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HORMONES AND CANCER THE BASICS Flashcards

1
Q

In cancer, what do hormones do?

A

Drive proliferation and hormone dependency

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2
Q

In post menopausal women, what 2 therapies can be used for oestrogen dependent cancers?

A

Most of the sex steroids are produced in the adrenal gland most menopausally. The most common sex steroid is DHEA sulfate and estrone sulfate which act as biological pools of oestrogen. Use sulfatase inhibition to stop conversion to oestrogen. Also aromatase inhibitors. sulphatase activity can be 50 times higher in breast cancer tissue

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3
Q

What treatment can be used for prostate cancer?

A

Prostate cancer cells undergo apoptosis in absence of androgen. LHRH agonists cause an initial increase in androgens but then a decrease as there is down sensitivity of the receptors

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4
Q

What can there be over production of with specific reference to breast cancer?

A

Growth factors such as the permanently activated ERBb2

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5
Q

What is a key function of the PI3 pathway in terms of the cell cycle?

A

Inactivate p53, a tumour suppressor that binds to MDM2

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6
Q

What is the most successful tyrosine kinase inhibitor?

A

Imatinib. An ATP analogue that binds to BCR-ABL. Displaces and competes with ATP stopping BCR from working. ABL is a tyrosine kinase involved with DNA repair

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7
Q

How to tyrosine kinase inhibitors generally work?

A

Generally they block receptor tyrosine autophosphorylation by competing for ATP binding sites and then induce dimerisation and internalisation of the receptor. Eg induce cell cycle arrest with up regulation of p27Kip1 (inhibitor of cyclin dependent kinases) to potentiate cytotoxin induced apoptosis and restore sensitivity to cytotoxic agents.

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8
Q

What are the three overall ways to treat cancer

A

Surgery, chemo and radiotherapy (chemo and radio do not kill cancer but damage cells to induce apoptosis)

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9
Q

Give any example of a chemotherapy

A

anthracylines (doxrubicin, epirubicin): disrupt DNA replication, •cyclophosphamide: disrupts DNA replication •5-Fluorouracil: inhibits DNA synthesis and repair •methotrexate: inhibits DNA synthesis and repair •mitomycin: cross-links DNA strands

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10
Q

What is the point of an adjuvant therapy?

A

Enhance sensitivity and prevent reoccurrence

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11
Q

How is a cancer mechanism linked to GF?

A

growth factors: over-production, e.g. of PDGF and TGFα, can lead to runaway positive feedback

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12
Q

Give an example of an intracellular mediator causing cancer

A

intracellular growth signal mediators: overproduction or unresponsiveness to inhibition, e.g. of ras and src

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13
Q

Give a list of hormone deprivation therapies

A

Gonadectomy, anti-oestrogens, SERMS, aromatase inhibitors, sulphatase inhibitors, LHRH agonists, antiandrogens

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14
Q

Why use SERMs over anti-oestrogens?

A

anti-estrogens such as faslodex completely block estrogen receptor which is associated with osteoporosis and menopausal symptoms but SERMs such as tamoxifen partially block the receptor so it has desired effects on bone and vasculature but blocks estrogen effects on cell division

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15
Q

In endometrial cancer, what stimulates proliferation?

A

The action of oestrogen without the opposing act of progesterone

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16
Q

Why might some cancers become resistant?

A

Typically hormone dependent cancer may be resistant to hormone deprivation (e.g ER –ve breast cancer in 1/3 of cases). Resistance may be due to epigenetic changes – upregulation of receptor cofactors or receptor mutations or may be due to activation of other growth factor pathways for example EGF may start to activate cell division.

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17
Q

How do you target growth factors? Give an example of one

A

Using monoclonal antibodies e.g. Herceptin which is an EGFR antibody it is also able to block erbB2

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18
Q

What is a disadvantage of blocking tyrosine kinase activity?

