9 Invasion, metastasis, Effects Flashcards
Neoplasia
❖ ..1… abnormal cell growth, triggered by a series of …2… (germline, acquired/somatic) affecting a single cell and its clonal progeny
❖ The ..3… mutations give the neoplastic cells a survival and …4.. advantage
❖ The result is excessive and …5… proliferation (independent of physiological growth signals)
- Uncontrolled
- mutations
- causative
- growth
- autonomous
what gives neoplastic cells a survival and growth advantage ?
causative mutations
what is autonomous proliferation independent of ?
physiological growth signals
neoplasm definition ?
an abnormal growth of cells that persists after the initial stimulus is removed
begnin definition ?
neoplasms that don’t invade nearby tissues or metastasise
malignant neoplasms definition ?
a neoplasm that invades surrounding tissues with potential to spread to distant sites
tumour definition ?
any clinically detectable lump or swelling , a neoplasm is just one type of tumour
cancer definition ?
any malignant neoplasm
a metastasis definition ?
a malignant neoplasm that has spread from its original site to a new non-contiguous site
Metastasis is when a malignant neoplasm has spread from its original site to a new non-contiguous site ,
what’s the original location and place which it has spread to site known as ?
- original location = primary site
- new place = secondary site
2 types of tumours ?
- non-neoplastic
- neoplastic
examples of non-neoplastic tumours ?
- abscess
- haematoma
- keloid scar - in dermis
- fracture callous
- epidermoid cyst
Dysplasia is ..1…. and ..2…
where as neoplasia is irreversible
- pre-neoplastic
- reversible
Progression from normal cells to cancerous ?
- cell with mutation
- hyperplasia
- dysplasia
- In situ cancer
- invasive cancer
What condition is dysplasia ?
a precancerous
Dysplasia is a ….1…. alteration in which cells show ..2…. organisation it is not …..3… because the change is reverible.
what is delayed for cell ?
- pre-neoplastic
- disordered tissue
- neoplastic
cell maturation and differentiation
3 examples of dysplasia ?
1. epithelial
2. oesophagus
3. colon
- Cervix (CIN)
- Barrett’s with dysplasia
- adenomatous polyps
Benign vs Malignant neoplasms
What does differentiation tell about tumour cells ?
how abnormal the tumours cells look when compred to the surrounding healthy tissues
what do well-differentiated cancer cells have the shape and structure of ?
something that resembles nearby healthy cells
what do poorly-differentiated cancer cells have a shape and structure of ?
a completely different shape and structure to healthy cells
what is grading of tumour cells based on ?
- the degree of differentiation of the tumour cells
- their rate of dividing
what is grading a measure of with cancer cells ?
how abnormal the cancer cells look under the microscope
What is staging with cancer cells ?
staging is the process of determining the extent to which a cancer has grown and spread
Explain stages 1 - 4 in staging (which tells how far cancer has travelled from the site of the original tumor)
- tumor is small and hasn’t spread
- tumor large but hasn’t spread
- tumors have spread to neighbouring lymph nodes
- tumors have spread to other organs
What is the TNM system ?
a staging system used by doctors for most types of cancers
It uses letters and number to describe the tumor (T), lymph nodes (N), whether or not the cancer has spread or metastases (M)
Meaning of TX ?
there is no information about the tumor or it cannot be measured
meaning of T0 ?
there is no evidence of a tumor
meaning of ‘Tis’ ?
refers to a tumor “in situ”
= tumor is only found in the cells where it started. It has not spread to any surrounding tissue.
meaning of T1-T4 ?
describe the size and location of the tumor, on a scale of 1 to 4.
A larger tumor or a tumor that has grown deeper into nearby tissue will get a higher number
what are lymph nodes near :
1. where the cancer started
2. other parts of body
- regional lymph nodes
- distant lymph nodes
what is stage if :
1. cancer has not spread ?
2. cancer has spread to other parts of the body ?
