43. Neoplasia: The Molecular & Cellular Basis Of Tumour Growth (HT) Flashcards

Question

What are some examples of DNA damage-based therapies for cancer and what their effect is?

Answer 1

These all work by inducing double-strand breaks.

Answer 2

* They chemically damage DNA. * Examples: Cyclophosphamide, Cisplatin

Answer 3

It is an alkylating agent: * In vivo it is oxidised to phosphoramide mustard * The chlorines can take part in displacement reaction, which cross-link the DNA strands and can induce damage It is effective in treating cancer and other conditions (e.g. rheumatoid arthritis)

Answer 4

* The aldophosphamide intermediate is detoxified by aldehyde dehydrogenase (ALDH) * This confers some selectivity for cells with low ALDH

Answer 5

It is an alkylating agent: * Displacement of the chlorine allows cross-linking of the DNA strands * This leads to cytotoxicity It is effective in treating cancer.

Answer 6

(Rosenberg, 1965): Discovered by chance observation of anti-bacterial properties of platinum electrolyte.

Answer 7

* It is very effective in testicular cancer, even if there is metastasis. * It led toa rise in cure rate from 10% to 80%.

Answer 8

Anti-tumour antibiotics

Answer 9

* They bind to DNA and can lead to double-strand breaks. * Examples: Doxorubicin

Answer 10

It is a topoisomerase inhibitor (a type of anti-tumour antibiotic): * It inhibits DNA topoisomerase II, which is involved in mitosis * This inhibition essentially leaves both DNA strands broken (i.e. causing double-strand breaks) It is effective in treating cancer.

Answer 11

* Topoisomerase is expressed most during G2 of the cell cycle. * This means that the cells in this phase are most susceptible to doxorubicin.

Answer 12

* They inhibit mitosis by blocking microtubule action * Example: Vinca alkaloid (e.g. vincristine)

Answer 13

It is a microtubule poison: * Inhibits tubulin polymerisation * This prevents the spindle assembling properly during mitosis * This causes the cell to be unable to progress past metaphase and it dies by apoptosis at the next mitotic checkpoint. It is effective in treating cancer.

Answer 14

* They are severely neurotoxic, since they inhibit microtubules, which are essential in neurons for neurotransmitter transport. * Therefore they cannot be administered into the CSF, but must be administered via IV.

Answer 15

* Reversible cytotoxic effects (e.g. damage to bone marrow, lymphoid tissue, GI epithelium, hair) * Irreversible toxicity to organs with little/no cell growth (kidney, nerves, heart & lungs).

Answer 16

They limit the concentrations of chemotherapy drugs that can be used.

Answer 17

Bone marrow: * Destruction of the bone marrow can lead to low neutrophil counts (and low levels of other cells) * This makes the individual susceptible to infections * A neutrophil count of \<0.5 x10⁹/L with fever is strongly predictive of bacteraemia (neutropenic sepsis) * Thrombocytopenia and anemia also common

Answer 18

* In the case of infection, IV / oral antibiotics are essential * Recombinant G-CSF is used prophylactically to boost neutrophil levels

Answer 19

* Occurs from 2 days to a few weeks after therapy * Hair returns around 3-6 months after stopping treatment * A cold cap can be used to reduce blood flow to the hair, so that hair loss is limited

Answer 20

* When chemotherapy drugs are administered via IV, the drug may leak from the bloodstream into surrounding tissue due to poor insertion of the canula or due to weakness of the blood vessel * This leads to severe damage of surrounding tissue * Therefore, a peripherally-inserted central catheter (PICC) can be used to deliver the drug straight to the vena cava, so that it is very rapidly diluted -\> This reduces the risk of damage upon extraversion

Answer 21

* A skin reaction around 2-12 days after chemotherapy * It invovles vessel damage in the hands and feet * Symptoms incude tingling, burning pain, peeling * Resolution occurs 1 to 2 weeks after stopping treatment

Answer 22

* Staggered schedule and/or synergy can increase efficacy/reduce toxicity * Minimises the likelihood of developing resistance

Answer 23

* The idea that most cytotoxic therapies for cancers are also carcinogenic * This can lead to new tumours forming that are distinct from the original disease * Around 1 in 6 of all new cancer diagnoses in the UK are due to this

Answer 24

* Hormonal therapies * Molecularly targeted therapies They are used because cytotoxic therapies are very toxic and lead to severe side effects.

