Case 17: cancer basics

Question 1

Types of cellular communication

Answer 1

• Endocrine
• paracrine (adjacent target cells)
• autocrine (target sites on same cell)
• juxtacrine (contact dependent, including contact inhibition of further growth)
• Errors in cell communication lead to cancer and autoimmunity

Question 2

Mechanisms of signal transduction

Answer 2

• Direct ligand gated channel
• G protein coupled
• tyrosine kinase linked
• intracellular receptors

Question 3

How does signal transduction via direct ligand gated channels work

Answer 3

• when a signal binds to the receptor, the gate allows specific ions through a channel
• Example: nicotinic Ach receptors- GABA receptors

Question 4

How does signal transduction via G protein couples receptors work:

Answer 4

• hormone binds to inactive receptor which activates G alpha subunit
• muscarinic Ach receptors- adrenergic receptors

Question 5

Tyrosine kinase linked receptors work

Answer 5

• signalling molecule binds causing dimerisation of the molecule, activating tyrosine kinase regions which then become phosphorylated and activate relay proteins
• Example: binding of specific ligands (EGF and TGF-a) to EGFR activates the receptor and triggers signal transduction cascades that affect cell proliferation
• Tyrosine kinase inhibitors e.g. gefitinib and erlotinib target signal transduction pathways: they bind to the intracellular tyrosine kinase domain which inhibits autophosphorylaltion and downstream intracellular signalling

Question 6

Signal transduction via intracellular receptors

Answer 6

• intracellular receptors are found in the cytosol of the nucleus of target cells small hydrophobic chemical messengers can cross the membrane and activate receptors
• which drugs can target signal transduction pathways: - monoclonal antibodies. Tyrosine kinase inhibitors
• Monoclonal antibodies e.g. trastuzumab and cetuximab target signal transduction pathways by binding to the extracellular domain of EGFR which blocks growth factor binding and signal transduction

Question 7

The 10 hallmarks of cancer

Answer 7

• sustained proliferative signalling
• evading growth suppressors
• avoiding immune destruction
• enabling replicative immortality
• tumour promoting inflammation
• activating invasion and metastasis
• inducing angiogenesis
• genome instability and mutation
• resisting cell death
• dysregulating cellular energetics

Question 8

How do cancer cells sustain proliferative signalling by

Answer 8

• producing growth factor ligands
• structurally altering receptor molecules via mutation
• elevating levels of receptor proteins

Question 9

Common cancer mutations

Answer 9

• what growth factor receptor do many cancers express: EGFR/ HER (involved in cell proliferation)
• what type of cancer is EGFR mutation commonly associated with: NSCLC
• what type of cancer is high levels of HER2 associated with: breast cancer
• what do growth suppressor programmes depend upon: tumour suppressor genes e.g. TP53 (codes for p53) and RB1 (codes for retinoblastoma protein)
• function of retinoblastoma protein (pRb): gatekeeper of cell cycle progression
• in what conditions is retinoblastoma protein (pRb) inactivated: - retinoblastoma. some SCLCs

Question 10

Immune system and cancer

Answer 10

• What type of growth inhibition is lost in cancer cells: contact inhibition
• How might cancer cells disable components of the immune system: they can recruit inflammatory cells that are immunosuppressive e.g. regulatory T cells and myeloid derived suppressor cells which can suppress CD8
• How does immuno stimulation therapy help treat cancer: enhances immuno-surveillance to assist the immune system to recognise tumour cell antigens

Question 11

Cancer cells and immortality

Answer 11

• how do cancer cells have replicative immortality: they have high levels of telomerase which adds telomere repeat segments to the ends of telomeric DNA
• how does telomestatin therapy work to treat cancer: telomestatin is a telomerase inhibitor in trial which causes telomere shortening and activation of proliferative barriers

Question 12

How do cancers progress

Answer 12

• Neoplastic lesions contain immune cells: they supply growth factors, survival factors and angiogenic factors to the tumour microenvironment
• Release of reactive oxygen species promotes cancer progression: mutogenic
• Tumour associated inflammatory responses such as vasodilation and increased permeability of vessels
• increased permeability allows migration of leukocytes from blood into tissues
  (extravasation) but also allows leakage of plasma proteins and fluid into tissues
  which causes swelling
• The complement system is activated due to tumour promoted inflammation: coagulation and fibrinolytic systems

