Week 4- Cancer and Imaging Flashcards
What is embryology?
The study of development of an embryo from the stage of fertilisation until the fetal stage
What are the three stages of life before birth and give their timings?
Preimplantation stage- week 1
Embryonic stage/ Organogenesis- weeks 2-8
Fetal stage- week 8-40
Give a summary of events of week 1 of an embryo
Fertilised embryo (oocyte egg + sperm)
Embryo undergoes cleavage divisions
Cells compact against each other to form morula
Blastocyst forms and first signs of differentiation occur
Blastocyst hatches out of the zona pellucida
When is a zyogte formed?
When an oocyte (egg) comes into contact and is fertilised by a sperm in the uterine tube
What is cleavage?
A process of cell division
Occurs when the zygote starts to develop and the maternal and paternal pro-nuclei fuse together to form the embryonic genome
What happens to the size of a cell during cleavage and why?
Overall size of the cell remains the same but cells within the embryo get smaller
Cell is dividing but has to remain small enough to passage down the narrowest part of the uterine tube called the isthmus
What is the name of the coating around an embryo and what is its role?
Zona Pellucida
Tough glycoprotein coat
Prevents premature implantation and regulates the size of the embryo
What is the morula and when does it occur?
A cluster of cells that are maximising contact and held together by tight junctions
Approx 4 days after fertilisation
What are the first two key features of cellular differentiation in an embryo?
Inner cell mass
Outer cells trophoblast
What does the inner cell membrane go on to form?
Embryo and extraembryonic tissues
What does the outer cell trophoblast go onto form?
The placenta
What occurs in the embryo as it enters the uterine cavity?
Fluid enters via the zona pellucida into spaces of inner cell mass and a fluid filled blastocyst cavity forms
Briefly describe the process of hatching
Blastocyst begins to run out of nutrients as the only source of nutrition are fluid in uterine tube and uterus
ICM cells undergo proliferation and fluid builds up in the cavity causing pressure to build up
Pressure increases and the blastocyst hatches from the zona pellucida and facilitates implantation
Trophoblast cells make contact with uterine lining, attach and implant
What is implantation?
The interaction between the embryo and the endometrial layer of the uterus
Where does decidualisation occur and when?
Stromal cells of the uterus
When the blastocyst makes contact with the endometrium of the uterus
What does decidualisation form?
The maternal component of the placenta
What does the process of decidualisation result in?
Several changes in endometrium to prepare it for pregnancy
Process triggers the production of several molecules and promotes trophoblast cells to become invasive
What are the two layers of trophoblast cells formed in differentiation and where are they located?
Cytotrophoblast- single layer of cells closest to the inside of the embryo
Syncytiotrophoblast- outer invasive layer and is a syncytium of cells
What does it mean for a structure to be a syncytium?
a single cell or cytoplasmic mass containing several nuclei, formed by fusion of cells or by division of nuclei.
What are the two layers the inner cell mass forms?
Epiblast
Hypoblast
What are the two layers of the ICM collectively known as?
Bilaminar disc
What is a key process that occurs at the end of week 2 of an embryo’s life?
Implanting syncytiotrophoblast cells communicate with maternal side of placenta and begin to establish a connection to enable diffusion of oxygen, waste and nutrients via blood supply
What is the hormone present in early pregnancy and what is its role?
Human chorionic gonadotrophin (hCG)
Induces a stable blood vessel connection between the mother and foetus and promotes overall maternal recognition of pregnancy
What is a key histological feature of endometrium cells during implantation and why?
Enlarged and elongated at the site closest to implantation
Due to decidualisation
What is a result of an abnormal implantation?
Ectopic pregnancy
Name the 4 extra-embryonic membranes
Amnion
Chorion
Yolk sac
Allantois
Where is the amnion located, what is its structure and what is its role?