Answer 25

* Tamoxifen * Aromatase inhibitors * Orchidectomy * Drugs to depress LH release * Anti-androgens (These are the ones mentioned in the spec)

Answer 26

It is a hormonal therapy for breast cancer: * It is metabolised to hydroxytamoxifen * This is an estrogen receptor (ER) antagonist * Thus, it stops the growth of breast cells * It may also have other unknown mechanisms of action

Answer 27

It has estrogenic (agonist) effects in endometrium, which is opposite to the effect it has on the breasts.

Answer 28

They are a hormonal therapy for breast cancer: * Block peripheral estrogen synthesis in post-menopausal women * Used in breast cancer

Answer 29

* Therapeutic antibodies against growth factor receptors (e.g. trastuzumab) * Small molecule inhibitors of cell cycle enzymes (e.g. imatinib)

Answer 30

* Chronic myeloid leukaemia is caused by a translocation between chromosomes 9 and 22 * This generates a BCR-ABL fusion gene, which has deregulated tyrosine kinase activity -\> This leads to the cancer * It can be treated using imatinib

Answer 31

It is a small molecule inhibitor used in targeted therapies: * Inhibitor of tyrosine kinase activity * This means it blocks the activity of the BCR-ABL seen in chronic myeloid leukaemia * It is also effective against other tyrosine kinases, so it is effective against multiple types of cancer

Answer 32

It is a therapeutic antibody: * It binds to HER2 receptors on HER2+ breast cancer cells * This down-regulates the growth factor signals that are mediated by the HER2 receptors and it also induces antibody-dependent cellular cytotoxicity (ADCC) * This means it is useful in treating breast cancer

Answer 33

* It is a receptor for growth factors * It is overexpressed, often as a result of gene amplification, in ~25% of breast cancers * This overexpression leads to overproliferation

Answer 34

* Decreased drug entry into cells * Altered expression or mutation of target enzymes * Improved DNA repair activity * Decreased tendency to apoptosis * Improved detoxification * Drug extrusion (multi-drug resistance)

Answer 35

* Earlier diagnosis -\> Cancer biomarkers / DNA in peripheral blood * Further biological therapies based on differences between cancer cells and their normal counterparts: * Small molecule inhibitors * Therapeutic antibodies * Immunotherapies * Personalised medicine

Answer 36

* Excessive proliferation of one cell type * Results from cumulative genetic and epigenetic changes; usually clonal * Abnormal, unbalanced histology * No useful function * Progressive; spontaneous regression is rare

Answer 37

* No, most cancers require multiple mutations in sequence within the same cell. * This explains the higher incidence of cancers with ageing.

Answer 38

It suggests that it is the result of the accumulation of several independent events.

Answer 39

* DNA repair proteins, involved in: * Mismatch repair * Nucleotide excision repair * Homologous recombinational repair * DNA polymerases ẟ and ɛ * Cell cycle checkpoint proteins, e.g. p53, ATM, CHK2, NBS1 Most of these genes have been found to be mutated in sporadic cancers and many were identified through germline mutations that give rise to familial cancer syndromes.

Answer 40

* Multiple mutations are required (as per the 6 hallmarks of cancer), since the tumour must have multiple properties in order to grow uncontrallably * Each mutation conveys one of these properties to the cell * This means that inheritable disorders, such as xeroderma pigmentosum, convey an increased likelihood of some of these changes, but do not necessarily mean that a cancer always develops This of inherited disorders as giving the cell a head start in collecting sufficient mutations to develop a cancer.

Answer 41

* Dominant (gain of function) -\> Proto-oncogenes becoming oncogenes * Recessive (loss of function) -\> Mutations in tumour suppressor genes Note that this classification may be insufficient, since some genes may fall into both catergories.