- M0
- M1
What may the prefix of benign epithelial neoplasms may describe ?
the growth pattern
Give some examples of prefix of benign epithelial neoplasms that decribe the growth pattern
- cystadenoma
- papillary
- villous or tubular adenoma
How is a tubular adenoma characterized in terms of villosity fraction?
having less than 25% fraction of villosity
What percentage range of villosity fraction defines a tubulovillous adenoma?
having 25-75% fraction of villosity
What is the villosity fraction for a villous adenoma?
has more than 75% fraction of villosity
What does fraction of villosity refer to ?
a quantifiable measure related to the villi
3 examples of which epithelium malignant epithelial neoplasms “carcinomas” found ?
- stratified squamous - squamous cell carcinoma
- glandular - adenocarcinoma
- transitional - transitional cell carcinoma / urothelial carcinoma
- others: basal cell cacrinoma
Examples which organs are squamous cell carcinoma found ?
skin , mouth , cervix
Examples which organs are adenocarcinoma found ?
- stomach
- colon
- lung
- prostate
- breast
- kidney
- pancreas
Examples which organs urothelial carcinoma found ?
bladder , ureter, renal , pelvis
Give 11 examples of tumor types that are exceptions to the rule [separate cards !!]
- melanoma
- lymphoma
- seminoma
- glioma
- mesothelioma
- neuroblastoma
- retinoblastoma
- hepatoblastoma
- plasmacytoma
- astrocytoma
- leukemia
germ cell neoplasms:
1. tumors derived from ?
2. organs that they can occur in ?
3. have varying potential for ?
- germ cells
- testis or ovary
- malignancy
are germ cell neoplasms in the testis usually benign or malignant ?
malignant
what is a seminoma ?
type of germ cell tumor of the testis that is typically malignant and is known for its sensitivity to radiation therapy
why types of teratomas can be found in the testis ?
- differentiated/ mature, immature or undifferentiated with undifferentiated form being referred to as a embryonal carcinoma
Are germ cell neoplasms in the ovary usually benign or malignant ?
benign
3 examples of ovary benign germ cell neoplasms ?
- mature cystic teratoma / dermoid cyst - often differentiated tissues contains
- struma ovarii - rare type of ovarian teratoma, predominantly composed of thyroid tissue
mature cystic teratoma:
1. also known as ?
2. commonly found ?
- dermoid cyst
- ovary benign germ cell tumor
What is struma ovarii?
a rare type of ovarian teratoma
predominantly composed of thyroid tissue
can occasionally produce thyroid hormones.
What do germ cell rarely undergo ?
malignant change in benign epithelium (carcinomas)
neuroendocrine tumor
What is a well-differentiated NET commonly referred to as?
a “carcinoid tumor”
neuroendocrine tumor
Where do phaeochromocytomas typically arise, and are they usually benign or malignant?
in the adrenal glands and are usually benign
neuroendocrine tumor
What is an example of a poorly differentiated NET?
small cell lung carcinoma
what is evolving for neuroendocrine tumours ?
terminology
2 cancer cell models ?
- clonal evolution model
- hierarchical cancer stem cell model
Why would a collection of cells be monoclonal ?
if they all originated from a single founding cell
what study does evidence that neoplasms are monoclonal come from ?
X- linked gene for the enzyme glucose- 6-phosphate dehydrogenase (G6PD) in tumour tissue from women.
what does X- linked gene for the enzyme glucose- 6-phosphate dehydrogenase in tumour tissue from women have ?
several alleles encoding different isoenzymes
what is lyonisation also known as ?
also known as X-chromosome inactivation
what does lyonization ensure for females ?
that like males , females have one functional copy of the X chromosome in each body cell, leading to dosage compensation between the sexes
What process is lyonisation (X-chromosome inactivation) ?
a process that occurs early in female embryogenesis where one of the two X chromosomes in each cell is randomly inactivated
What does it mean by in heterozygous women normal tissue will be a patchwork of each type of allele ?
include example of heat stable / labile isoenzyme
this is what the study for if neoplasms are monoclonal studied ?
some cell will express isoenzyme for heath stable allele while other cells will express isoenzyme for heat labile isoenzyme resulting in patchwork pattern expression, where both types of cells coexist.