Continuous with the epiblast of the bilaminar disc
Lines a structure called the amniotic cavity which is filled with fluid and acts to protect the developing embryo
When is the amnion present until?
Birth
Where is the chorion located, what is its structure and what is its role?
Double layered membrane formed by the the trophoblast and extra embryonic membranes
Lines a chorionic cavity and forms the fetal component of the placenta
Where is the yolk sac located, what is its structure and what is its role?
Continuous with the hypoblast of the bilaminar disk
Important in nutrient transfer
Important in blood cell formation and formation of the gut
When is the yolk sac present until?
Week 20
When is the chorion present until?
Dissappears when the amniotic expands
What is gastrulation?
A process of cell division and migration resulting in the formation of three germ layers
When does gastrulation occur?
Week 3- formation of the trilaminar embryo from the bilaminar epiblast
What are the three layers of the trilaminar embryo from most superficial?
Ectoderm
Mesoderm
Endoderm
What are three important structures in the trilaminar embryo?
Primitive streak
Notochord
Neural tube
Which end of an embryo is the primitive streak located at?
Tail end
What does the primitive streak show and where does it migrate?
Beginning of gastrulation
First appears at tail end of embryo and grows towards future head
What is the primitive node?
A thickened area of cells at the end of the primitive streak creating a bulge
Describe process of gastrulation
Invagination process
Primitive streak encourages migratation of cells of epiblast towards
Reach primitive streak cells move down through the embryo, pushing down and out to side to create mesoderm
Some cells move futrher down and push past the hypoblast creating endoderm
Cells left on top where epiblast was creates ectoderm
What does the ectoderm go on to produce?
Outside structures such as brain, epidermis, teeth and sensory receptors
What does the mesoderm go on to produce?
Muscles and bones, structural features such as the muscoskeletal system
What does the endoderm go on to produce?
Formation of the gut eg. GI tract and other things involved in digestion
What colours are layers of the embryo given in diagrams?
Ectoderm- blue
Mesoderm- red
Endoderm- yellow
What is a teratoma?
A type of tumour with tissue or organ components resembling derivatives of germ layers
What can teratomas be derived from?
Germ cells, oocytes or embryonal stem cells
Where are germ cell teratomas usually identified?
Gonads
What is the definition of cell cycle?
The interval between two successive mitotic divisions resulting in the production of two daughter cells, with chromosomes identical to the parent cell.
What are the two broad phases of the cell cycle?
Interphase
Mitotic phase/ cytokinesis
What are the 3 sub phases of interphase?
G1
Synthesis
G2
What occurs during G1?
Cells grow back towards their optimum size after cytokinesis
Monitoring external environment for optimal conditions for cell division- presence of growth factors
RNA and protein synthesis occurring in preparation for S phase
What occurs in S phase?
Synthesis of DNA
What occurs in G2?
Further growth of cell
Cell organelle replication
Preparation for mitosis
What are the phases of mitosis?
Prophase
Prometaphase
Metaphase
Anaphase
Telophase
What occurs in prophase?
Chromatin condensation (chromatin shortens, thickens and resolves into recognisable chromosomes)
Nucleolus disappears
Centrioles move to poles (parallel microtubules assembled between them to create the mitotic spindle)
What occurs in prometaphase?
Nuclear membrane dissolves
Chromosomes attach to spindle microtubules and begin moving
What occurs in metaphase?
Spindle fibres align the chromosomes along the middle of the metaphase plate
What occurs in anaphase?
Paired chromosomes separate and move to opposite sides of the cell
What occurs in telophase?
Chromatids arrive at opposite poles of cell
New membranes form around daughter nuclei
Chromosomes decondense
Spindle fibres disperse
What occurs in cytokinesis?
Cleavage of cells to produce daughter cells
What is G0?
The phase when cells are not actively dividing
What is another term for G0?
Quiesence
What is the typical length of the cell cycle broken down into each phase?