A

There are many side effects as cells are dependent on it for normal function

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19
Q

Give an example of some of the intracellular signalling targets of monoclonal antibodies

A

trametinib is a MAP kinase inhibitor, dabrafenib is a B-raf inhibitor. Tipifarnib is a farnesyl transferase inhibitor

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20
Q

Give specific examples of genome targetting

A

Killer T cells which were genetically modified to attack metastatic melanoma. Put genes coding for t cell receptors to tumour markers into a lymphocyte. Also replace any missing or altered genes (eg p53). Introduce genes into the tumour cell that convert a harmless pro-drug into its active form so normal body cells aren’t affected. Introduce genes which block angiogenesis (major rate limiting step in tumor growth)

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21
Q

How can the genome be targetted?

A

Antisense oligos: oligonucleotides that bind to and block complementary messenger or micro RNA. Ribozymes: RNAs with specific enzyme activity. Small-interfering RNAs (siRNAs): target specific mRNAs for degradation - used in an animal model against anti-apoptotic Bcl2

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22
Q

What are three forms of epigenetic changes?

A

DNA methylation, histone modification and altering microRNA

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23
Q

Describe what happens in DNA methylation?

A

DNA methyl transferase takes S-adenosyl methionine and transfers its methyl group onto a cytosine (only happens of cytosines adjacent to guanine) –> methylation pattern to the newly synthesized DNA strand

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24
Q

What is methylation associated with?

A

Methylation is associated with gene silencing in GENE PROMOTERS – makes histone tight and unable for genes to be transcribed

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25
Q

What are epigenetic changes?

A

Transmissable changes in gene expression that do not involve changes in the primary DNA sequence

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26
Q

How is imprinting carried out?

A

Through methylation

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27
Q

With respect to methylation, what can happen in cancer?

A

Hypomethylation can activate proto-oncogenes and can lead to chromosomal instability

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28
Q

What is hypermethylation linked to

A

Gene silencing, can also occur with tumour suppressors e.g. protein Retinoblastoma

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29
Q

How can methylation be targetted in cancer therapy? What is a potential problem?

A

Can inhibit DNA methyltransferase to regain tumour suppressor function. Hypomethylation is associated with long term gene instability. For eliminating hypermethylation: Antisense oligo nucleotides can eliminate DNA methyltransferase activity.

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30
Q

What is histone modification?

A

It is the process by which DNA methylation modulates gene transcription. Proteins that bind to methylated CpG recruit histone methyl transferase and histone deacetylases. Histone methylation packs the nucleosome to prevent gene transcription

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31
Q

Describe the epigenetic mechanism microRNA?

A

This NEGATIVELY regulates gene expression post transcriptionally and controls certain pathways by targeting oncogenes and TSG in cancer. Carcinogenic microRNA involvement has been found in relation to many cancer related genes and miRN profiling can improve cancer subtype profiling and prognosis.

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32
Q

Specific examples of micro RNA

A

Micro RNA 15 and 16 act as tumour suppressors by suppressing anti-apoptotic BCL2. MicroRNA21 suppressing PTEN.

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33
Q

What is an epigenetic tag?

A

Epigenetic “tags” (eg histone acetylation) sustain cell identity. Eg c-Myc→ major target in cancer promotion but is not druggable.

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34
Q

What are some of the acquired mutations?

A

Unrestrained cell growth, evasion of apoptosis, angiogenesis, immortalization and metastasis.

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35
Q

Overall what is hypermethylated and what is hypomethylated?

A

Oncogenes + chromosomal instability – hypomethylation

Tumour suppressor genes – hypermethylation

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36
Q

What can hypermethylation do?

A

‘lock’ differentiation-related genes in a silent state, resulting in differentiation arrest, expansion of progenitor cells and facilitation of tumour development

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37
Q

What are some of the epigenetic changes occurring in cancer?

A
  • Global hypomethylation
  • Promoter specific hypermethylation
  • Histone deacetylation
  • Global down regulation of microRNAs
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38
Q

What are some of the problems associated with epigenetic cancer targeting?