Answer 42

* Viral oncogenes within oncogenic viruses -\> These lead to insertion of oncogenes into the human cell or other indirect oncogenic effects (e.g. inflammation) * Cellular proto-oncogenes that mutate into oncogenes or are overexpressed

Answer 43

* Human cells proto-oncogenes produce mRNA * This RNA is transformed into the viral genome, presumably using reverse transcriptase (CHECK WHY) * Now these viral oncogenes can be inserted into human genomes, predisposing to cancer

Answer 44

* The viral genome is small and therefore when an oncogene is inserted, it often displaces important genes * This means that the virus may be helped by a helper virus that encodes components of the virus, such as gag, pol and env * Together, they are selected for because they increase cell proliferation and thus the rate of generation of new viruses

Answer 45

* Study of oncoviruses * Since oncovirus oncogenes are derived from host cell proto-oncogene mRNAs, the sequencing of the oncovirus genome has enabled these oncogenes and host cell proto-oncogenes to be identified * Transfection of DNA fragments from cancer cells to healthy fibroblasts * The fibroblasts that grow out of control and rapidly are the ones that contain fragments that include oncogenes * Activation of oncogenes by virus infection * Mouse mammary tumour virus (MMTV) inserts its DNA randomly into the host cell DNA, and it causes upregulation of adjacent genes due to strong transcriptional enhancers. By studying the cells that develop tumours, you can find suspect oncogenes by looking at where the viral DNA has been inserted. * Studying cancers caused by translocation or gene amplification * The location and type of the translocation or gene amplification tells you what the oncogene is.

Answer 46

* They mostly cause increased proliferative signalling (or evasion of growth suppressors) -\> These lead to uncontrolled growth and proliferation * They can also have other effects, such as reducing apoptosis, which contribute to tumour development (Check this, but it seems that oncogenes must cause increased proliferation, but can also have other effects on the hallmarks of cancer)

Answer 47

The oncogenes can encode mutated proteins at various points along the proliferative pathways. For example, in receptor tyrosine kinase pathways there may be: * Mutated growth factors (e.g. v-sis oncogene) * Mutated growth factor receptor (e.g. v-erbB oncogene) * Mutated RAS protein, so that it is more likely to bind GTP (e.g. v-ras oncogene) * Mutated RAF protein (e.g. v-raf oncogene)

Answer 48

* Genome projects have allowed the creation of a 'consensus' human genome sequence * This allows deviations from the sequence in cancers to be studied, in the hope that some of these may be the cause of the cancer

Answer 49

(Davies, 2002): * Sequencing studies of tumours of malignant melanoma found a single nucleotide mutation in 60% of tumours * This mutation involved a single nucleotide change on one of the chromosomes encoding the BRAF protein (shown in the diagram) * Thus, this mutation could cause cancers by stimulating the receptor tyrosine kinase pathways shown (Patton, 2005): * This was demonstrated by use of animal models * Zebrafish with this BRAF V600E mutation demonstrated that this protein induced a high rate of development of melanomas in the fish compared to controls (Chapman, 2011): * Deduction of the structure enabled the creation of an inhibitor called vemurafenib (BRAF inhibitor) * This induced clinical responses in 77% of metastatic melanoma patients with the BRAF V600E mutation

Answer 50

* BCR-ABL in chronic myeloid leukaemia: Imatinib (Glivec) and 2nd/3rd generation inhibitors * BRAF V600E in melanoma: vemurafenib * HER2 overexpression in breast cancer: trastuzumab (Herceptin) * EGRF overexpression in colorectal carcinoma: cetuximab – but no benefit if tumour has mis-sense KRAS mutation

Answer 51

Mutations in the promoter region of the telomerase reverse transcriptase (TERT) gene, which encodes part of telomerase, can lead to increased telomerase activity that maintains the cell's lifespan. However, note that telomerase is not strictly a proto-oncogene since it does not lead to increased cell proliferation!

