Cellular Growth, Differentiation, and Adaptation Flashcards
Repair of tissue generally occurs by one of what two processes?
- regeneration (make new cells of same type as those lost)
- replacement by CT (i.e. fibrosis, fill in space previously occupied by lost cells with scar)
Cell growth and proliferation capabilities are important for regeneration. These are affected by a variety of stimulators and inhibitors, most important are factors for what?
- bringing cells from the G0 state into the cell cycle
- activating/recruiting stem cells
What are the three categories of cells based on proliferative capabilities?
- labile
- stable
- permanent
Labile
- continuously dividing; therefore continuously in cell cycle
- replace cells being lost constantly
e. g. stratified squamous epithelial cells of skin; columnar epithelium of GI tract; hematopoietic cells
Stable
- quiescent
- normally at low replication level (mostly in G0) but may be stimulated to division by reaction to injury, going from G0 into G1
e. g., hepatocytes; vascular endothelial cells
Permanent
- non-dividing
- have permanently left cell cycle and cannot undergo mitotic division
e. g. CNS neurons
Successful reconstruction of tissue by regeneration of labile or stable cells requires preservation of what?
the stroma architectural support network (intact basement membrane)
Stem cells
- have capacity for self-renewal and can generate differentiated cell lineages
- maintained throughout the life of an organism by asymmetric replication or stochastic differentiation
Cells respond to external signals delivered through what routes?
- autocrine (act on self)
- paracrine (act in neighborhood)
- endocrine (act remotely)
Signals act on molecular pathways in the target cells with the end result being cell growth, differentiation, or adaptation. This frequently involves a change in what?
in gene expression that is mediated by the activation or repression of transcription factor(s)
The unusual proliferation of cancer cells frequently involves what?
dysregulation of a signaling pathway
There are three major classes of cell surface receptors that initiate signal transduction pathways. What are they?
- receptor tyrosine kinases
- cytokine receptors
- G-protein coupled receptors (largest class)
Receptor tyrosine kinases
- have intrinsic kinase activity and undergo autophosphorylation upon ligand binding
ex:
- epidermal growth factor receptor (EGF)
- fibroblast growth factor receptor (FGF)
- vascular endothelial growth factor receptor (VEGF)
- platelet-derived growth factor (PDGF)
- transforming growth factor Beta (TGF-Beta)
Clinical correlate of receptor tyrosine kinases
The proliferation of vascular cells seen in glioblastome (an aggressive type of brain cancer) is attributed to VEGF production by the malignant cells. The progressive fibrosis seen in the autoimmune disorder, systemic sclerosis, is associated with abnormal tissue levels of TGF-Beta.
What specific aberration in a cell signaling pathway is seen in glioblastome multiforme?
- glioblastome is an aggressive type of brain cancer
- attributed to VEGF production by the malignant cells
*VEGF is a receptor tyrosine kinase
What specific aberration in a cell signaling pathway is seen in systemic sclerosis?
- systemic sclerosis is an autoimmune disorder resulting in fibrosis
- it is associated with abnormal tissue levels of TGF-Beta
*TGF-Beta is a receptor tyrosine kinase
Cytokine receptors
- lack intrinsic kinase activity (unlike receptor tyrosine kinases) and rely on cytosolic proteins called Janus kinases to phosphorylate the receptor
- this type of signaling is very common in hematopoietic cells
ex:
- erythropoietin (Epo) receptor
- granulocyte colony stimulating factor (G-CSF)
- interleukin (IL) receptors
- Interferon (IFN) receptors
What are Janus kinases?
cytosolic proteins that phosphorylate cytokine receptors
Clinical correlate of cytokine receptors
The bone lesions seen in multiple myeloma have been linked to inappropriate IL-6 signaling through a JAK/STAT pathway.
What specific aberration in a cell signaling pathway is seen in myeloma?
- myeloma result in bone lesions
- linked to inappropriate IL-6 signaling through a JAK/STAT pathway
*IL-6 is a cytokine receptor
G-protein coupled receptors
- largest class of receptors
- the cytoplasmic portion of these receptors interacts with GTP-binding proteins
ex are receptors for:
- small biogenic amines like histamine neurotransmitter peptides like bradykinin
- parathyroid hormone
- many pharmaceutical drugs
The underlying mechanism of aberrant proliferation in cancer can involve points in the signal transduction pathways that are downstream of the above receptors.
