tumour pathology Flashcards
what are the properties of cancer cells
- loss of tumour suppressor genes
- gain of function of oncogenes
- Altered cellular function
- Abnormal morphology - key for evaluating tumour and making diagnosis of type and likely behaviour
- Cells capable of independent growth - one of the defining factors of tumours
- No single feature is unique to cancer cells
- Tumour biomarkers - specific genes/proteins which are used to make an assessment of a tumour in a clinic for a particular purpose
give 3 examples of tumour suppressor genes
exist in normal cells and keep them under regulatory control
• Adenomatous polyposis (APC) - colon, benign which can turn into cancer
• Retinoblastoma (Rb) - tumour suppressor gene
BRCA1 - breast cancer tumour suppressor gene
give 6 examples of oncogenes
normally silent in cells
* B-raf * Cyclin D1 * ErbB2 * C-Myc * K-ras, N-ras
cellular function in cancer cells
- Loss of cell to cell adhesion - normal cells stick together, cancer cells are less likely to stick together making them more likely to spread to other sites in the body
- Altered cell to matrix adhesion
- Production of tumour related proteins
Tumour biomarkers
what are tumour biomarkers
protein/gene expressed in a specific type of tumour which can be exploited clinically to aid diagnosis, treatment and prognosis
- Onco-foetal proteins - present in normal foetal life, switched off post-natally, switched on in tumours
- Oncogenes
- Growth factors and receptors
- Immune checkpoint inhibitors - used in treatment of cancer
what is the clinical utility of tumour biomarkers
- Screening (of asymptomatic patients for specific types of cancer, allows early detection)
- Diagnosis
- Prognostic - Identifying patients with a specific outcome (good or bad)
- Predictive - Identifying patients who will respond/won’t respond to a particular therapy (means treatment can be avoided if it will only cause side effects and wont have any clinical effect)
clinical use of alpha-fetoprotein
equivalent to albumin, produced in the liver, switched off following birth, switched on in tumours, can be measured in the blood
• Teratoma of testis
Hepatocellular carcinoma
clinical use of carcino-embryonic antigen
onco-foetal protein, useful to monitor patients following diagnosis, increased level indicates onset of metastatic disease
• Colorectal cancer
clinical use of oestrogen receptor
high proportion of breast cancer tumours express oestrogen receptors
Breast cancer
clinical use of prostate specific antigen
- found in prostate gland, useful in diagnosis and response to treatment
Prostate cancer
give 5 clinically useful predictive tumour biomarkers
Kras = Colorectal cancer
Braf = Melanoma
EGFR (epidermal growth factor receptor), PD-L1 (molecule in the immune system)= Lung cancer
Her2 = Breast cancer, gastric cancer
Morphology of cancer cells
- Cellular and nuclear pleomorphism
• Marked variation in size and shape
Mitoses present and often abnormal - as cancer is a growing tissue
tumour growth
- Tumour growth is balance between cell growth and cell death
Angiogenesis - New blood vessel formation by tumours
apoptosis - mechanism of programmed cell death
angiogenesis in tumour growth
○ Required to sustain tumour growth (nutrients into the tumour), need own blood supply once bigger than 1mm
○ Provides route for release of tumour cells into circulation
○ More blood vessels in a tumour = poorer prognosis - tumour cells are more likely to be released into the blood vessels and into the circulation, higher chance of metastases forming
apoptosis in tumour growth
○ Active cell process
○ Regulates tumour growth
○ Involved in response to chemotherapy and radiotherapy - higher rate of apoptosis are more likely to be responsive to therapy and more likely to be destroyed
spread of cancer
fundamental property of cancer, invasion and metastases
invasion and metastases
- Multi-step process
- Increased matrix degradation by proteolytic enzymes - creates a track through which the tumour can move
- Altered cell to cell and cell to matrix adhesion - allows the tumour to move
what is the clinical significance of cancer spreading
- Major clinical problem is formation of metastatic (2y) tumours - look identical to the 1y tumours
- Prognosis depends on extent of cancer spread
- Patients can present with metastatic disease
modes of spread of cancer
• Local - invasion
○ Trans-coelomic - special form of local spread, spread of tumour cells across body cavities e.g. pleural or peritoneal cavities (potential space). Tumours of lung, stomach, colon and ovary show trans-coelomic spread. Can lead to multiple tumour deposits quite rapidly
• Lymphatic - to regional lymph nodes
• Blood - to many different tissue types throughout the body