A

BUT, hypomethylation may promote long-term genomic instability
BUT, the same type of tumour may be caused by disruption of methylation at different gene loci
BUT, gene silencing may be re-established despite DNA
methyl-transferase inhibition as a result of other gene silencing mechanisms
BUT, HDAC inhibitors have high toxicity

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39
Q

What is an oncogene? Give an example

A

PROTO-ONCOGENES are genes for GROWTH FACTOR SIGNALLING so when mutated (one hit required) there is constitutive activation. C-erb, c-ras, c-src, c-myc and c-fos.

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40
Q

What are tumour suppressor genes? Example

A

are growth inhibitory factors so that when mutated (2 hits required) you get constitutive growth promotion signaling. P-Rb (suppresses progression through G1 phase), P53 (important for deciding DNA repair or apoptosis), APC, PTEN (inhibits PI£ kinase signaling) and BRCA 1 (promotes DNA repair).

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41
Q

What are the different broad types of growth factor?

A

They can either be ENDOcrine (E2, testosterone, IGF1, insulin and GH), PARAcrine/AUTOcrine (EGF, FGF, PDGF, VEGF, NGF and inflammatory cytokines) or INTRAcrine (Ras, PI3K and G protein).

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42
Q

How does intracellular communication generally occur?

A

Through the exchange of phosphates which is regulated by kinases

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43
Q

How do receptor tyrosine kinases work? Give an example specifically with EGFR.

A

Ligand binding causes AUTOphosphorylation of the intracellular portion and dimer or heterodimer formation. Then recruitment of various binding partners. Eg EGFR recruits adaptor protein SHC and GRB2. GRB2 mediates the interaction between SOS and Ras. Ras is a small guanosine triphosphate phosphatase that is activated by GTP and inactivated by GDP. SOS promotes dissociation of GDP from Ras and uptake of GTP activating it.

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44
Q

When can PIP3 be recruited?

A

At p21Ras through PI3 kinase. PIP3 can lead to the activation of AKT. Then mediates a cell survival signal as well as cell division allowing cells to progress into the S phase of the cell cycle

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45
Q

What does PTEN do?

A

A phosphatase that breaks down PIP3 and can thus inactivate AKT activity

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46
Q

What happens in apoptosis?

A

Programmed cell death (essential for development, maintenance and renewal of cells), highly regulated, no membrane rupture and ATP dependent.

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47
Q

Give examples of regulatory apoptosis in the body

A

For example ovarian cells atresia by apoptosis, lactating breast to return to normal state, sculpting of tissues during normal development, autoreactive t cells in thymus and virally infected cells.

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48
Q

What are the key events in apoptosis?

A

DNA fragmentation, chromatin condensation, breakdown of nuclear lamins, membrane enclosed apoptotic bodies form which then undergo phagocytosis, then caspases (exist as pro-caspases so DNA transcription not necessary) that then do proteolysis of key elements

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49
Q

What activates the extrinsic pathway? What is it also known as?

A

The death receptor pathway is activated by the binding of external ligands to cell surface death receptors (caspase 8+10), mainly viruses. Signalling via TNF family and Fas ligand. Balance between FADD and FLIP determines whether cell death proceeds.

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50
Q

What activates the intrinsic pathway?

A

2) INTRINSIC (MITOCHONDRIAL DEATH PATHWAY) is activated by internal signals (caspase 2 and 9). Cytochrome c is the main pro-apoptotic protein. APAF 1 is a cytoplasmic protein with caspase activation and recruitment domain that binds to cytochrome c. Controlled by BCL2 family and by IAPs (inhibitors of apoptosis) that inhibit conversion of procaspase 3 to caspase 3. SMAC/ DIABLO released from the mitochondria on initiation of apoptosis and inhibits IAPS

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51
Q

What is a telomere?

A

Protective non genomic strands of DNA at each end of the chromosome that shortens with cell division.

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52
Q

What eventually happens to telomeres?

A

After 50-60 divisions, SENESCENCE sets in with no more cell divisions but the cell remaining viable.

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53
Q

What can restore telomeres?

A

REVERSE TRANSCRIPTASE can restore telomeres but is switched off in most cells.

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54
Q

What does proto-oncogene activation do to telomeres?