Answer 52

* Cell fusion studies: * Henry Harris performed cell fusion studies and found that the fusion of a cancer cell and a normal cell caused a loss of the tumour-forming ability * Tumourgenicity returned when the normal chromosomes were lost * Comparatively rare familial cancer syndromes e.g. retinoblastoma

Answer 53

* Both copies of a tumour suppressor gene must be mutated in order for a cancer to develop * This means that familial pre-dispositions to cancer arise when one of the alleles encoding the tumour suppressor gene is already mutated, so that only one more must be mutated in order to cause cancer NOTE however, that both tumour suppressor alleles being mutated is not usually sufficient for the development of a malignant tumour. Other mutations must happen in addition to this, as per the hallmarks of cancer.

Answer 54

The tumourgenicity of the cell is lost because the normal chromosomes encode functional tumour suppressors.

Answer 55

* Linkage and positional cloning involve identifying the approximate locus of the tumour suppressor gene by studying which polymorphic markers it is most frequently inherited with. * Association of gene product with DNA viral oncoprotein involves looking at which host cell proteins are affected by oncoviruses, meaning that these proteins may be tumour suppressor proteins. * Cancer genome projects that use NGS have accelerated the speed at which tumour suppressor genes are found.

Answer 56

The restriction point (R) is the point in G1 that marks commitment such that the cell no longer needs growth factors to finish the cell cycle. It may be affected by tumour suppressor gene mutations: * RB inhibits the E2F-DP transcription factor complex that leads to transcription of genes that are needed for S phase -\> RB mutations can predispose to familial retinoblastoma and various sporadic cancers * Cyclin D is a CDK that phosphorylates the RB, inhibiting the inhibition of the transcription factors -\> Cyclin D may be overexpressed due to gene amplification and oncogene signalling, which predispose to cancers (so this is really a proto-oncogene) * CDK inhibitors inhibit the action of cyclin D -\> p16 mutation / promoter methylation, increase p27 degradation and CDK4 mutation (causing dysfunctional interaction with p16) may all predispose to cancers

Answer 57

For example, tumour suppressor gene mutations may affect the HIF pathway: * In hypoxia, HIF-alpha leads to transcription of various genes including VEGF * This VEGF leads to increased angiogenesis * VHL is part of the complex that degrades HIF upon return to normoxia -\> Mutations in VHL lead to sustained angiogenesis (VHL is a tumour suppressor gene)

Answer 58

For example, p53 tumour suppressor gene mutations: * p53 is a tumour suppressor gene responsible for inducing cell cycle arrest, apoptosis or differentiation in cells affected by DNA damage, hypoxia and oncogene activation: * p53 stimulates inhibitors of CDK, such as p21 and 14-3-3-sigma -\> This halts the cell cycle * p53 stimulates BAX, noxa and PUMA, which lead to release of cytochrome c from mitochondria. p53 also drives the expression of death receptors. -\> This leads to apoptosis * p53 mutations therefore predispose to various types of cancers

Answer 59

* Sporadic oncogene mutations occur more frequently than the total incidence of cancers * This can partly be explained by the fast that oncogene activation leads to p53 activation * p53 induces apoptosis and prevents the tumour from growing to a detectable size

Answer 60

* TP53 (the gene encoding p53) mutations are found is very many cancers * However, in some cancer types, a lack of p53 mutation may be compensated for by a different mutation * For example, renal cancers very commonly have VHL mutations instead of p53 mutations

Answer 61

* Li-Fraumeni syndrome -\> This is a rare inherited cancer predisposition disorder * It is diagnosed when 3 closely-related family members develop cancer younger than 45, with at least one of these cancers being a sarcoma * Tumourigenesis occurs when there is loss of the remaining normal allele * (Malkin, 1990) studied this

Answer 62

* p53 is usually unstable because one of its effects is MDM2 transcription, which feeds back and degrades the p53 * However, ATM (increased by DNA damage) and ARF (increased by oncogene activation) inhibit this feedback degradation * This means there is more p53 available to carry out apoptosis, etc.