tumour invasion process
malignant tumour –> invasion into connective tissue –> invasion into lymph/blood vessles
tumour metastasis via lymphatics
adherence of tumour cells to lymph vessels –> invasion from lymphatics –> invasion into lymph node –> formation of metastasis in lymph node –> clinical evidence of metastasis
tumour metastasis via blood
ASSUMES CANCER CELLS ARE WITHIN THE BLOOD VESSEL
adherence of tumour cells to blood vessels –> invasion from blood vessels –> invasion into tissue –> formation of metastasis –> clinical evidence of metastasis
sites of tumour metastases are not related to …
tissue blood flow
formation depends on tumour and tissue related factors
common sites of metastasis
- Liver
- Lung
- Brain
- Bone (axial skeleton) - limb bones are much
less likely to develop metastases - Adrenal gland
- Omentum (fat found within the abdominal cavity)/peritoneum
uncommon sites of metastasis
- Spleen
- Kidney
- Skeletal muscle
Heart
tumours which commonly metastasise to specific sites
breast –> bone
prostate –> bone
colorectal –> liver
ovary –> omentum/peritoneum
local effects of benign tumours
- Pressure - mass of tissue growing against an anatomical structure
Obstruction - if the mass if adjacent to or within a hollow structure
local effects of maligant tumours
- Pressure
- Obstruction
Tissue destruction - bleeding
- pain
- Effects of treatments - local and systemic effect, killing off the tumour can result in setting off inflammatory reaction - swelling and obstruction
tissue destruction as an effect of malignant tumours
Ulceration/infection
bleeding as a result of malignant tumours
ulceration exposes the underlying blood vessels
• Anaemia - slow loss of blood, common with tumours in the GI tract
• Haemorrhage - tumour hits a large blood vessel, large and sudden loss of blood
pain as a result of malignant tumours
- Pressure on nerves
- Perineural infiltration - tumour grows along the nerve
- Bone pain from pathological fractures - fractures of weakened bone as a result of being destroyed and replaced by metastatic tumours
systemic effects of malignant tumours
- Weight loss-cancer cachexia
- secretion of hormones
- paraneoplastic syndromes
- effects of treatment
weight loss cancer cachexia
characteristic of any sort of cancer irrespective of site and spread, weight loss not related to lack of food intake
secretion of hormones a a result of malignant tumuors
patients can present with symptoms of the hormone imbalance, not the underlying malignancy
• Normal: produced by tumours of an endocrine organ
• But abnormal control of hormone production/secretion
• Abnormal/inappropriate: produced by tumour from an organ that doesn’t normally produce hormone
• E.g. ACTH, ADH - lung cancer
Patients present with signs and symptoms of the abnormal hormone production
paraneoplastic syndromes
muscle pain and weakness • Cannot be explained by local or metastatic effects if tumours e.g. neuropathy, myopathy • Hard to explain and treat • Immune mechanism Production of hormone/growth factor
early detection of cancer
- Important to detect cancer at early stage
- Reduce/prevent morbidity/mortality
- Detection at pre-invasive stage (pre-malignant state)
• Identification of dysplasia/intraepithelial neoplasia - Requires effective test: sensitive/specific, acceptable
- E.g. Cervical cancer screening
• Established NHS programme, aims to reduce incidence of squamous carcinoma of cervix, detection of dysplastic cells from squamous epithelium of cervix - E.g. breast cancer screening
dysplasia
- Pre-malignant change
- Earliest change in the process of malignancy that can be visualised
- Identified in epithelium
- No invasion - if it has invaded it is a cancer
- But can progress to cancer
features of dysplasia
• Disorganisation of cells: increased nu size, increased mitotic activity, abnormal mitoses
• Grading of dysplasia: high grade/low grade (how abnormal the cells are, higher grade - higher degree of abnormality and higher risk)
No invasion
what is the cell cycle
cell cycle = ordered series of events between mitotic divisions
Nuclear division plus cytokinesis produces 2 genetically identical diploid daughter cells
what are the 3 periods of the cell cycle
- INTERPHASE: (G1, S, G2)during which the cell grows and accumulates nutrients needed for mitosis; the cell is synthesizing RNA, producing protein and growing in size. The molecular events that regulate the cycle are ordered and directional- it is impossible to reverse the cycle
- MITOSIS: phase during which the cell splits itself into two distinct cells
- CYTOKINESIS: new cell is completely divided
Each phase of the cycle has a distinct set of specialised biochemical processes that prepare the cell for division.
