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 Metaplasia?
Reversible change of one differentiated cell type to another.
Often seen in epithelial tissues and is due to altered stem cell differentiation.
Occurs secondary to signals from molecules such as cytokines and growth factors.
The result of metaplasia is to change one epithelium to another more suited to withstand an altered environment.
No metaplasia across germ layers. Occurs only in cells that can replicate.
