CANCER INVASION
cancer biology or molecular basis of cancer include the following item Cancer Invasion
first what are the tumour or neoplasm progression means
Neoplastic progression is a term that refers to the generation of sub-clone the tumour. These sub-clones occur by accumulation of further genetic mutations and have an increasingly aggressive phenotype, allowing invasion and metastasis to distant sites
Neoplastic or cancer invasion
The ability to invade and spread determines the difference between a benign and a
malignant phenotype
Invasion is due to
Changes in adhesion molecules by the following methods
1- Cell-to-cell interactions
2- Cell-to-matrix interactions
Proteolysis , Migration and chemotaxis
Changes in adhesion by
Loss of cell-to-cell adhesion
E-cadherin is the major cell adhesion molecule in epithelia; these cell adhesion
are down-regulated in several carcinomas
Loss of cell-to-matrix interactions
Integrins and cadherins bind epithelial cells to the basement membrane; loss of associated with increased invasive potential. In particular the integrin alphaV Beta 3 mediates adhesion to laminin, fibronctin and fibrinogen. It is overexpressed on the basemen membrane of' new blood vessels and its activation results in increased cell motility and proteolysis
cell adhesion to basement membrane normal epithelial cells laminin receptors are expressed on one side of the cell and bind to laminin on the basement membrane: tumour cells have increased numbers of laminin
receptors on all sides
proteolysis
degradation of collagen by by proteolytic enzymes is a vital step. Up-regulation of proteolytic
enzymes groups; the matrix metalloproteinases (MMPs) and plasminogen activators (tPA
correlates with increased invasivenesse
-tumour cell migration
tumour cells coordinate proteolysis with migration. Migration consists of intermittent and limited attachment and detachment. The direction of migration is stimulated by chemotaxis as follow
host growth factors eg insulin-like growth factors (lGF), HGF, FGF, and TGF-beta tumour-secreted factors called autocrine motility factors
gradient of degraded extracellular matrix components
Cancer invasion also can be explained as follow
A feature of malignant cells is their ability to invade the surrounding normal tissue, Tumors in which the malignant cells appear to lie exclusively above the basement membrane are referred to as in situ cancer. while tumors in which the malignant cells are demonstrated to breach the basement membrane., penetrating into surrounding stroma, are termed invasive cancer. The ability to invade involves changes in adhesion, initiation of motility. and proteolysis of the extracellular matrix ECM
Cell-to-cell adhesion in normal cells involves interactions be
tween cell-surface proteins. Calcium adhesion molecules of the cadherin family (E-cadherin. P-cadherin, and N-cadherin) are thought to enhance the cells' ability to bind to one another and suppress invasion. Migration occurs when cancer cells penetrate and attach to the basal matrix of the tissue being invaded; this allows the cancer cell to pull itself forward within the tissue. Attachment to glycoproteins of the ECM such as fibronectin, laminin, and collagen is mediated hy tumor cell integrin receptors. lntegrins are a family of glycoproteins that form heterodimeric receptors for ECM molecules. The integrins can form at least 25 distinct pairings of its alpha and beta subunits. and each pairing is specific for a unique set of ligands. For example. alpha V beta 1 selectively binds fibronectin. In addition to regulating cell adhesion to the ECM, integrins relay molecular signals regarding the cellular environment that influence shape. survival. proliferation. gene transcription, and migration.
Cell motility has been linked to motility factors that convert the
cell to a motile status. which is characterized by the appearance of membrane ruffling. lamellae, and pseudopodia. Factors that are thought to play a role in cancer cell motility include autocrine motility factor. autotaxin, scatter factor (also known as hepatocyte growth factor). TGF-alpha. EGF. and insulin-like growth factors
Serine. cysteine. and aspartic proteinases and matrix metallopro reinases (MMPs) have all been implicated in cancer invasion.Urokinase and tissue plasminogen activators (uPA and tPA) are serine proteases that convert plasminogen into plasmin. Plasmin. in retum, can degrade several ECM components, including fibrin. fibronectin. laminin. and proteoglycans. Plasmin also may activate several MMPs. such as MMP-I. MMP-3. and MMP-9 uPA has been more closely correlated with tissue invasion and metastasis than tPA. Plasminogen activate- inhibitors (PAI-l and PAI-2) are produced in tissues and counteract the activity of plasminogen activators.
