Cancer cell Biology Flashcards
What is neoplasia and describe its characteristics briefly
Neoplasia is the formation of a tumour
-tumours can be benign or malignant
-Cancer typically refers to malignant growths (metastatic)
-There are 4 major types of tumour classified by the site where they formed
Cancer on epithelial cells are referred to as carcinomas and they can be squamous carcinomas and secretory
Incidence
Cancers do not occur in the same frequency across populations.
Migratory populations develop the risk profile of the host population within a generation.
Suggests that most cancers are caused by environmental factors.
such as;
-carcinogens are mutagenic which cause a change in DNA structure that is likely to cause us costs but not all cancers are formed from carcinogens.
Factors that influence tumorigenesis
Genetic susceptibility
Inheritance of defective tumour suppressor genes increases risk of specific forms of cancer
Environmental carcinogens
Genotoxic / mutagenic (benzo(a)pyruvate, radiation)
Non-genotoxic.
Viral infection
Acutely transforming and non transforming viruses. Viruses can initiate tumour genesis by expressing genes, modifying proliferation and cell death. HPV =high risk of inducing cancers
Risk of cancer
The risk of developing a tumour increases with age.
This observation and other experimental evidence led to the concept that tumour development is a rare event and occurs over a protracted period.
roughly 40% will develop a tumour but most of those will be benign in nature. Cancers are most likely to develop after 50 and increase in likelihood exponentially after.
What is the Knudson’s multi-hit hypothesis
Knudson studied the occurrence of retinoblastoma. (recessive gene)
-Familial bilateral forms in both eyes
-Sporadic unilateral form in one eye
Modelled the kinetics of these types as if the Rb gene was recessive.
Found that the predicted one and two mutations needed matched the actual rate of occurrence.
Therefore, a tumour requires at least 2 mutations to develop.
Properties of normal vs. tumour cells
Tumour cells differ from normal cells in a variety of ways.
This is termed transformation
Transformation must occur before a tumour can form.
Properties of transformed cells
- Altered morphology (rounded shape, refractile in phase-contrast microscope)
-Loss of contact inhibition (ability to grow over one another) of Ability to grow without attachment to solid substrate (anchorage independence)
-Ability to proliferate indefinitely (immortalization)
-Reduced requirement for mitogenic growth factors
-High saturation density (ability to accumulate large numbers of cells in culture
-Inability to halt proliferation in response to deprivation of growth factors nation dish)
-Increased transport of glucose
-Tumorigenicity
Transformed cells can be identified by examining cellular and nuclear structure and staining
Absolute nuclear size/shape
Nuclear cytoplasmic ratio (NCR)
Chromatin pattern
Chromatin distribution
Regularity of the nuclear membrane
Intensity of nuclear staining
Mitotic figures
Tumours arise from normal tissues
*Carcinomas arise from epithelial cells where 80% of tumours are carcinomas
-Squamous cell carcinomas (protective role)
-adenocarcinomas (secretory role)
*Sarcomas derived from mesenchymal cells or connective tissue
*Haematopoietic tumours
- leukemias and lymphomas
*Neuroectodermal: cells of the central and peripheral nervous system
-medulloblastomas
Cancers develop progressively
The formation of a malignant tumour from a normal tissue does not occur as a single step it takes years and even decades.
There are cytological identifiable changes during carcinogenesis.
Hyperplasia (increase number of cells) /Metaplasia (one normal tissue type is replaced by another normal tissue type but it is in the wrong location.
Dysplasia (more de-differentiation)
Neoplasia (Carcinoma in-situ)
Metastasis
Molecular changes in oncogenes and tumour suppressors
For a tumour to develop a cell must have at least
-Gain of function in oncogenes
-Loss of function in tumour suppressors
The nature of the genes affected varies between and within cancer types
Breast Cancer Classification: molecular
Classification based on immunohistochemical and DNA analysis
Can be subdivided at a molecular level into several subtypes.
Classification is continually evolving as more is understood regarding tumour development
Classification based on receptor expression, proliferation markers
In terms of breast cancer there are 4 major molecular sub-types, luminal A , luminal B, HER2 and basal-like(TNBS)
Common Genes Disrupted in Prostate Cancer
GWAS studies have identified at least 260 risk variants associated with PC.