A
  • further cell divisions, driven by proto-oncogene activation completely erode the telomeres
  • errors in DNA copying at the chromosome end then initiate apoptosis
  • the human telomerase reverse transcriptase (hTERT) gene codes for the catalytic subunit of telomerase, which contains an RNA segment coding for telomere DNA
  • Replicative immortality is achieved by hTERT re-expression, which occurs in 1 in 10 million cells
  • telomerase is re-activated in >90% of cancers
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55
Q

What are the two types of breast cancer?

A

70-80% over express ER alpha – slow growing, responsive to estrogen ablation and have good prognosis
20% ER negative but erbB2 positive

56
Q

What is the Warburg hypothesis?

A

cancer cells showed increased glycolysis and oxidative metabolism and that glucose is a metabolic fuel. Cancer cells are adapted to cope with les oxygen. The driver of tumourigenesis is caused by reduced cellular respiration from insult to mitochondria

57
Q

What are homologous cell-cell interactions?

A

CADHERINS and catenins for signal transduction. e.g. E-cadherin plays a role in cell-cell adhesion, and its underexpression may lead to a greater probability of tumor invasion or metastasis; in oral cancer E-cadherin was found to be silenced by hypermethylation.

58
Q

What are heterologous cell-cell interactions?

A

SELECTINS (glycoproteins that are cation dependent and bind to carbohydrates and mucins, are major player in leukocyte trafficking), CAM (Cell Adhesion Molecules) that are part of the immunoglobin superfamily

59
Q

Cell-matrix interactions?

A

INTERGRINS (alpha/beta heterodimers that bind to ECM)

60
Q

What is the normal blood vessel composed of?

A

Endothelium, smooth muscle, stroma and basement membrane proteins.

61
Q

What does invasion require? Which molecules?

A

Invasion requires the penetration of its basement membrane, remodeling at the level of the ECM involving MMP (matrix metalloproteinases that destroy the ECM), TIMPS (Tissue inhibitors of MMPs) and ADAMS (A Disintegrin And Metalloproteinase family). MMP starts as a zymogen with TIMP blocking a site on the MMP that overhangs on to the active site. Then chemotaxis and destruction of cells at the invasion front (apoptosis/necrosis).

62
Q

What is angiogenesis?

A

normally outgrowth of endothelial cells from existing blood vessels.
• Breakdown of integrity of original vessel (Leukocyte effects + other regulators)
• Loss of smooth muscle layer if present.
• Outgrowth of endothelial cells (Proliferation and invasion)
• Reformation of vascular integrity

63
Q

What is the difference between ang 1 and ang 2?

A

ANG 1 – maintains vascular integrity and ANG 2 - destabilizes vessels.

64
Q

Which genes are required for blood vessel formation?

A

Occurs through specific transcription factors – HIF that activates specific genes as well as cytokines (growth factors, MMPs for invasion and leukocyte chemotaxis). Requires VEGF, potential to block

65
Q

What does pRB do?

A

retinoblastoma protein suppresses progression through G1 phase

66
Q

What does BRCA1 do?

A

inhibits cell division, promotes DNA repair by recombination, loss of function promotes genetic instabiliy

67
Q

What are the two main types of breast cancer?

A

70-80% of breast tumours over-express oestrogen receptor α (ERα) .ERα +ve tumours are slow growing, responsive to oestrogen ablation and have good prognosis ~20% of breast tumours are ERα -ve, but over-express the growth factor receptor erbB2/HER2/neu erbB2/HER2/neu +ve tumours respond to Herceptin.

68
Q

Why does prostate cancer spread to bone so easily?

A

osteoblasts in bone marrow release chemoattractant cytokines, e.g.SDF-1, which promote stem cell homing. metastatic prostate cancer cells also respond to these cytokines and accumulate in bone marrow

69
Q

What does invasion require in terms of molecules?

A

Remodeling at the level of the ECM involving MMP (matrix metalloproteinases that destroy the ECM), TIMPS (Tissue inhibitors of MMPs) and ADAMS (A Disintegrin And Metalloproteinase family). MMP starts as a zymogen with TIMP blocking a site on the MMP that overhangs on to the active site. Then chemotaxis and destruction of cells at the invasion front (apoptosis/necrosis).