Give some examples
- PI-3 kinase pathway via Akt
- MAP kinase pathway via RAS/RAF/MEK/ERK
- Inositol triphosphate pathway via Phospholipase Cγ / IP3/ DAG/ Ca2+ release
- Janus kinase pathways via STATS (signal transducers and activators of transcription)
- G-protein coupled pathways via cAMP
What are different methods of inhibition of cell growth?
- contact inhibition (local control of cell growth)
- signal transduction pathways include mechanisms for turning signaling back off
- some of the proteins encoded by tumor suppressor genes function to turn signaling off
Known inhibitors of growth signaling include:
- Neurofibromin 1 and 2
- TGF-Beta
- WT-1
- Interferon-Beta
Loss of certain tumor suppressor genes (anti-oncogenes) are associated with what?
uncontrolled growth of neoplasms
Neurofibromatosis Type 1
How does this relate to control of cell growth?
- syndrome seen in individuals who inherit one mutant allele of the NF1 gene that encodes neurofibromin 1 (inhibitor of growth signaling)
- benign neurofibromas develop upon inactivation of the second copy of the gene
- neurofibromin 1 is a GTPase-activating protein (GAP) and converts Ras from the active form to the inactive form
The extracellular matrix is composed of what?
- fibrous structured proteins (collagen and elastin)
- matrix of adhesive glycoproteins (immunoglobulin family cell adhesion molecules, cadherins, integrins, and selectins)
- a gel of proteoglycans and hyaluronan
The ECM forms a significant volume of any tissue and severs several key functions including:
- sequesters molecules such as water and minerals required by the tissue
- serves as a reservoir of growth factors
- provides a substratum for cells to adhere, migrate, and proliferate (basement membrane)
For tissues capable of cell division, if the basement membrane is not intact, how does repair occur?
via fibrosis
What does cellular adaptation allow for?
response of cell/tissue to stress
What are the two general patterns of cellular adaptation?
- up- or down-regulation of cell receptors
- qualitative or quantitative changes in protein synthesis
Hyperplasia
define, give causes and examples
- increase in number of cells as a result of cell proliferation, often with increase in the size of the tissue or organ
Causes:
- hormonal stimulation or increased functional demand
- may be PHYSIOLOGIC (e.g., proliferation of endometrial glands due to normal estrogenic stimulation during menstrual cycle; proliferation of glandular epithelium of female breast at puberty and during pregnancy)
- may be COMPENSATORY, which occurs in an organ following loss of part of its normal volume (such as in the liver following partial hepatectomy)
- may be PATHOLOGIC, caused by excesses of hormones or growth factors acting on target cells (e.g., proliferation of prostatic glands in older men)
*pathologic forms of hyperplasia may provide a setting for cancer or pre-cancer
Partial hepatectomy as a model for hyperplasia
- “Priming” signals (breakdown of extracellular matrix) activate early growth response genes (proto-oncogenes)
- Proto-oncogenes (c-fos, c-myc, c-jun) initiate liver cell
growth - Growth factors & cytokines (TFG-α, IL-6, TNF-α and hepatocyte growth factor) promote liver cell mitosis
- Hormones (insulin) may facilitate
- Growth inhibitors stop liver cell proliferation after liver mass is restored
*within 48 hours after partial hepatectomy, there are 10x more liver cells replicating than normal
Hypertrophy
define, give causes and examples
- increase in cell size, generally with increase in organ size
- Hypertrophy and hyperplasia may occur together; however, in non-dividing cells, only hypertrophy occurs (DNA content of such cells may increase, but they do not undergo mitosis)
Causes: increased hormonal stimulation or functional demand
- PHYSIOLOGIC: (e.g., increase in smooth muscle of uterus under hormonal influences of pregnancy); involves signaling through the PI-3 kinase/Akt pathway
- PATHOLOGIC: (e.g., increase in myocardial volume because of elevated systemic vascular pressure in hypertension, against which the heart must pump); involves signaling through G protein-coupled receptors
Cellular mechanisms related to cardiac hypertrophy
- Signals may be mechanical (stretch) or trophic (vasoactive agents)
- Increased protein synthesis (more myofilaments)
- Long-term adaptation can involve a change in type of contractile proteins
Atrophy
define, give causes and examples
- decrease in cell volume (resulting from decreased protein synthesis and increased protein degradation) or cell number (due to apoptosis)