Question 13

Regulators and proteins in cancer

Answer 13

• reduction in E-cadherin allows invasion of cancer
• Angiogenesis is important in cancer: tumours require nutrients and
  oxygen as well as an ability to evacuate metabolic waste and carbon dioxide
• what is the key mediator of angiogenesis in cancer: VEGF
• what causes up regulation of VEGF: oncogene expression, growth factors and hypoxia
• why do cancer cells have increased rates of mutation: they compromise the surveillance systems that normally monitor genomic integrity

Question 14

Give example of cancers associated with DNA repair defects

Answer 14

• Lynch syndrome
• xeroderma pigmentosum
• Bloom’s syndrome
• Fanconi anaemia
• hereditary breast/ ovarian cancer

Question 15

Genes in cancer

Answer 15

1. which gene is the central guardian of the genome: TP53 (codes for p53)
2. role of BRCA1/2 and PALB2 in genomic integrity: repair of double stranded
   DNA
3. role of PARP1 in genomic integrity: repairing single stranded breaks in DNA
4. how do PARP inhibitors work: they prevent repair of cancer cells with damaged DNA, leading to death of these cells
5. loss of function of p53 in cancer cells may allow them to resist cell death: causes apoptosis in damaged cells
6. how might cancer cells dysregulate cellular energetics: they can up regulate glucose transporters (GLUT1) to increase glucose import into the cytoplasm and increase glycolysis

Question 16

TMN cancer staging system

Answer 16

• what is Tx in cancer staging: primary tumour can’t be assessed
• what is T0 in cancer staging: no evidence of primary tumour (cancer of unknown primary)
• what is Tis in cancer staging: pre-invasive cancer (cancer in situ)
• what is T1-3 in cancer staging: different degrees of local spread
• what is T4 in cancer staging: invasion to adjacent organs
• what is M0 in cancer staging: cancer has not spread to other parts of the body
• what is M1 in cancer staging: cancer has spread to other parts of the body

Question 17

What causes clinical manifestations of cancer

Answer 17

• direct effects due to compression
• obstruction of a conduit (airway, biliary tract, bowel, ureteric system)
• ulceration of a serial or mucosal surface
• metastases
• paraneoplastic syndromes

Question 18

How might obstruction of a conduit due to cancer present

Answer 18

• jaundice due to biliary obstruction
• stridor due to airway obstruction
• DVT due to venous obstruction
• facial congestion due to SVC obstruction
• absence of stool/ flatus, anorexia and dehydration due to bowel obstruction

Question 19

What causes paraneoplatic syndrome

Answer 19

• production of substances from tumour
• depletion of normal substances
• immunological response to tumour
• why does eradicating the cancer not always resolve the paraneoplastic
  syndrome: some are immunological so the antibody will still be present even if the
  cancer is gone

Question 20

Examples of paraneoplastic syndrome

Answer 20

• ACTH overproduction
• SIADH
• gonadotropins
• hypercalcaemia due to PTH like peptide
• neurological paraneoplastic syndromes
• Lambert Eaton syndrome
• dermtomyositis
• acanthosis nigricans
• haematological paraneoplastic syndromes

Question 21

What cancers cause lymphadenopathy in different areas

Answer 21

• lymphadenopathy in the face is suggestive of which types of cancer: ENT cancers
• lymphadenopathy in the supraclavicular/ axillary nodes is suggestive of which types of cancer: cancers in the thorax: breast, lung, oesophagus, stomach
• lymphadenopathy in the inguinal/ femoral nodes is suggestive of which
  types of cancer: gynae, pelvis, scortal or penile cancers
• lymphadenopathy in the pelvic/ para-aortic nodes (not the inguinal nodes)
  is suggestive of which types of cancer: ovarian or testicular cancer

Question 22

Tumour markers

Answer 22

• what are tumour markers: serum secreted proteins produced by cancers that
  are detectable in the serum
• Tumour markers are generally used for: rarely diagnostic, more useful in monitoring and surveillance for early relapse
• ideal sensitivity and specificity of tumour markers: - sensitivity above 50%, specificity above 95%
• when useful tumour marks are often measured: - with each cycle of chemo to assess response. at clinical reviews as part of follow up

Question 23

Features of an ideal tumour marker

Answer 23

• produced by malignant cells only
• exclusive to a certain malignancy
• detectable at all levels of disease
• obtained in a non-invasive manner
• levels should equate to disease burden