70
Q

What does angiogenesis require?

A
  • Breakdown of integrity of original vessel (Leukocyte effects + other regulators)
  • Loss of smooth muscle layer if present.
  • Outgrowth of endothelial cells (Proliferation and invasion)
  • Reformation of vascular integrity
71
Q

What are examples of failures of apoptosis?

A 
Failure of apoptosis in cancer  
downregulation of caspase 8 
upregulation of FLIP 
phosphorylation and inactivation of procaspase 9 by Akt overexpression 
upregulation of Bcl-2 
upregulation of IAPs, e.g survivin 
downregulation of Smac/DIABLO 
downregulation of Fas and production of Fas decoy receptor DcR3
72
Q

How can apoptosis be used in cancer therapy?

A

failure of apoptosis is central to the development of cancer
recovery of apoptotic function during tyrosine kinase inhibitor therapy can result in recovery of sensitivity to chemotherapy
in human studies, administration of Bcl-2 gene anti-sense oligonucleotides has enabled recovery of sensitivity to chemotherapy
experimental studies have demonstrated that insertion of an active, wild-type p53 gene or recombinant Smac/DIABLO into cancer cells can enable recovery of apoptosis

73
Q

What does low oxygen lead to?

A

HIF transcription factors that: HIF leads to
Glucose transporters
oProteases (MMP-1, MMP-2, MMP-9)
oCytokines (pro-inflammatory)
oGrowth factors (mainly vascular, includes VEGF)

74
Q

What is the Warburg hypothesis?

A

Driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria. noted that cancer cells showed increased glycolysis and oxidative metabolism and that glucose is a metabolic fuel. Cancer cells are adapted to cope with les oxygen. The term Warburg effect describes the observation that cancer cells, and many cells grown in-vitro, exhibit glucose fermentation even when enough oxygen is present to properly respire.

75
Q

What was one of the initial studies linking insulin to cancer?

A

It has been thought that inhaled recombinant insulin causes increased rates of lung cancer and that insulin-glargine (insulin analogue which is designed to stay in the body for a longer time)

76
Q

What are confounders looking at insulin and cancer?

A
  • confounding by diabetes – people who go on these more advanced analogues
  • have worse diabetes and therefore may be the poorly control diabetes acting as a confounder – they have more comorbidities as they are worse off
  • confounding by variations in diabetes therapy
  • confounding by insulin resistance (normaly given if normal insulin doesn’t work)
  • confounding prescription bias
77
Q

What is one of the simple reasons insulin allows cell proliferation?

A

Allows glucose to enter cell and have the energy to proliferate.

78
Q

In the insulin signalling pathway, what remains sensitive to insulin?

A

The IRS does not remain sensitive to insulin however the MAPK pathway does leading to increased cell growth and survival

79
Q

What is the consequence of insulin resistance?

A

The IRS pathway is inhibited, meaning that glut 4 is not stimulated meaning glucose does not enter cell. AKT can not inhibit FOXO so gluconeogenesis occurs. The elevated glucose will cause the pancreas to work harder meaning that there is hyperinsulinaemia with hyperglycaemia. More over, the MAPK pathway is not inhibited meaning there is further growth signalling.

80
Q

What other receptor can insulin activate?

A

The IGF 1 receptor which is a potent stimulator of cell proliferation. IGF1 and 2 are overexposed in many cancers

81
Q

What can the IGF1 receptor do? Think another field, plus mechanisms.

A

IGF1 receptor can ACTIVATE THE OESTROGEN RECEPTOR INDEPENDENTLY OF OESTROGEN. Stimulation of P13K or MAPK signalling via the IGF-1 receptor promotes phosphorylation of TAF-1 of the oestrogen receptors, promoting oestrogen-independent cell growth and division in oestrogen-sensitive tissues

82
Q

What action does insulin have with another hormone?