24 hrs
G- 11 hours, S- 8 hours, G2- 4 hours, M- 1 hour
Why is regulation of the cell cycle important?
To prevent uncontrolled cell growth and to ensure DNA replication is checked for harmful mutations
What is a CDK?
Cyclin dependent kinase
What does it mean for a CDK to be a serine/ threonine kinase?
A kinase that phosphorylates other proteins on either serine or threonine in a target protein
What is the CDK present abundantly in G1?
CDK46- cyclin D
What is the CDK most abundant in S?
CDK2- Cyclin E
What is the CDK most abundantly present in G2?
CDK2-Cyclin A
What is the CDK most abundant in the early stages of mitosis? What is its alternative name?
CDK1- cyclin B
What regulates CDK activity?
Cyclins
Whether they are themselves phosphorylated or not
CKIs
What are cyclins?
Activator proteins that are up or down regulated depdning on the phase of the cell cycle
How is a cyclin activated?
Associated with CDK
What is a CKI?
Cyclin dependent kinase inhibitor
What are the two main ways CKIs work?
Forming an inactive complex or acting as a competitive ligand
What are the 3 families of CKIs?
p21 CIP
p27 KIP
p16 INK
Describe the role of CDK cyclins in the progression from G2 to M phase
Inactive form CDK1 is present in a net phosphorylated state
Cyclin B synthesis begins in G2 and Cyclin B is transcribed and translated in G2 until sufficient levels are reached
Formation of active kinase complex
Enough cyclin B associates with CDK1
Net loss phosphorylation state of CDK1 and it is now an active kinase
What does CDK1/cyclin B phosphorylate that results in entry to M phase and beginning of mitosis?
Breakdown of nuclear envelope by phosphorylating lamins that results in the disassembly of intermediate filaments in nuclear lamina
Chromosome condensation by phosphorylating histones and condensins
Spindle formation by phosphorylating microtubule associated proteins
What are checkpoints?
Points in the eukaryotic cell division cycle where progress through the cycle can be halted until conditions are suitable for the cell to proceed
What do cell checkpoints check for?
Favourable external environment- presence of growth factors
Favourable internal environment- sufficient growth
DNA damage
Replication errors
Spindle attachment
Chromosome integrity
What are the 4 main checkpoints?
Restriction checkpoint
Growth 1 checkpoint
Growth 2 checkpoint
Metaphase checkpoint
What is the restriction point?
A checkpoint for cell cycle progression that is determined by the presence of growth factors. If there is sufficient signal, cell cycle progression. If there is insufficient signal, cell cycle arrest
What occurs after restriction point?
The cell no longer requires growth factors to complete the cell cycle and commits to cell division
What is the ‘gate keeper’ at the restriction point?
Retinoblastoma (RB) protein
What is the progression through the restriction checkpoint dependent on?
Accumulation of cyclin D
What occurs at the restriction point if there is no growth factor present?
Cell remains in G1
Nucleus of cell no genes necessary for S phase are transcribed
Occurs because: RB is associated with and inhibiting E2F which is a transcription factor that would normally transcribe for S phase
What occurs at the restriction checkpoint when growth factor is present?
Growth factor detected
Cell starts making cyclin D and activates CDK4/6
CDK4/6 cyclin D complex phosphorylates the RB no longer binds to E2F transcription factor and now free to transcribe genes necessary for S phase
Give 5 examples of growth factors
Platelet derived growth factor (PDGF)
Vascular endothelial growth factor (VEGF)
Colony stimulating factor (CSFs)
Thrombopoietin
Erythropoietin
What is the function of PDGF?
Matrix formation (increased numbers and activity of fibroblasts)
Remodelling (production of proteases)
What is the function of VEGF?
Angiogenesis (endothelial cell proliferation and migration)
What is the role of colony stimulating factor?
Myeloid lineage in haematopoiesis
What is the role of thrombopoietin?
Production of platelets
What is the role of erythropoietin?