Disruption of Androgen signalling
PTEN and p53
TMPRSS2 promoter-ERG fusions (40-80% of cases)
Heredity prostate cancer 1 gene- RNAase L and autophagy/apoptosis
BRACA 1 and BRACA-2 (5-10% of cases)
homeobox gene HOXB13 and epithelial differentiation
Metastasis
preferential metastasis, where does the cancer mostly ends up?
This occurs when the tumour has become malignant
The formation of secondary tumours is a major cause of morbidity & mortality.
This is not always a random event and many cancers preferentially metastasise to specific organs.
prostate –> bone marrow
colon–>liver
breast–>bone marrow
pancreas–>liver
What is Paget’s Seed and Soil hypothesis?
Metastatic cells “seeds” will only thrive in certain tissues “soils.”
Stephen Paget based on Fuch’s original idea.
Reciprocal interactions between cancer cells and tissue gives proliferative and survival advantages.
Can’t explain metastasis of all types of cancer.
Metastasis is likely to be a product of frequency and ease of colonisation (environment provided by pre-metastatic niche).
Malignancy- stages of metastasis
*dissemination phase
-activation
-dissociation
-migration
-intravasation
-release
circulation
*colonisation phase
-arrest
-diapedesis
-(extravasation)
-migration
-setting
-growth
Epithelial-mesenchymal transition
Malignancy is associated with epithelial-mesenchymal transition (EMT).
Enables cells to leave the primary tumour and invade local tissue.
Dependent on changes in expression of a range of cellular proteins.
EMT
Epithelial-Mesenchymal Transition (EMT) is a biological process where cells transform from tightly connected epithelial cells to more mobile and invasive mesenchymal cells. This process is vital in development, wound healing, and cancer progression. During EMT, cells lose adhesion to each other, change shape, and gain migratory capabilities. In cancer, EMT is associated with increased invasiveness and metastasis. Understanding EMT is crucial for cancer research as it provides insights into tumor progression and potential therapeutic targets.
Stromal signals facilitate EMT
Mesenchymal markers only displayed by cells in contact with stroma.
Metastases tend to revert to epithelial phenotype.
transforming growth factor=TGF-beta (most important) , TNF-alpha, IGF-I and EGF.
only cells round the stroma are expressing mesenchymal marker. Signals from stromal cells round the tumour which is driving EMT.
Transcription factors
Multiple stromal derived signals act via signalling cascades to promote EMT
These induce several transcription factors associated with EMT
Act in a pleiotropic fashion to repress epithelial markers and promote mesenchymal differentiation
Activation is induced by interaction with stromal cells
Invasiveness
Proteases enable ECM remodelling and cancer cell migration through stroma.
Stromal cells produce several proteases
Matrix metalloproteinases (MMP)
Urokinase plasminogen activator (uPA)
These are not only important for infiltration but also at other metastatic stages.
Invasiveness: ECM interactions
Changes in cadherin and integrin expression enable breakdown of tight junctions and transient interactions with stroma
Proteases enable breakdown of ECM and BM. CAM interactions enable intravasation and extravasation at secondary sites
Tumours promote formation of pre-metastatic niches
Tumour derived exosomes / growth factors promote niche formation (stromal cell infiltration, immunosuppression, extracellular remodelling, vascularization)
Support tumour infiltration/colonization/survival
Death, Dormancy or Colonisation
Most disseminated tumour cells die (~99.99%)
Colonisation is a rare
Some DTC become dormant and resistant to therapy (minimal residual disease,leukaemia)
Dormant cells could be detected with epithelial markers (cytokeratin) and DNA markers
Some start to proliferate and form micro mets, this can happen instantly or later.
Dependent on niche environment
Some carcinomas revert back to epithelial type (MET).
-May help stabilise colonisation
-Stimulate angiogenesis
Conclusions
Tumours are characterised by their tissue origin.
Requires multiple mutations or events that may take decades to occur.
Progression can be staged histologically.
Metastasis requires disrupted cell adhesion and motility proteins and is not necessarily a random event.
What is the most commonly prescribed form of anti-resorptive therapy?
bisphosphonates-nitrogen or non-nitrogen containing
Which cells initially respond to elevated PTH levels leading to osteoclast formation?
osteoblasts
What primary effect would an increase in OPG have on bone
decreased bone resorption
The inorganic component of bone tissue formed by osteoblasts is collectively termed
osteoid
What general form of cancer develops from secretory epithelial cells such as goblet cells?
adenosarcomas
What general form of cancer develops from basket cells of the cerebellum?
neuroectodermal cancers
Is there typically an increase in bone mass in Paget’s disease of bone?
yes