cell cycle control
- Cycle phases must be in correct sequence
- DNA synthesis and mitosis must occur sequentially
- Quality control: Each daughter cell must receive a full chromosome complement; genetic damage must be detected and repaired
- Division is coordinated and tightly controlled and ensures the correct type of cells grow in the correct environment - prevents uncontrolled cell division and genetic damage passing on
The genome is replicated only once; daughter cells missing all or part of crucial genes die. Errors in mitosis can either kill a cell or cause mutations. Possession of extra copies of certain genes also deleterious.
checkpoints in the cell cycle
- Monitor and regulate progress and achieve control
- Prevent progression at specific points
G1/S checkpoint and the G2/M checkpoint.
- Prevent progression at specific points
what is the rate-limiting step in the cell cycle
G1/S transition
known as restriction point
G1/S restriction point
signals cells with inadequate nutrients or DNA damage to stop growing
where would the cycle be stopped if cells had inadequate nutrient supply or external stimulus was lacking
G1 arrest
if the cell was an abnormal size or DNA damage was detected where would be cycle be stopped
G1 or G2 arrest
if DNA wasnt replicated where would the cycle be stopped
S arrest
if chromosomes were misaligned where would the cycle be stopped
M phase arrest
what external factors may influence the cell cycle
hormones, growth factors, cytokines
what are cell cycle checkpoint activators
- System of cyclically active and inactive enzyme switches
- Catalytic subunit CDKs activated by a regulatory subunit cyclins
- The active enzyme complex = cdk/cyclin complex
what are the 2 key classes of regulatory molecules
cyclins and cyclin dependent kinases
- Different CDK/cyclin complexes operate at sequential stages of the cycle
- Active CDK/cyclin complexes phosphorylate target proteins which results in the proteins being activated/inactivated
Substrates regulate events in the next cycle phase
action of CDKs
When activated by a bound cyclin, CDKs perform phosphorylation that activates or inactivates target proteins –> coordinated entry into the next phase of the cell cycle.
Different cyclin-CDK combinations determine the downstream proteins targeted.
A pro-mitotic extracellular signal, induces G1 cyclin-CDK complexes- become active and prepare the cell for S phase, promoting the expression of transcription factors that in turn promote the expression of S cyclins and of enzymes required for DNA replication.
cell cycle inhibitors
- CDK inhibitors (CKIs) - inhibitor molecules that bind to cyclin/CDK complexes
- INK4A gene family - p16 (act at a very specific point of the cell cycle)
- CIP/KIP gene family - p21, p27 (act at different points in the cell cycle)
Multiple ways of inhibiting the cell cycle means they can respond to more than one stimulus
what prevents cell cycle progression and how? (cell cycle inhibitors)
Two families of genes, the cip/kip family and the INK4a prevent cell cycle progression
The INK4a family includes p16INK4a, which binds to CDK4 and arrests the cell cycle in G1 phase, and p14 which prevents p53 degradation
The cip/kip family includes the genes p21, p27 and p57. They halt cell cycle in G1 phase, by binding to, and inactivating, cyclin-CDK complexes. p21 is activated by p53
the retinoblastoma gene
- Encodes a 110 kDa phosphoprotein (pRb) expressed in almost every human cell
- Hypophosphorylated pRb is active i.e. not phosphorylated
• cells remain in G1 phase (puts a brake on the cell cycle) - Active cyclin D/CDK complexes phosphorylate pRb as the cell cycle progresses
• Rb gene mutations favour cell proliferation - brake in cell cycle is removed
• Mutations in other genes controlling pRb
phosphorylation mimic the effect of pRb loss
• Mutational activation of cyclin D or CDK4
• Mutational inactivation of CDKIs also drive proliferation
what is the role of hypophosphorylated retinoblastoma
pRb is active and carries out its role as tumor suppressor by inhibiting cell cycle progression.
