Session 8 Flashcards
Is Cell Proliferation physiological or pathological?
Cell proliferation may occur as the result of physiological or pathological conditions.
Excessive physiological stimulation can become pathological e.g. Prostatic hyperplasia.
Proto-oncogenes regulate normal cell proliferation.
What does the size of a cell population depend on?
Depends on rate of cell proliferation, cell differentiation and cell death by apoptosis.
Increased numbers are seen with increased proliferation or decreased cell death.
Signalling biochemistry is complex but the final outcomes are limited. What are they?
Divide (I.e. Enter cell cycle)
Differentiate (take on specialised form and function)
Survive (I.e. Resist apoptosis)
Die (I.e. Undergo apoptosis)
Describe the types of Cell Signalling
Autocrine: cells respond to the signalling molecules that they themselves produce.
Intracrine: cell produces a hormone that acts inside the cell, regulating intracellular events (special type of autocrine signalling).
Paracrine: a cell produces the signalling molecule, this acts on adjacent cells. The responding cells are close to the secreting cell and are often of a different type.
Endocrine: hormones are synthesised by an endocrine organ, then conveyed in the blood stream to target cells to affect physiological activity.
What can cell to cell signalling be via?
Hormones
Local mediators
Direct cell-cell or cell-stroma contact
What are Growth Factors?
Particularly important for cell proliferation.
Some act on many cell types, some have restricted targets.
They are polypeptides that act on cell surface receptors.
Coded by proto-oncogenes.
They bind to specific receptors and stimulate transcription of genes that regulate the entry of the cell into the cell cycle and the cell’s passage through it.
What processes do growth factors affect?
Cell proliferation and inhibition
Locomotion
Contractility
Differentiation
Viability
Activation
Angiogenesis
Give some examples of growth factors
Epidermal growth factor: mitogenic for epithelial cells, hepatocytes and fibroblasts; produced by keratinocytes and macrophages and inflammatory cells; binds to epidermal growth factor receptor (EGFR)
Vascular endothelial growth factor: potent inducer of blood vessel development (vasculogenesis) and role in growth of new blood vessels (angiogenesis) in tumours, chronic inflammation and wound healing
Platelet-Derived Growth Factor: stored in platelet alpha granules and released on platelet activation; also produced by macrophages, endothelial cells, smooth muscle cells and tumour cells; causes migration and proliferation of fibroblasts, smooth muscle cells and monocytes.
Granulocyte Colony-Stimulating Factor - useful clinically in chemotherapy where function of bone marrow is impaired as GCSF stimulates bone marrow to produce granulocytes particularly neutrophils.
What happens when a cell receives an instruction to divide?
The cell enters the cell cycle.
After completion the cell either restarts from G1 or exits (enters G0) until further growth signals occur.
Cells in G0 can undergo terminal differentiation.
Increased growth of a tissue occurs either by shortening the cell cycle or by conversion of quiescent cells to proliferating cells by making them enter the cell cycle.
Only mitosis is distinctive under light microscopy. The rest of the cell cycle is called Interphase.
How is cell cycle progression controlled?
Controlled by key “checkpoints” which sense damage to DNA and ensures cells with damaged DNA do not replicate.
The Restriction (R) Point, towards the end of G1 is the most critical checkpoint and the majority of cells that pass the R point will complete the full cell cycle.
Passage beyond the R point is governed by the phosphorylation of the Retinoblastoma Protein (pRb).
The R point is the most commonly altered checkpoint of the cell cycle in cancer cells.
What does Checkpoint Activation involve?
The p53 protein which delays the cell cycle and triggers DNA repair mechanisms or apoptosis if the DNA cannot be repaired.
Defective cell cycle checkpoints are a major cause of genetic instability in cancer cells.
Progression through the cell cycle, particularly the G1/S transition is tightly regulated by proteins including cyclins and associated enzymes called cyclin-dependent kinases (CDKs). CDKs become active by binding to and complexing with cyclins.
What do activated CDKs do?
They drive the cell cycle by phosphorylating proteins e.g. Retinoblastoma susceptibility (RB) protein, which are critical for progression of the cell to the next stage of the cell cycle.
The activity of cyclin-CDKS complexes is tightly regulated by CDK inhibitors.