Production of red blood cells
What is the role of DNA damage checkpoints and where are they?
Check integrity of DNA
One before entering S phase, one before entering M phase
What molecule is used in DNA damage checkpoints?
Tumour suppressor gene- p53
Describe process DNA checkpoint works
1) damage to DNA is detected by p53
2) production of cyclin-dependent kinase inhibitor p21 CIP
3) p21 CIP binds to CDK2- Cylcin E/A in G1/s transition, and CDK1- cyclin A/B in G2/M transition
4) Halts progression into next stage
What is p53?
A transcription factor that directly transcribes genes to halt the cell cycle
What occurs in low levels of DNA damage?
p21 expression for DNA repair
What occurs in high levels of DNA damage?
Transcribing genes leading to apoptosis
What is the point of the metaphase checkpoint?
Spindle assembly checkpoint that delays the onset of anaphase until chromosomes are correctly attached to the mitotic spindle
How does the metaphase checkpoint work?
Surveillance mechanism that delays anaphase- anaphase promoting complex is inhibited until all chromosomes are attached to it
What are tumour suppressor genes?
Encode normal proteins whose role is to suppress cell proliferation to ensure that the cell can maintain integrity of its genome and only divide when necessary
What occurs when a tumour suppressor gene finds abnormality?
Cell cycle arrest until appropriate conditions are met or repairs are made to the cell
Give 3 examples of tumour suppressor genes and how they work
Rb-blocks entry to the cell cycle
p53- detects DNA damage
BRCA1- DNA repair
What are 6 key examples of types of radiological investigation?
Xray
Ultrasound
Computed tomography (CT scan)
MRI
PET
Interventional radiology
What are 3 benefits of ultrasound?
Cheap
Easy access
No radiation involved
Give 4 key scenarios where ultrasound is used
Pregnancy
Kidneys
Gall bladder
Liver
When are PET scans mainly used?
Cancer diagnosis
Give 4 scenarios when interventional radiology can be used
Stop bleeding
Fix aneurysm
Tumours
Save limbs
Define the term ‘neoplasm’
A tumour- a new and abnromal growth resulting from autonomous cell division
Define the term ‘benign’
Of a neoplasm, to grow slowly and remain localised at the site of origin
What does malignant mean?
Invade and spread to different sites- cancerous
What does metastasis mean?
Multi-step process by which tumour cells move from a primary site to colonise a secondary site
Define oncogene
A gene whose product is involved in inducing cancer
Define proto-oncogene
A normal cellular gene that encode a protein usually involved in regulation of cell growth and proliferation, and when mutated, becomes a cancer promoting oncogene
Define tumour suppressor gene
A gene whose encoded protein directly or indirectly inhibits progression through the cell cycle and in which a loss of function mutation is oncogenic
What are 4 key features of cancer cell morphology?
Large variably shaped nuclei
Many dividing cells- disorganised arrangement
Varied in size and shape
Loss of normal features
Why does a cancer cell stain bluer?
Divide faster
More rRNA and mRNA accumulates in the cytoplasm
More basophilic (acidic structures!)
Stains bluer with H&E
What is anaplasia?
Tumour cells becoming less like their tissue of origin and losing many of their differentiated features
What are 6 key features of cancer cells?
Uncontrolled cell proliferation
Increased growth capacity
Blocked differentiation
Increased cell motility
Acquired tissue invasion capability
Loss of genomic stability
What is tumourgenesis?
A multi-step process where a normal cell accumulates a number of mutations over many years to acquire new characteristics
Describe the process of tumourigenesis
Initiation- environmental carinogens such as chemicals or radiation initiate process
Accumulation- many more mutations accumulate, activate oncogenes, some genes lose tumor suppressor gene activity, further enhancing proliferative potential
Further mutations- malignancy
What are the 6 key characteristics of cancer?