What happens in neoplastic tissue using example of heat stable isoenzyme, heat labile isoenzyme and lysonisation ?
these tissues only express one isoenzyme indicating a monoclonal group of cells
What are the 7 steps of metastasis that follow after primary tumor ?
- proliferation
- angiogenesis
- local invasion, detachment and intravasation
- embolisation and survival
- arrest and extravasation at target organs
- micro-metastasis
- metastasis
metastasis = malignant neoplasm that has …
spread from its original site to a new non-contiguous site (new site directly connected to existing site)
What greatly increases tumour burden ?
ability of malignant cells to invade and spread to distant sites
If metastasis is untreated, what does this result in ?
vast numbers of “parasitic” malignant cells
which tumours do not metastasise
benign tumours
what is parabiosis ?
refers to a surgical technique where two living organisms, typically animals like mice, are surgically joined together to create a shared circulatory system
What must malignant cells do to get from a primary site to a secondary site ?
- grow and invade at the primary site
- enter a transport system
- grow at the secondary site to form a new tumour
what must malignant cells do at all points of it’s multi-step journey ?
evade destruction by immune cells
how efficient is whole process of invasion and metastasis ?
it’s inefficient
How many type of epithelial to mesenchymal transitions are there ?
3 types
* type 1 EMT - embryogenesis
* type 2 EMT - tissue regeneration
* type 3 EMT - cancer progression
Invasion of cancer involves 3 important alterations which collectively create a carcinoma cell phenotype which appears more like a mesenchyma cell than an epithelial cell (EMT)
what are these 3 alterations ?
- altered adhesion - E-cadherin reduction, altered adhesion between malignant & stromal proteins involves changes in integrin expression
- stroma proteolysis - cells must degrade BM & stroma to invade successfully (proteases, matrix metalloproteinases (MMPs))
- motility altered - invovles change in actin cytoskeleton , signalling via integrins is important and occurs via small G proteins such as members of the Rho family
What are the main steps involved in invasion of extracellular matrix ?
- Detachment of tumour cells from one another
- degradation of the extracellular matrix
- loss of adhesion of cells from integrins
- migration of tumour cells through the extracellular matrix
Describe the main steps involved in invasion of the ECM by tumour cells
- detachment of tumour cells from one another by unzipping of the anchor protein E-cadherin
- degradation of the ECM by collagenase which attacks the collagen fibres of the basement membrane
- loss of adhesion of cells from integrins
- migration of tumour cells through ECM
How does detachment of tumour cells from one another happen ?
unzipping of the anchor protein E-cadherin
how does degradation of the extracellular matrix happen ?
collagenase attacking the collagen fibres of the basement membrane
the growth of cancer cells at a secondary site is known as …
colonisation
What do malignant cells that take advantage of nearby non-neoplastic cells form together ?
a cancer niche
What is stromal invasion in the context of cancer progression?
process where malignant cells breach the basement membrane and invade into the surrounding connective tissue (stroma) in order to spread and metastasize
stromal invasion involves 3 important alterations which are …
- cells degrade basement membrane & stroma using proteases (matrix metalloproteinase, MMP)
- malignant cells take advantage of other nearby non-neoplastic cells = which forms cancer niche. Normal cells provide growth factors / proteases that help cancer thrive
- altered motility involves changes in actin cytoskeleton
local factors facilitate tumour cell invasion and eventually ….
Malignant cells can be transported to distant sites via 3 routes , what are they ?
- transcoelomic spread = fluid in body cavities (pleura, peritoneal, pericardial, brain ventricles)
- lymphatic vessels
- hematogenous = blood vessels via capillaries/venules
what are circulating tumour cells (CTCs) ?
Tumor cells that have passed from tumor into blood; primary; place in research
circulating tumour cells
Although CTCs are rare in blood of cancer patients, when is it detectable in blood ?
in both early and late stages of disease of cancer patients
circulating tumour cells
Why is detection of CTCs useful ?
May aid in :
early cancer diagnosis
prognosis
prediction
stratification
pharmacodynamics
CTC diagram slide 36
What challenges do cancer cells evade in circulation ? [CHANGE !]