Answer 63

No, p53 dysfunction (leading to predisposition to cancer) may also be caused by: * MDM2 overexpression * Loss of ATM function * Viral infection * Loss of ARF -\> Involving deletion or promoter methylation of the CDKN2A gene that codes for ARF and p16

Answer 64

* Most frequently one allele is deleted while the other has a missense point mutation * Most frequently, these missense mutations are at codons 175, 248 or 273 -\> These are in the DNA-binding domain of the p53 protein

Answer 65

* Often they are, which means that there is a lack of p53 function and thus there is reduced apoptosis, etc. * However, sometimes mutations in regions of the p53 protein other than the DNA-binding domain may be gain of function mutations * These gain of function mutations can 'poison' other p53 molecules in a tetramer, inactivating them -\> This is actually a dominant effect, which means that even one of these mutations can leads to a significant reduction in apoptosis, etc., even if the other allele is still unaffected

Answer 66

* Cell cycle continues, even if there is unrepaired DNA damage * Lack of senescence when telomeres are shortened * No apoptosis/cell cycle arrest driven by oncogene activation * Logically, a treatment for this would be p53 replacement, but it is delivering this treatment to cells that is difficult

Answer 67

* Loss of growth control * Limited to the site of origin, often encapsulated * Clinical signs related to the occupying space or due to production of hormones/active molecules * Often cured by surgery

Answer 68

* Loss of growth control + Loss of positional control + Loss of tissue organisation * Invasion into local tissues + Dissemination and survival in distant tissues via the blood * More difficult to cure by surgery if spread

Answer 69

* Lung (1.4 million deaths) * Stomach (740 000 deaths) * Liver (700 000 deaths) * Colorectal (610 000 deaths) * Breast (460 000 deaths)

Answer 70

More than 70% of all cancer deaths occurred in low- and middle-income countries.

Answer 71

Metastasis

Answer 72

* Normal tissue (e.g. epithelial) has excess growth, forming a primary tumour * There is also angiogenesis and secretion of proteases (by tumour cells or stromal cells) that destroy the tissue structure * When there is loss of contact between cells, there is deattachment of cells * If the basement membrane at the boundary of the organ is affected by proteases, this releases cells from the tumour * The cells invade lymphatic and blood vessels * The cells are deposited at distant sites that can remain dormant for long periods of time, but they are be reactivated by a similar process to the initial tumour, leading to new tumours

Answer 73

* At the top, there are the steps needed for a primary tumour to grow and then the environmental changes required for it to spread to vessels. * In the middle, there are the steps involved in transit to a metastatic site. * At the bottom, there are the steps involved in invasion developing a metastatic tumour. Note that not all of these steps are required always and they may not happen in this exact order.

Answer 74

* Microenvironmental changes are contributed to by two-way interactions between tumour cells and stromal cells, such as macrophages and fibroblasts. * In experiments, cultured macrophages alone produce a small amount of MMP (matrix metalloprotease) and breast cancer cells alone produce very little MMP. * However, when macrophages and breast cancer cells are combined, the MMP production is greatly increased. * This is because the CSF on cancer cells activates macrophages' MMP and EGF production * Then EGF (a growth factor) on macrophages reciprocally stimulates proliferation * High levels of MMP lead to degradation of the tissue structure, including basement membrane breakdown, etc. -\> This causes release of cells that can enter the bloodstream

Answer 75

* Epithelial-to-mesenchymal * This is because epithelial cells have strong basolateral cell-to-cell adhesions that maintain the structure * Without this, the cells are more free to cross the basement membrane into the vessel (i.e. greater migratory potential)

Answer 76

* Loss of basolateral adhesions that maintain rigid structure -\> So they can move more freely Other changes: * Cell becomes more elongated * (Maintained/Increased?) Expression of focal cell-cell contacts that enable some adhesion to other cells but importantly also to the ECM -\> So greater migratory potential

Answer 77

* The process is the same as in the creation of mesoderm (the 3rd germ layer) from the epithelial layers during gastrulation * The mechanism involves a cascade that results in reduced expression of adhesion molecules (cadherin), which frees up the cells for migration * The signalling pathway for this is retained later in life and chance alterations in expression (genetic or epigenetic) of some of the factors in these pathways leads to unwanted epithelial-to-mesenchymal transitions in cancers. This leads to metastasis. * In carcinomas, the pathway is more complicated though (shown on the left), and also includes loss of desmosomes and changes to the cytoskeleton.