- Self-sufficency in growth signals; cancer cells acquire an autonomous drive to proliferate
- Insensitivity to growth-inhibitory signals; inactivation of tumour suppressor genes that normally inhibit growth
- Evasion of programmed cell death (apoptosis); suppress and inactivate genes and pathways that normally enable cells to die
- Limitless replication potential; activate specific gene pathways that render them immortal even after generations of growth
- Sustained angiogenesis; acquire the capacity to draw out their own supply of blood and blood vessels
- Tissue invasion and metastasis; acquire the capacity to migrate to other organs, invade other tissues and colonise these organs
What is a tumour?
A tumour is formed by an excessive, uncontrolled proliferation of cells as a result of an irreversible genetic change which is passed from one tumour cell to its progeny
What is neoplasia?
Neoplasia is the new growth of these abnormal cells
What is a monoclonal tumour?
A tumour derives from one cell only
What do tumour pathologists look at?
Cell proliferation: normal vs abnormal
Tumours: benign vs malignant
Naming of tumours by tissue of origin
Modes of spread of malignant tumours
Clinical effects of tumours
Pathological diagnosis of cancer
What are the three ways tissue are classified?
Labile
Stable
Permanent
What is a labile tissue?
A very quick turnover and replacement of cells within a tissue
Give an example of a labile tissue
Epidermal cells on the surface of the skin
Blood cells
What are stable tissues?
Tissues with a slower turnover rate
Give an example of a stable tissue
Bone cells
What is a permanent tissue?
Cells that have no turnover and we have to live with for the rest of our lives
Give an example of a permanent tissue
Nerve cells
What is hyperplasia?
An increase in the size of an organ as a result of cell proliferation eg. uterus in pregnancy
What is hypertrophy?
An increase in the size of an organ due to an increase in the size of the constituent cells eg. left ventricle of heart in hypertension
What is apoptosis?
Programmed cell death
What is necrosis?
Death of cells in living tissue caused by external factors such as infection trauma or toxins
Describe the differences in growth patterns between benign and malignant tumours
Benign- expansion, remain localised
Malignant- infiltrate locally, spread to distant sites
Describe the differences in growth rate between benign and malignant tumours
Benign- generally slow
Malignant- faster
Describe the mitotic pattern of benign and malignant tumours
Benign- few, normal
Malignant- numerous including atypical forms
Describe the nuclei of benign and malignant tumours
Benign- small, regular and uniform
Maligant- larger, pleomorphic (increased DNA content)
Describe the differences in histology between benign and malignant tumours
Benign- resembles tissue of origin
Malignant- may differ from tissue of origin, disconnected from basement membrane
Describe the differences in clinical effects between benign and malignant tumours
Benign- local pressure effects, hormone secretion
Malignant- local pressure and destruction, distant metastases, inappropriate hormone secretion
Describe the differences between benign and malignant tumour treatment
Benign- local excision
Malignant- local excision and perhaps radiotherapy and/or chemotherapy
What is metaplasia?
Change from one type of differentiated tissue to another, with the resulting tissue often better adapted to the environment
Give an example of normal metaplasia
Oesophagus from squamous epithelium to glandular epithelium which is more protective after acid reflux
What are two key characteristics of dysplasia?
Loss of architectural orientation
Development of cellular atypia
What is dysplasia?
A tumour growing that is confined to the epithelium
Give 4 major modes of tumour spreading
Local invasion
Lymphatic spread
Blood spread
Transcoelomic spread
What is local invasion?
Nearby cells invade by bashing their ways through other normal cells, collagen and fibrous tissue
What are the drawbacks to local invasion?
Slow and difficult for neoplastic cells to invade
What is lymphatic spread?
Neoplastic cells that invade the lymphatic system will travel towards the nearest lymph node and therby the thoracic duct and systemic circulation
Which cancers commonly used lymphatic system to spread?
Breast cancer and melanomas
What is transcoelomic spread?