A

It up-regulates hepatic GH receptors. Insulin can up-regulate hepatic GH receptors, and receptor-mediated GH signalling in the liver is the principal stimulus for IGF-1 release. So hyperinsulinaemia will increase IGF-1 levels

83
Q

What can insulin and IGF do?

A

Form heterodimers.

84
Q

What other actions does insulin have?

A

It down regulates IGF binding proteins 1 and 2. Increases 3.

85
Q

How does insulin augment IGF1 growth factor signalling?

A

Insulin>IR>SHC>GRB2>SOS>Ras>Raf>Mek>Erk—–>phosphorylates farnesyl transferase that leads to 21 Ras GDP plus farnesyl becoming P21Ras GTP—–> feeds into IGF1 receptor signalling—> Raf>Mek>Erk. FGTP-bound ras must become physically associated with the cell membrane for downstream effects on growth and cell division
this requires farnesylation of ras by farnesyl transferase

86
Q

What are SHC and GRB2?

A

Adaptor proteins, mediate the reaction between sos and as

87
Q

What happens in cancer concerning insulin?

A

Cancer cells can have 2-6 times increase in insulin receptor expression. Cancer cells loose their ability to down-regulate insulin receptors in response to hyperinsulinaemia

88
Q

What is worth noting with insulin resistance?

A

Factors that affect insulin sensitivity can independently affect cancer risk

89
Q

What 3 key actions are mediated through IRS?

A
  • PKC→ Glut 4
  • FOXO→ gluconeogenesis
  • Foxa2→ hepatic triglyceride production (inhibited by AKT)
90
Q

What action does metformin have?

A
  • Inhibition of hepatic glucose and lipid production
  • Increased muscle glucose uptake
  • AMPK can inhibit cell growth and proliferation possibly by inhibition of mTOR
91
Q

What Does metformin do?

A

Augments signalling via ampk

92
Q

How does inflammation lead to cancer?

A

Inflammation→activated macrophages→ROS→ JNK→ increased serine phosphorylation of IRS, decreased tyrosine phosphorylation
TNF alpha also leads to increased serine phosphorylation
Inflammation→ activated macrophages→ cytokines→ toll like receptor→ IKKB inhibits IKB inhibits NFKB (leads to cell proliferation and survival) inhibits PPAR gamma (also leads to cell proliferation and survival)

93
Q

How does obesity lead to cancer?

A

Pro-inflammatory state.
Also NEFAs compete with glucose as a metabolic fuel meaning glucose levels rise.
Leptin > cell proliferation and survival
Aromatase> oestradiol
Also lowers sex hormone binding levels to increase sex hormone
Less anti-inflammatory adiponectin

94
Q

What is a factor you always forget about when it comes to insulin sensitivity?

A

Sirtuins are HISTONE DEACETYLASES which are important in cell replication and promote insulin sensitivity. They allow TYROSINE to get phosphorylated on IRS and stops serine from being phosphorylated. SIRT1 can diminish inflammatory pathway signalling by deacetylating the p65 transcription factor subunit of NF-κB and can deacetylate Foxo1, thus promoting transcription of the adiponectin gene.

95
Q

Diabetes is a risk factor for which cancers?

A

Liver, pancreas and endometrial. Medium for breast, colon and bladder.

96
Q

What evidence is there to show that hyperglycaemia may not be linked to cancer?

A

In colon cancer, rates of second tumours did not alter between those who did and did not get a second tumour.

97
Q

What evidence is there for insulin?

A

Insulin injections have been shown to increase rat colon cancers. Rates also increased by a high fat diet and reduced by calorie restriction.

98
Q

What is a problem when looking at insulin resistance and cancer?

A

They have many common risk factors. age, obesity, physical inactivity, metabolic syndrome

99
Q

What is a clinical example for IGF1 increasing cancer rates?

A

Patients with acromegaly have increased IGF1 and increased rats of colon cancer.

100
Q

What effect does insulin have when it comes to sex?

A

Reduces sex hormone binding levels to increase free levels

101
Q

What is the outcome of diabetes in cancer?