- ACTIVE pRb applies a brake to the cell cycle
how is pRb inactivated
phosphorylated
failure of cell cycle control
carcinogenesis
- Balance between proliferation and apoptosis disrupted
- Mutations in genes regulating cell division, apoptosis, and DNA repair cause a cell to lose control of proliferation
- Uncontrolled proliferation of cells forms tumours
what are the 2 frequently disrupted regulatory pathways in the cell cycle
- The cyclin D-pRb-E2F pathway
2. p53 pathway
p53 regulatory pathway and its role in the cell cycle
P53 maintains the integrity of the genome.
Cells with mutated p53 don’t G1 arrest or repair damaged DNA.
Genetically damaged cells proliferate and from malignant neoplasms - the mutant cells inherit the damaged DNA and mutations continue. Normally the p53 is activated and binds to the damaged DNA and the cell is either repaired (cell cycle stops at G1 or the repair fails and the cell undergoes apoptosis.
balance between proliferation and apoptosis - carcinogenesis
Cell division normally balances proliferation and apoptosis,
Carcinogenesis is caused by mutations that upsetting this normal balance resulting in uncontrolled cell division, rapid proliferation leading to tumours.
gene mutations - carcinogenesis
More than one mutation is necessary for carcinogenesis: a series of several mutations to certain classes of genes is usually required
Only mutations in those certain types of genes which play vital roles in cell division, apoptosis (cell death), and DNA repair will cause a cell to lose control of its cell proliferation.
Virutally all canders are dysregulated at G1-S. Mutated cell cycle regulating genes: cyclin D, CDK4, p16, Rb
cells with mutated p53 proliferate and form malignant neoplasms
what factors can cause carcinogenesis
• Environmental agents
○ Chemicals
○ Radiation
○ Oncogenic viruses
• Inherited factors (passed on from parents to offspring)
Genotoxins cause irreversible genetic damage or mutations by binding to DNA.
Genotoxins include chemical agents like N-nitroso-N-methylurea (MNU) or non-chemical agents such as ultraviolet light and ionizing radiation.
Certain viruses can also act as carcinogens by interacting with DNA.
two hit hypothesis of oncogenesis
Retinoblastoma - tumour of the light detecting cells in the eye, usually in children, tumour arises from retinal tissue in the eye. There are 2 forms of retinoblastoma (inherited - multiple tumours in both eyes, younger children. Sporadic - tumour in one eye, older children)
Retinoblastoma cells are growing very rapidly following birth
Inherited - mutation inherited from parents which explains early age of development
Sporadically accumulating mutations in both alleles - develops at a later age
Gene function is recessive
tumour suppressor genes (anti-oncogenes)
- Normal regulatory genes that protect a cell from forming cancers
- Generally follow the “two-hit hypothesis”
- Tumour suppressor alleles are usually recessive
- Loss of both normal allelic copies gives rise to cancer
- Mutation causes ‘loss of function’
- Normal regulatory genes
• Mutation causes loss of function - removing the brake which leads to proliferation
normal regulatory genes
○ Normal growth-inhibiting genes
□ Genes negatively regulating mitosis – Rb, INK4A family
□ Genes regulating apoptosis – p53
○ Genes regulating DNA repair
inherited cancer syndromes
• Cancer is a molecular disease but can be hereditary
• account for 5-10% of all cancers
• genetic predisposition to develop cancer
early onset of multiple tumours in established familial cancers - cancers at an early age, multiple cancers
inherited predisposition to cancer
- Familial retinoblastoma
- Familial adenomatous polyposis.(FAP) of colon
- Hereditary Breast & Ovarian Cancer Syndrome (BRCA)
- Hereditary Non-polyposis Colorectal Cancer Syndrome
- Li-Fraumeni Syndrome
- multiple endocrine neoplasia
- Von Hippel- Lindau syndrome
familial retinoblastoma
Carriers have 10 000x risk of bilateral retinoblastoma (both eyes)