- Atrophy represents a new state of equilibrium for the cell, at which the cell size/function are better suited to its resources and demands (This represents a new balance of protein synthesis vs. degradation)
Causes: may be physiologic or pathologic
- Decreased workload
- Loss of innervation
- Diminished blood supply (relative ischemia rather than total ischemia)
- Decreased nutritional resources (e.g., chronic over-production of tumor necrosis factor in cachexic cancer patients)
- loss of endocrine stimulation
- aging
- local pressure
Examples:
- Loss of muscle mass with immobilization or following denervation
- cerebral atrophy in aging
*Degraded cell constituents are contained in autophagic vacuoles; may persist indefinitely as residual bodies (i.e., lipofuscin pigment which may impart brown color to entire organ - brown atrophy)
Clinical correlate of Atrophy
Cystic Fibrosis
Cystic fibrosis is a disorder of ion transport in epithelial cells that affects fluid secretion from glands. The disruption of normal ion exchange leads to plugging of the exocrine pancreas ducts and eventually, pressure atrophy of the epithelial cells. The clinical consequence is gastrointestinal and nutritional abnormalities.
Metaplasia
define, give causes and examples
- replacement of one differentiated cell type (frequently epithelial but may be mesenchymal) by another differentiated cell type
- The morphology and architecture of metaplastic cells resembles the new tissue type (i.e., they have the NORMAL APPEARANCE for that tissue)
- Progenitor (or stem) cells expressing new cell characteristics that are better adapted to an altered tissue environment (generally, an adaptive response to stress); mature, fully differentiated cells do not change their composition
- Most common form of metaplasia is the transformation of columnar epithelium to squamous epithelium
Examples:
- Metaplasia of respiratory epithelium to squamous
epithelium in airways of smokers
- metaplasia of squamous esophageal epithelial cells to intestinal-like columnar cells (Barrett esophagus)
Clinical correlate of Metaplasia
Barrett esophagus
- metaplasia of squamous esophageal epithelial cells to intestinal-like columnar cells (Barrett esophagus)
- Patients diagnosed with >3 cm of Barrett esophagus have a 30-40x increased rate of developing esophageal adenocarcinoma and merit close monitoring.
Dysplasia
- indicates loss in control of normal cell growth, with possible progression to neoplasia
- Dysplastic cells often display considerable cellular pleomorphism (variation in size and shape), alteration in nuclear size, shape, and chromatin density of individual cells; with disturbance of normal orderly architectural arrangement of cells (“architectural anarchy”)
Cause: generally is a response to chronic injury or stimulation; may be reversible
Examples:
- Dysplasia of airway lining epithelium in smokers (usually occurs on a background of squamous metaplasia)
- dysplasia of uterine cervical epithelium (also with background metaplasia)
- a tissue can become dysplastic without going through metaplasia first (e.g., prostatic intraepithelial neoplasia - PIN lesion)
- when dysplastic changes are marked and involve the entire thickness of epithelium, the lesion is considered to be a pre-invasive neoplasm and referred to as ‘carcinoma in situ’ (in site = in its original place)
Neoplasia
- abnormal proliferation of cells whose growth is uncoordinated with respect to host’s needs, and generally continues despite removal of stimuli
- implies autonomous cellular proliferation, without normal response to control
- ultimately, neoplastic growth may injure or kill the host
- “Cancer” is a generic term for malignant neoplasms
Increase in cell size, generally with increase in organ size. What is this?
hypertrophy
replacement of one differentiated cell type (frequently epithelial but may be mesenchymal) by another differentiated cell type
metaplasia
decrease in cell volume (resulting from decreased protein synthesis and increased protein degradation) or cell number (due to apoptosis)
atrophy
abnormal proliferation of cells whose growth is uncoordinated with respect to host’s needs, and generally continues despite removal of stimuli
neoplasia
increase in number of cells as a result of cell proliferation, often with increase in the size of the tissue or organ
hyperplasia
indicates loss in control of normal cell growth, with possible progression to neoplasia
dysplasia