Spread of tumours across the peritoneum and the peritoneal cavity
Give examples of transcoelomic spread
Ovaries and stomach where the cancer spreads on external surface of the stomach
For carcinomas what is the likelihood of lymphatic, blood and transcoelomic spread?
Lymphatic- common
Blood- common
Transcoelomic- stomach and ovary
For melanomas, what is the likelihood of lymphatic, blood and transcoelomic spread?
Lymphatic- common, early
Blood- common, late
Transcoelomic-rare
For sarcomas, what is the likelihood of lymphatic, blood and transcoelomic spread?
Lymphatic- rare
Blood- common, early
Transcoelomic- rare
What are the clinical effects of a benign tumour?
Presence of a lump which may or may not cause pain, could apply pressure to adjacent tissue if in confined space, may be substances produced by tumour
What are the local effects of malignant tumours?
Palpable mass that is often associated with pain
Tumour may ulcerate (lose its surface and bleed to cause anaemia)
Tumour may obstruct a hollow organ
Give common metastatic effects of a liver tumour
Hepatomegaly, jaundice, liver failure
Give common metastatic effects of lung cancer
Haemoptysis, pneumonia, pleural effusion
Give common metastatic effects of brain cancer
Seizures, stroke, raised intracranial pressure
Give common metastatic effects of bone cancer
Pain, fracture, spinal cord compression
Give common metastatic effects of bone marrow cancer
Anaemia, leukopaenia, thrmbocytopaenia
Give 4 non-metastatic effects of cancer
Loss of appetite, weight loss and wasting (cachexia)
Generally unwell
Anaemia
Fever
Give the common effects of lung cancer
Cough, haemoptysis, chest pain, pneumonia
Give the common effects of colon cancer
Altered bowel habit
Obstruction
Anaemia
Liver metastases
Give the common effects of prostate cancer
Urinary symptoms
Bony metastases
Give the common effects of pancreatic cancer
Jaundice and back pain
Give the common effects of lymphoma
Enlarged lymph nodes
Infection
Give the common effects of leukaemia
Infection
Bleeding
Anaemia
Why do we have a skeleton?
Support
Protection
Locomotion
Mineral reserve- 99% bodies calcum
Haematopoiesis
What is the functional unit that makes up bone called?
Osteon- layers of bone laid in rings
What is an osteon composed of? Give percentages
Organic component- 30%- made of type 1 collagen- giving tensile strength and allow for bending
Inorganic component- 70%- calcium and phosphate salts- hard mineral components making bone sturdy and giving it compressive strength
Why do osteons contain blood vessels
Provide nutrients to the cells
What are the two cells that mainly make up bone?
Osteoblasts- lay down new bone
Osteoclasts- break down old bone
What are the 6 key features of most bones?
Long tube like diaphysis
Two epiphyses
Medullary cavity
Epiphyseal growth plate
Periosteum
Endosteum
What is the role of the diaphysis and what is it made of?
Gives strength, provides limited flexibility
Mostly compact bone
What is the role of the epiphyses?
Acts as an articular surface for joints
What is the structure of the epiphyses?
Spongy bone (honeycomb structure- struts which sit in the direction of the force through the bone)
Appears compact on the surace
Some cartilage present to protect surface of the bone forming the joints
What is the medullary space and what is its role?
Empty space that is common in longer bones, find bone marrow here
What is the role of the epiphyseal growth plate?
Separates diaphysis from epiphysis and is the site of growth during development
What happens to the epiphyseal growth plate after development?
Plate ossifies and forms the epiphyseal line
What is the role of the periosteum?
Connective tissue layer that covers the outside of the bone
Attachment site for tendons
What is the endosteum?
Similar structure to periosteum
Lines internal surfaces of cavities within bones
Describe the structure of a flat bone
No medullary cavity
Two sheets of compact bone that sandwich the spongy bone marrow in the middle (diploe)
Diploe filled with red bone marrow