- shear force and turbulence
- surveillance and attack from immune cells (NK cells)
- lack of substratum
- entrapment in capillary bed
How do cancer cells overcome the challenges they face during circulation ? [CHANGE Q!]
- release of coagulation factors resultin in formation of an outer platelet shield
- and then a tumour platelet microthrombi
What 2 events does release of coagulation factors protect cancer cells from ?
- protects from shearing and turbulence forces
- prevents immune detection using platelet derived MHC class I coating
what is tumour dormancy ?
when a malignant neoplasm relapses years after an apparent cure, it is typicaly due to one or more micrometastases starting to grow
At the secondary site, malignant cells must get out of the vessel (..1…) and then grow to form a clinical metastasis. This is a dynamic process, involving ..2…., vascular ….3…. and endothelial ..4….
- extravasation
- adhesion
- migration
- remodelling
Where must malignant cells grow to form a clinical metastasis ?
at a secondary site
What must malignant cells do at a secondary site to form a clinical metastasis ?
get out of a vessel (extravasation) then grow
What kind of process is it when malignant cells at a secondary site undergo extravasation and then grow ?
a dynamic process that includes adhesion , vascular migration and endothelial remodelling (twist gene)
What happens to many malignant cells (tiny cell clusters) that lodge at secondary sites ?
they often either die or fail to grow into clinically detectable tumours
What are called micrometastases ?
survivng microscopic depositis that do not grow.
When a malignant neoplasm relapses years after an apparent cure what is it typically due to ?
one or more micrmetastases starting to grow
In order for a micrometastasis to develop into a growing metastasis there must be an alteration in what ?
- microenvironment becoming more favourable
- immune status
- angiogenic switch
The site of a secondary neoplasm depends on 2 factors - what are they ?
- regional drainage
- seed-and-soil phenomenon
What does regional drainage involve ?
- lymphatic metasis -> lymph nodes, transcoelomic spread -> other areas in acoelomic space / adjacent organs , bloodborne metastases -> to next capillary bed encountered
What can the seed-and-soil phenomenon explain ?
the unpredictable distribution of blood-borne metastases and is often due to the interactions between malignant cells & local tumour environment (the niche) at the secondary site
carcinomas typically spread via …?
lymphatics
sarcomas typically spread via…
bloodstream
neoplasms that most frequently spread/metastasise include…
- breast
- bronchus
- kidney
- thyroid
- prostate
common site of bloodborne metastasis include…
- lung
- bone
- liver
- brain
GI tract malignancies and melanoma tend to spread to …
liver
sarcomas and renal cell carcinoma tend to spread to …
lung
what is lymphatic metastasis ?
what is transcoelomic spread ?
what is blood-borne metastasis ?
metastatic organotropism - slide 43
what is the clue for the primary origin of a carcinoma ?
- cell differentiation (biopsy)
- regional lymph node involvement
Which lymph node invovled with :
melanoma of leg
inguinal lymph node
Which lymph node invovled with :
lung carcinoma
thoracic hilar lymph nodes
Which lymph node invovled with :
cervix carcinoma
iliac lymph nodes
Which lymph node invovled with :
breast cancer
axillary lymph nodes
Which lymph node invovled with :
seminoma of testis
para-aortic lymph nodes
Where do metastases tend to form first ? regarding blood borne metastasis ?
first capillary bed encountered
Small cell bronchial carcinoma and hilar tumour are examples of some malignant neoplasms that are more …. and …. very early in their course
aggressive
metastasise
How are the cells in small cell carcinoma usually arranged ?
featureless, disorganised sheets
what do basal cell carcinoma of the skin almost nerve do ?
metastasise
features of dysplasia ?
- loss of normal maturation
- pleomorphism
- increased mitotic activity
- high nuclear/ cytoplasmic ratio
some examples of malignant tumours
- multiple myeloma
- osteosarcoma
- lymphoma
common sites of metastasis
- brain
- liver
- bone marrow
A benign neoplasm that has cells that closely resemble the parent tissue is …. differentiated ?
well
malignant neoplasms range from …. to ….. differentiated
well to poorly
cells with NO resemblance to any tissue = ?
anaplastic
