime by apoptosis, which maintains homeostasis; Uncontrolled growth and mutations in genes leads to a tumour which can be benign or malignant; Mutations lead to rapid proliferation; Failure to stop growing by Tumour suppressor gene mutations; Failure of DNA Damage Repair increases invasiveness.

Answer 71

Over 100 different types of cancer. Carcinoma - Cells that line the inside and outside of the body (epithelium). Adenocarcinoma - Glands, secrete mucusor fluids (e.g. breast/prostate. Squamous carcinoma - Skin, lining of organs (e.g. lung). Basal cell carcinoma - Skin (BCC). Transitional cell carcinoma - Bladder. Sarcoma - Bones, Ligaments, Blood vessels (connective tissue). Haematological - leukaemia, lymphoma. Others - Brain and Spinal cord; neuroendocrine; carcinoid; germ cell tumour, etc.

Cancer Flashcards

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