Answer 78

* These transcription factors control EMT during gastrulation and similar processes. * However, they can also by chance become expressed in tumours, which causes the cells to be disorganised and separated from each other. * This increases the likelihood of the cancer cells crossing the basement membrane into blood and lymph vessels.

Answer 79

No, they do not have signalling from other cells and they are exposed to shear forces. This means that relatively few survive before they can extravasate from the blood.

Answer 80

The half life of a circulating tumour cell is about 1 - 2.4 hours (Meng, 2004).

Answer 81

Host cell properties: * The primary tumour secretes cytokines that drive the release of endothelial progenitor cells (EPCs) and haematopoietic progenitor cells (HPCs), as well as their seeding in distant tissues * VEGFR1+ HPCs present an integrin (VLA-4) that allows them to adhere to fibronectin and create a pre-tumour environment characterised by tumour adhesion and survival molecules such as SDF-1. * The recruitment of VEGFR2+ EPCs increases vascularisation. * Thus, to an extent it is the host cells themselves that determine where the metastasis will form. Exosomes released from tumours cells: * Exosomes are membrane-bound vesicles released from tumour cells * These exosomes present integrins that enable them to enter normal host cell * The exosomes contain protein, lipid and nucleic acids, which can direct the formation of a tissue-specific pre-metastatic niche, predisposing to tumour formation * MicroRNAs and non-coding RNAs in the exosomes regulate recipient function, resulting in a wide range of effects * The integrins that the exosome expresses determine the tissue type it preferentially binds to (e.g. lung), which increases the likelihood of a pre-metastatic niche forming there predisposes to tumour formation

Answer 82

* Exosomes with different integrins bind at different sites in the body * They are taken up by cells and alter their function (e.g. by reprogramming energy metabolism), such that a pre-metastatic niche forms * This increases how favourable the environment is for tumour formation, so that circulating tumour cells may enter there and start a tumour

Answer 83

(Paget, 1889): * The theory that metastatic tumor cells will metastasise to a site where the local microenvironment is favorable, similar to how a seed grow only if it lands on fertile soil. * This has been shown to be largely true and we now know that endosomes released by tumour cells can influence which sites in the body become favourable for metastasis development (see flashcards). * However, the theory does not account for why the contralateral organ is rarely a site of metastasis (e.g. one lung to the other), since it would be

Answer 84

* Seed and soil hypothesis -\> The theory that metastatic tumor cells will metastasise to a site where the local microenvironment is favourable. How favourable a site is is largely determined by exosome release (from tumour cells), which bind to a specific tissue based on their integrins and create a pre-metastatic niche there. * Mechanical mechanisms hypothesis -\> The theory that patterns of blood flow determine the site of tumour formation. Neither of these can fully explain trends for all metastatic tumours seen clinically, so it is likely that both contribute somewhat.

Answer 85

* When a circulating tumour cell reaches a capillary it is often too large to pass through * This causes it to damage the endothelium, leading to recruitment of platelets and thrombus formation * As the thrombus is lysed, there is also some damage to the endothelium, so that the tumour cell can attach to the basement membrane. * Proliferation of the tumour cells leads to physical rupture of the basement membrane. * MMP release by the tumour cells also aids this rupture.

Answer 86

No, it is very inefficient. Very few tumour cells survive long enough in the blood or manage to cross the basement to invade a new site. This means that a primary tumour can shed over a million cells a day into the bloodstream without developing a secondary tumour. Even those that do invade other tissues may remain dormant for long periods of time, which is a therapeutic challenge.