Question 24

hCG and AFP

Answer 24

• what is hCG: a glycoprotein formed in the syncytotropioblast of the placenta
• uses of hCG: to diagnose and monitor pregnancy, gestational trophoblastic disease and germ cell tumour
• what is APF: serum protein synthesised by foetal yolk sac, liver and intestine acts as albumin like carrier protein in foetus
• increased levels of APF are seen in which cancers: - HCC, germ cell tumours of testes, ovaries, mediastinum and pineal gland

Question 25

Placental ALP, CA19-9, inhibin

Answer 25

• what is placental ALP: an isoenzyme of ALP
• elevated placental ALP may be seen in which conditions: - testicular seminoma, ovarian dysgerminoma
• main use of CA19-9: monitor response to treatment in gastric and pancreatic
  cancer
• what is inhibin: protein secreted by granulosa cells including Sertoli cells that
  inhibits FSH
• inhibin may be used to monitor which type of tumour: rare granulosa cell
  tumours of the ovary

Question 26

CEA, CA15-3

Answer 26

• what is CEA: a glycoprotein
• main use of CEA: monitor treatment in colorectal cancer
• what is CA15-3: mucin like antigen
• main use of CA15-3: elevated levels have been found in breast cancer. elevation increases with stage (highest levels seen in patients with liver or bone metates). rising level during follow up can detect relapse 2-9 months before clinical signs
  develop

Question 27

CA-125, PSA

Answer 27

• CA125 is present at the surface of non-mutinous epithelial ovarian tumours
• main use of CA125: monitoring response to chemo in ovarian cancer and detection of relapse
• high levels of CA125 prior to surgery is associated with: worse prognosis
• why is CA125 not useful for screening ovarian cancer: only elevated in 50%
  of patients with stage 1 disease
• main use of squamous cell carcinoma associated antigen: monitor treatment of squamous cell cervical cancer and head and neck squamous carcinoma
• PSA: protease produced by prostate epithelium. Elevated in prostate cancer, BPH

Question 28

Calcitonin, thyroglobulin, LDH, beta 2 microglobulin

Answer 28

• which cancer may cause elevated calcitonin: medullary thyroid carcinoma
• which cancers may cause elevated thyroglobulin: papillary and follicular
  thyroid carcinoma
• main uses of LDH: - measure bulk of disease. can identify rapidly growing tumours and patients at risk of tumour lysis syndrome
• which cancers may raise beta 2 microglobulin: myeloma, non Hodgkin’s lymphoma
• main use of beta 2 microglobulin: prognostic

Question 29

Classification of cancer treatment intent

Answer 29

• palliative, curative
• Types of cancer treatments: - palliative, adjuvant, neoadjuvant, chemoprevention

Question 30

what needs to be assessed prior to giving chemoprevention:

Answer 30

• survival benefit as many agents are carcinogenic
• e.g. tamoxifen reduces breast cancer incidence but increases the risk of endometrial cancer and is also thromboembolic

Question 31

Timing of cancer treatment

Answer 31

• within what time period should cancer patients start treatment: - within 31
  days of agreeing plan, within 62 days of 2ww referral
• how long is one cycle of treatment usually: 21 days or 28 days
• how many cycles are normally given in a course of treatment: up to 6

Question 32

Dosing approaches in cancer

Answer 32

• Low dose therapy
• high dose therapy
• dense dose therapy
• alternating therapy

Question 33

Low dose in chemotherapy

Answer 33

• how is low dose therapy given: the next cycle is commenced once bone
  marrow function has recovered
• what indicates bone marrow recovery following cancer treatment: -
  netrophils above 1, platelets above 100
• what may be given if bone marrow recovery is delayed following cancer
  treatment: G-CSF

Question 34

Options to increase the rate of bone marrow recovery following high dose
therapy:

Answer 34

G-CSF. autologous stem cells can be harvested and re-adminstered to repopulate bone marrow faster (allows recovery within 16-21 days as opposed to 6-7 weeks)

Question 35

Sites of action of cytotoxic agents

Answer 35

• purine and pyrimidine synthesis (antimetabolites)
• DNA formation and replication (alkylating agents and intercalating agents)
• microtubules (spindle poisons)

Question 36

How might existing cancer drugs be improved

Answer 36

• improved tolerability (e.g. wrap doxorubicin in liposomal monolayer)
• increased spectrum of activity
• altered delivery e.g. continuous infusion