Increased risk of second cancers e.g. bone sarcomas (which are relatively rare sporadically)
Familial adenomatous polyposis.(FAP) of colon
□ Thousands of polyps on the colon
□ 100% risk of colon cancer by age 50 years
Colon is removed before polyps become cancerous
Hereditary Non-polyposis Colorectal Cancer Syndrome
□ Germline mutations in DNA mismatch repair genes are inherited
hMSH2, hMLH1, MSH6
Li-Fraumeni Syndrome
p53 abnormality, one copy inherited from parents
Multiple Endocrine Neoplasia
tumours of endocrine organs, present with multiple tumours at multiple sites
Von Hippel-Lindau Syndrome
hemangioblastoma, renal tumours
inherited mutations of tumour suppressor genes
APC - Signal transduction - FAP colon cancer
p53 - Cell cycle/apoptosis after DNA damage - Li-Fraumeni syndrome; multiple carcinomas, sarcomeres
Rb - Cell cycle regulation - Retinoblastoma, osteosarcoma
P16 (INK4a) - Inhibits CDKs - Malignant melanoma
proto-oncogenes
• Normal genes coding for normal growth regulating proteins
• Growth factors
• Growth factor receptors
Signal transduction
oncogenes
cancer causing genes
Derived from proto-oncogenes with ‘gain of function’ (i.e. normal genes with a gain of function mutation)
Activated by –
Alteration of proto-oncogene structure
Dysregulation of proto-oncogene expression
• HER2 and breast cancer - these genes can multiply and be amplified in breast cancer, tend to cause very aggressive breast cancer
Oncoproteins are diagnostically and therapeutically important
Alteration of proto-oncogene structure
- point mutation
- chromosome rearrangements + translocations
○ Overexpression: Burkitt lymphoma (malignancy of B cells in blood); Mantle cell lymphoma - cyclin D1 gene-IgH
○ Recombination to form chimeric proteins
Chronic myeloid leukaemia
Dysregulation of proto-oncogene expression
- gene amplification
- over-expression
chemical carcinogenesis
helps explain non-inherited cancer presentations
• Purine and pyrimidine bases in DNA are critically damaged by oxidizing and alkylating agents
• Chemical carcinogens react with DNA forming covalently bound products (DNA adducts)
• Cell machinery can no longer detach the strands from each other - causes jumps and problems in DNA replication e.g. loss of anti-oncogene function
• Adduct formation can lead to activation of oncogenes and loss of anti-oncogenes
radiation carcinogenesis
• Purine and pyrimidine bases in DNA are critical targets for radiation damage
• High-energy radiation is carcinogenic if received in sufficient doses
• ultraviolet radiation (UV-B present in sunlight)
• X-rays (e.g. diagnostic CT scan)
Gamma radiation
viral carcinogenesis
• ONCOVIRUSES
• virus genome inserts near a host proto-oncogene
○ viral promoter causes proto-oncogene over-expression
• virus directly inserts an oncogene into host DNA causing cell division
• Viruses known to cause cancer in humans
• HPV (genital, throat and anal cancers) - higher risk ones are HPV 16 and HPV 18
○ HPV AND CERVICAL CANCER: High oncogenic HPV types –> integration –> viral sequences act as oncogenes –> E6 - p53 / E7 - RB binding (bind to important molecules which are involved in centrally controlling the cell cycle)
• Hepatitis B (liver cancer)
• EBV (lymphoma) - Epstein Barr virus
multistep carcinogenesis
• All sporadic cancers harbour multiple genetic aberrations
• Mutations accumulate with time
Activation of several oncogenes and loss of two or more anti-oncogenes occurs in most cancers
what is the highest risk factor for cancer
age
over expression of growth factor PGDF (sis) causes
astrocytoma, osteosarcoma
amplification of growth factors receptors - EGF family (her2/neu) causes
breast
ovarian
lung
stomach cancers
point mutation of signal transducers - GTP binding (ras) causes
lung
colon
pancreas cancer
leukaemia
translocation of nuclear regulatory proteins - transcriptional activators (myc) causes
burkitt lymphoma
translocation/amplification of cell cycle regulators (cyclin D) causes
mantle cell lymphoma
amplification of CDK 4 causes
melanoma
sarcoma