Some growth factors work by stimulating the production of cyclins and some work by shutting off production of CDK inhibitors.
How can Cell Populations be classified?
Labile
Stable
Permanent
What is meant by Labile cells?
E.g. Surface epithelia such as epidermis and gut epithelium, bone marrow
Normal state is active cell division
Usually rapid proliferation - to replenish losses.
What is meant by Stable cells?
E.g. Liver hepatocytes, bone osteoblasts, fibroblasts, smooth muscle cells cells, vascular endothelial cells
They are in G0 (resting state) but can enter (G1). For them to do so requires the activation of a large number of genes e.g. Proto-oncogenes, genes required for ribosome synthesis and protein translation.
Speed of regeneration is variable
What is meant by Permanent cells?
E.g. Brain neurones, cardiac and skeletal muscle.
The mature cells have left the cell cycle and cannot replicate.
If neurones are destroyed the tissue space is filled by glial cells.
Skeletal muscle only has a very limited regenerative capacity through stem cells attached to the endomysial sheath.
No stem cells represent in cardiac muscle so damage to the heart e.g. Myocardial infarction, heals with a scar.
Describe stem cells in the different types of cell populations
Stem cells have prolonged proliferative activity and show asymmetric replication (one of the daughter cells remains as a stem cell while the other differentiates into a mature non-dividing cell).
Labile: stem cells divide persistently to replenish losses.
Stable: stem cells are normally quiescent or proliferate very slowly, however they can proliferate persistently when required.
Permanent: stem cells are present but cannot mount an effective proliferative response to significant cell loss)
How are embryonic stem cells different to adult stem cells?
They are pluripotent and can give rise to any of the tissues of the human body.
Adult stem cells are lineage specific - can usually only give rise to one type of adult cell.
Explain about Regeneration
This is the replacement of cell losses by identical cells in order to maintain the size of a tissue or organ.
It can occur after injury if the harmful agent is removed and if there is limited tissue damage
However if the harmful agent persists, if there is extensive tissue damage or if the damage occurs to a permanent tissue, then regeneration and resolution is not possible and instead the tissue will heal with a scar.
Regeneration is seen in the liver after partial hepatectomy and in the replacement of the epidermis by keratinocytes, following a skin burn.
What is meant by Reconstitution?
Replacement of a lost part of the body (requires the coordinated regeneration of several types of cells).
Explain about Hyperplasia
An increase in tissue or organ size due to increased cell numbers.
It is a response to increased functional demand and/or external stimulation.
Can only occur in labile or stable cell populations and it remains under physiological control and is reversible (compared to neoplasia, which is not under physiological control and is usually irreversible).
Biologically similar to regeneration but rather than replacing what is lost, results in an increase in tissue/organ.
What is Physiological Hyperplasia?
Either hormonal, when the result is an increased in functional capacity or compensatory, when there is an increase in tissue mass after tissue damage.
Physiological hyperplasia examples include bone marrow production of erythrocytes in response to low oxygen and the proliferation of the endometrium under the influence of oestrogen.
What is Pathological Hyperplasia?
Hyperplasia can occur secondary to a pathological cause - the cellular proliferation is a normal response to an abnormal condition (unlike neoplasia in which the proliferation itself is abnormal).
Pathological hyperplasia usually occurs secondary to excessive hormonal stimulation or growth factor production.
Neoplasia is a risk in hyperplastic tissue as the repeated cell divisions that occur in hyperplasia expose the cell to the risk of mutations.
Pathological hyperplasia examples include epidermal thickening in chronic eczema or psoriasis and enlargement of the thyroid gland in response to iodine deficiency.
Explain about Hypertrophy
Increase in tissue or organ size due to an increase in cell size without an increased in cell numbers.
Cells become bigger because they contain more structural components (not due to cell swelling).
Occurs in many tissues especially in permanent cell populations as these cell populations have little or no replicative potential and so an increase in organ size must occur via hypertrophy.
Like hyperplasia it is a response to increased functional demand and/or hormonal stimulation.
Hypertrophic cells contain more structural compounds and hence the cellular workload is shared by a greater mass of cellular components.
In cells where division is possible, hypertrophy may still occur but often occurs alongside hyperplasia.
In such cases both hyperplasia and hypertrophy are triggered by the same stimulus.