Question 37

Summary of how we measure response to cancer treatment

Answer 37

• overall survival rate: % that are alive for a certain period of time after the diagnosis (usually 5 year survival rate)
• remission rate: % that achieve a state where the cancer is no longer detectable and signs and symptoms have disappeared
• disease free survival: length of time after treatment during which a
  patient survives with no signs or symptoms of the disease
• residual disease: that left at completion of planned treatment and if presence indicates resistance to treatment (adverse prognostic factor). Detect with fine needle aspirate or biopsy of residual
  lesion

Question 38

Causes of cancer

Answer 38

• single biggest preventable cause of cancer: tobacco
• which infections may increase the risk of cancer: - HPV, H pylori, hep B/C

Question 39

What is cytology

Answer 39

• examination of cells from sputum/ urine/ cervix/ pleural
  effusions/ ascites
• cytological features of malignancy: - altered polarity, tumour cell enlargement, increased nuclear to cytoplasmic ratio, pleomorphism (variation in size and shape), clumping of chromatin, atypical or bizarre mitoses, mutlinucleated

Question 40

carcinogenesis

Answer 40

• Process by which normal cells are transformed into
  cancer
• how does carcinogenesis occur: 1. a single cell multiplies and acquires
  additional changes providing survival advantage. Altered cells are amplified to generate billions of cells that constitute cancer (this takes time, hence why age is a risk factor)
• causes of carcinogenesis: - chemicals, radiation, occupational hazards, viruses, bacteria or parasites, drugs, hormones, lifestyle and genetics

Question 41

Describe how carcinogenesis due to chemicals leads to cancer

Answer 41

• initiation (single exposure to carcinogen may be sufficient): failure to repair chemically
  induced DNA damage resulting in mutation
• promotion (requires multiple exposures): produces selective growth advantage,
  usually without DNA mutation
• progression: irreversible, multiple complex DNA changes
• Chemicals including tobacco causes 80-90% of tumours

Question 42

Smoking can cause cancer in what organs and why

Answer 42

• lungs due to bronchial inflammation
• liver as transported through blood
• kidney and bladder as filtered into urine
• cervix and breast as compounds secreted by these organs
  also oropharynx, oesophagus, pancreas

Question 43

Germline and Somatic mutations

Answer 43

• what are germline mutations: present at embryogenesis (present in all cells
  of the host) can be passed on
• what are somatic mutations: acquired genetic changes that occur within the
  DNA of individual somatic cells (only affect cells in which they originally occurred and descendants of these) not inheritable

Question 44

Classes of genes implicated in carcinognesis

Answer 44

• proto oncogenes: promote proliferation (mainly encode growth factors, growth factor receptors, signal transducers or transcription factors). Dominant mutations
• tumour suppressor genes: inhibit proliferation. recessive inheritance (both functional gene copies have to be lost if sporadic)
• care taker genes: repair DNA damage, recessive mutations

Question 45

Tumour growth terms

Answer 45

• what is hypertrophy: increase in size due to increase in size of individual cells
• what is hyperplasia: increase in number of cells
• what is metaplasia: replacement of one fully differentiated tissue with another,
  usually in response to persistent injury
• what is dysplasia: architectural and cytological changes

Question 46

How a diagnosis of cancer is made

Answer 46

• Histological assessment of a biopsy or resected specimen
• Gross features: Tumour size, lymph node size and number
• Microscopic findings: tumour grade, margins, lymphovascular invasion, mitotic rate (Proliferation index Ki-67), Immunohistochemistry staining

Question 47

General histopathological features of cancer

Answer 47

• Abnormal cellular morphology
• Increased rate of mitosis
• Multinucleated cells
• Increased nuclear DNA and nuclear-cytoplasm ratio
• Less organised tissue architecture

Question 48

Cancer staging: general

Answer 48

• Invasive tumours: invade the basement membrane
• In situ: non invasive but has all other features of cancer

Question 49

Oncology terms

Answer 49

• -oma describes a benign tumour although some aren’t tumours i.e. granuloma
• -carcinoma: malignant epithelial tumour
• -sarcoma: malignant connective tissue tumour
• Terato-: malignant germ cell
• adeno-: glandular epithelium
• Osteo-: bone
• Lipo-: fat
• Angio-: vascular

Question 50

More unusual cancer terminology

Answer 50

• Can have more than one type of cancer tissue present within a single organ i.e. carcinosarcoma
• The cancer tissue may not fit within a known classification and is termed carcinoma NOS (Not otherwise specified)