Answer 87

(Malanchi, 2012): * In a mouse breast cancer metastasis model, using MMTV that causes breast tumours that metastasise efficiently to the lung, the cancer stem cell (CSC)-like cells with the CD24+ CD90+ phenotype form only 1-2% of the cells isolated from the tumour * Using the constitutive expression of GFP to track all the tumour cells, this model can be used to show that only the rare CD24+ CD90+ cells are able to form metastases in the lung * This shows that only a tiny fraction of the cells in this cancer are about to cause metastasis

Answer 88

No, they may go through all the same steps in intravasation, travel and extravasation, but they do not form secondary tumours.

Answer 89

* They are single cells that have undergone metastasis and are now located in distant tissue. * They can lie dormant for many years and can be activated by, for example, signalling from stromal cells, and subsequently lead to secondary tumour formation * They are a problem because they are negative for markers of replication (Ki67) and are therefore resistant to anti-mitotic chemotherapies and radiotherapies

Answer 90

The re-activation of dormant single-cell micro-metastases found in distant tissues.

Answer 91

* They are formed by tumour cells that have escaped a primary tumour, meaning that this property has been selected for. * Therefore, most of the cells that arise from the metastatic tumour (created when the micro-metastasis grows) already have the properties for escaping the site. * Thus there may be a cascade of new metastatic sites around the body.

Answer 92

* It was believed to be due to the expression of VEGF * However, it is now known that some VEGF is found in the ECM, which is cleaved by MMP (matrix metalloproteinases) to release this VEGF

Answer 93

* The vessel walls are abnormal and leaky, which means they are susceptible to movement of cells across them. * However, this could also perhaps be exploited in development of treatments that selectively only cross this barrier.

Answer 94

* BRCA1 mutations not only increase the risk of developing breast cancer, but also increase the risk of metastasis * This is because BRCA1 is thought to play a role in reducing the motility of cells * Thus, increased rates of metastasis are seen in the years after recovery in BRCA1 mutation-carrying patients * This is not only in breast cancers, but also in other cancers * Identification of genes that slow the rate of metastasis is a promising concept in developing drugs that prevent metastasis

Answer 95

* Papilloma (warts) -\> Epithelial tumour * Gliomata -\> Glial cell tumour (CNS) * Adenoma (e.g. colonic polyps) -\> Glandular tumour * Leiomyoma (e.g. uterine fibroids) -\> Smooth muscle tumour * Lipoma -\> Fat cell tumour

Answer 96

* Squamous cell carcinoma -\> Skin tumour * Adenocarcinoma -\> Glandular tumour

Answer 97

Smooth muscle (it is a benign tumour)

Answer 98

* Bleeding * Pressure * Endocrine toxicity (if glandular tissue affected) * Possible progression to malignancy

Answer 99

Local effects: * Pressure * Occupation of space (e.g. intra-thoracic or intra-cranial) * Obstruction of vessels or ducts * Intussusception of the gut * Haemorrhage * Infection Systemic effects: * Cachexia (weight loss, nausea, anorexia, lethargy) * Hormonal effects (over-secretion, ectopic secretion, or destruction of endocrine tissue) * Marrow destruction in leukaemias leading to infection (neutropenia) * Bleeding (thrombocytopenia) * Anaemia

Answer 100

* The direct extension and penetration by cancer cells into neighbouring tissues. * It is a characteristic of malignant tumours.

Answer 101

* Aberrant differentiation * Pleomorphism * Anaplasia

Answer 102

* The variability in the size, shape and staining of cells and/or their nuclei. * Several key determinants of cell and nuclear size, like ploidy and the regulation of cellular metabolism, are commonly disrupted in tumours.

Answer 103

* A condition of cells with poor cellular differentiation, losing the morphological characteristics of mature cells and their orientation with respect to each other and to endothelial cells. * This is a feature of malignant tumours. * In other words, the cells become less differentiated in tumours.

Answer 104

* Infiltration -\> Spread beyond the layer of tissue in which it developed and is growing into surrounding, healthy tissues. * Permeation -\> Spread of cancer cells in continuous columns within the lymph vessels.

43. Neoplasia: The Molecular & Cellular Basis Of Tumour Growth (HT) Flashcards

(137 cards)