A

A study showed a 1.4x increased risk of death. Another showed worse outcome in breast cancer

102
Q

Whats another problem when it comes to cancer and diabetes?

A

Difficult to manage glucose during chemo when body under increased stress.

103
Q

What pathway does EGFR activate?

A

SHC, GRB2, msos, p21 Ras then either mapk or PI3K

104
Q

What is SRC? What is its role in cancer?

A

It is steroid co-activator, tyrosine kinase proto oncogene. It can activate EGFR and IGF1 leading to PI3k and Mapk activation. SRC can be activated by oestrogen, androgen and progesterone dimerised receptors. It is over expressed in 50% of colon, liver, lung breast cancers. It could be a drug target.

105
Q

What is the relationship between growth factor signalling and steroid signalling?

A

Growth factor signaling can activate the steroid receptor signaling and vice versa. EGF signaling via the Ras/Mapk pathway can promote ligand independent activation of oestrogen and progesterone receptors

106
Q

What happens in angiogenesis?

A

HIF-1 stimulates release of vascular endothelial growth factor (VEGF), which causes differentiation of vascular cells, proliferation of vascular endothelium and formation of blood vessels
tumours hypersecrete VEGF
VEGF promotes transcription of genes for haemostatic factors, matrix metalloproteinases and other mitogens
blocking of VEGF signalling inhibits tumour growth

107
Q

What role does e-cadherin play?

A

E-cadherin plays a role in cell-cell adhesion, and its underexpression may lead to a greater probability of tumour invasion or metastasis; in oral cancer E-cadherin was found to be silenced by hypermethylation

108
Q

What way can you describe growth factors?

A

endocrine: between tissues via the blood stream
paracrine: between cells via extracellular fluid
autocrine: single cell at cell surface
intracrine: single cell intracellular

109
Q

What does recruitment of PI3 K cause?

A

Recruitment and activation of PI3K then results in phosphorylation of membrane lipids to produce phosphoinositide (3,4,5) triphosphate (PIP3). Leads to the activation of PDK1 and AKT

110
Q

What does AKT do, e.g. with epidermal growth factor?

A

Allows cells to progress to the s phase of the cell cycle.

111
Q

What are examples of growth factor related treatments?

A

anti-EGFR monoclonal antibodies (Cetuximab)
anti-HER2 monoclonal antibodies (Trastuzamab)
tyrosine kinase inhibitors (Gefitinib, Erlotinib)
farnesyl transferase inhibitors

112
Q

What evidence is there with insulin analogs?

A

B10asp insulin: 6-fold higher affinity for the IGF-1 receptor and 10-fold greater mitogenic potency in osteosarcoma cells than human insulin

B10asp insulin: more potent than human insulin in inducing proliferation of human breast cancer MCF7 cells

B10asp insulin: greater tumourigenic potential in rats – development abandoned

113
Q

For which cancers can GHRH agonists be used?

A

Breast and prostate.

114
Q

What is the PR required for in pregnancy?

A

Breast side branching in Puberty and Alveologenesis in Pregnancy.

115
Q

What is the role of progestins in breast?

A

Progestin response in the human breast is complex and influences both proliferation and differentiated function. Progestin therapy for metastatic breast cancer has been used principally as a second- or third-line therapy following selective estrogen receptor modulators and aromatase inhbitors. . The principal progestin used for metastatic breast cancer has been megestrol acetate

116
Q

What is progesterone’s role in the menstrual cycle?

A

Specifically, when progesterone levels are high during the luteal phase of the menstrual cycle, the glandular epithelium transforms from relatively inactive cells full of free ribosomes to very active polarized cells, containing giant mitochondrial profiles, intracellular deposits of glycogen/glycoprotein-rich material, and a complex intranuclear channel system. Decidualisation

117
Q

What is happening to the levels of endometrial cancer?

A

Increasing since HRT has become more common

118
Q

What are the risk factors for endometrial cancer?

A 
Obesity
Excess weight have 2 ~ 5 x greater risk
Fat cells (adipocytes) produce estrogen
Diabetes Mellitus and Hypertension
DM women have 2 x greater risk
Nulliparity
Progesterone counterbalances estrogen
Pregnancy lowers risk
119
Q

How is endometrial cancer diagnosed?

A

Endometrial sampling
Dilation and curettage / Endometrial aspiration

Imaging
TVS / CT scan / MRI
Hysteroscopy + targeted biopsy

Tumor marker
Ca 125 / 199

120
Q

What is the difference between the two types of endometrial cancer? Which tumour mutations are common?

A

Type I 70–80% .Are endometrioid in origin,
hormone-responsive, and prognosis is generally good. Mutations ingenes encoding PTEN, PI3K, KRAS, and beta-catenin and alsomicrosatellite instability are common. These tumors are associated with chronic exposure to estrogen and insufficient opposing progesterone.

Type II endometrial carcinoma: type II is an aggressive nonendometrioid cancer with papillary serous or clear-cell morphology. Tumors are not hormone-responsive, outcome is generally poor, and recurrence is frequent. Loss of p53 and chromosomal instability characterise this tumor type.

121
Q

What is the treatment for endometrial cancer? Mechanisms

A

total abdominal hysterectomy and bilateral oophorectomy with further staging depending on risk factors. Increasing progestin therapy, with effects seen from10 weeks but really need three months.Reversal of endometrial hyperplasia by progestins is thought to occur through activation of PRs, resulting in stromal decidualization and subsequent thinning of the endometrial lining

122
Q

What is the effect of progesterone treatment on endometrial cancer?

A

can inhibit cell growth, invasion, and expression of cellular adhesion molecules
promote differentiation to a secretory phenotype and induce replicative senescence

123
Q

Where is ER found? What happens when the ligand bind?

A

ER is in the cytoplasm and is activated when estrogen binds (heatshcok protein is shed so it is able to dimerise) and then the receptor can bind to the estrogen response element in DNA inducing gene expression (PR, cyclin d1, c-myc TGF-a) causing cell proliferation and breast cancer.

124
Q

Why are endocrine tissues particularly involved in menin deficiency?

A

Unable to compensate for the lack of cell cycle inhibitors (p18 and p27) that menin stimulates.

125
Q

How is Men1 hyperparathyroidism different?

A

MEN 1 hyperparathyriodism is different as it tends to be younger onset, multiple gland hyperplasia (not adenoma) and has a high recurrence rate.

126
Q

What mutation is commonly found in Men2?

A

In RET proto-oncogene, a transmembrane tyrosine kinase receptor that can be constitutively active leading to ligand independent activation. Increased activation through PI3 and MAPK

127
Q

Three hereditary forms of pituitary tumour?

A

Men 1, carney complex and FIPA

128
Q

What is commonly mutated in carney complex?

A

TSG protein kinase A that leads to enhanced intracellular PKA signalling

129
Q

What does SOS promote?

A

The uptake of sos to ras

130
Q

How are gastrinomas diagnosed?

A

Fasting gastrin sample off any medication. Octreotide, PPIs treatement

131
Q

What is hepatic embolisation?

A

Symptomatic treatment for any metastases

132
Q

What is arterial venous sampling and hepatic venous sampling?

A

Intra-arterial calcium injection causes hormone secretion which is then detected in hepatic vein sampling

133
Q

What are thyroid CT grades?

A

• CT grades. Thy 1 – inadequate, repeat. 2 – benign. 3 – follicular adenoma/ carcinoma. 4/5 malignant, remove entire thyroid.

134
Q

Which treatment would you advise for overweight type 2 DM and why?

A

Would propose METFORMIN that increases AMPK pathway, increases p53, map kinase and inhibits mtor

135
Q

What is particularly common in FIPA?

A

Gigantism is a particular feature of AIP mutations and occurs in more than one third of affected somatotropinoma patients.

136
Q

What proportion of FIPAs are caused by a mutation in AIP?

A

20%

137
Q

How is FIPA diagnosed?

A

In particular, familial isolated pituitary adenoma (FIPA), consisting of kindreds with two or more related members having pituitary adenomas in the absence of known genetic causes

Anna's (16 decks)

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