MMPs comprise a family of metal-dependent endopeptidases that includes more than 21 types. Upon ectivation, MMPs degrade a variety of ECM components, Although MMPs are often referred to by their common names. which reflect the ECM component they have specificity for a sequential numbering system has been adopted for standardization MMPs are up regulated in almost every type of cancer some of the MMPs are expressed by cancer cells while others are expressed by the tumour stromal cells it is exert it is
effects by cleaving not only structural components of the
ECM but also growth factor-binding proteins, growth factor precursors. cell adhesion molecules, and other proteinases. The activity of MMPs is regulated by their endogenous inhibitors. including alpha2-macroglobulin. membrane-bound inhibitors RECK (reversion inducing cysteine-rich protein with kazal domains). and tissue inhibitors of MMPs (TIMP-I. -2.- 3. and -4) . thus regulation of MMPs occurs at three levels: alterations of gene expression. activation of latent zymogens, and inhibition by endogenous inhibitors. Alterations of all three levels of control have been associated with tumor progression
tags:cancer,invasion
first what are the tumour or neoplasm progression means
Neoplastic progression is a term that refers to the generation of sub-clone the tumour. These sub-clones occur by accumulation of further genetic mutations and have an increasingly aggressive phenotype, allowing invasion and metastasis to distant sites
Neoplastic or cancer invasion
The ability to invade and spread determines the difference between a benign and a
malignant phenotype
Invasion is due to
Changes in adhesion molecules by the following methods
1- Cell-to-cell interactions
2- Cell-to-matrix interactions
Proteolysis , Migration and chemotaxis
Changes in adhesion by
Loss of cell-to-cell adhesion
E-cadherin is the major cell adhesion molecule in epithelia; these cell adhesion
are down-regulated in several carcinomas
Loss of cell-to-matrix interactions
Integrins and cadherins bind epithelial cells to the basement membrane; loss of associated with increased invasive potential. In particular the integrin alphaV Beta 3 mediates adhesion to laminin, fibronctin and fibrinogen. It is overexpressed on the basemen membrane of' new blood vessels and its activation results in increased cell motility and proteolysis
cell adhesion to basement membrane normal epithelial cells laminin receptors are expressed on one side of the cell and bind to laminin on the basement membrane: tumour cells have increased numbers of laminin
receptors on all sides
proteolysis
degradation of collagen by by proteolytic enzymes is a vital step. Up-regulation of proteolytic
enzymes groups; the matrix metalloproteinases (MMPs) and plasminogen activators (tPA
correlates with increased invasivenesse
-tumour cell migration
tumour cells coordinate proteolysis with migration. Migration consists of intermittent and limited attachment and detachment. The direction of migration is stimulated by chemotaxis as follow
host growth factors eg insulin-like growth factors (lGF), HGF, FGF, and TGF-beta tumour-secreted factors called autocrine motility factors
gradient of degraded extracellular matrix components
Cancer invasion also can be explained as follow
A feature of malignant cells is their ability to invade the surrounding normal tissue, Tumors in which the malignant cells appear to lie exclusively above the basement membrane are referred to as in situ cancer. while tumors in which the malignant cells are demonstrated to breach the basement membrane., penetrating into surrounding stroma, are termed invasive cancer. The ability to invade involves changes in adhesion, initiation of motility. and proteolysis of the extracellular matrix ECM
Cell-to-cell adhesion in normal cells involves interactions be
tween cell-surface proteins. Calcium adhesion molecules of the cadherin family (E-cadherin. P-cadherin, and N-cadherin) are thought to enhance the cells' ability to bind to one another and suppress invasion. Migration occurs when cancer cells penetrate and attach to the basal matrix of the tissue being invaded; this allows the cancer cell to pull itself forward within the tissue. Attachment to glycoproteins of the ECM such as fibronectin, laminin, and collagen is mediated hy tumor cell integrin receptors. lntegrins are a family of glycoproteins that form heterodimeric receptors for ECM molecules. The integrins can form at least 25 distinct pairings of its alpha and beta subunits. and each pairing is specific for a unique set of ligands. For example. alpha V beta 1 selectively binds fibronectin. In addition to regulating cell adhesion to the ECM, integrins relay molecular signals regarding the cellular environment that influence shape. survival. proliferation. gene transcription, and migration.
Cell motility has been linked to motility factors that convert the
cell to a motile status. which is characterized by the appearance of membrane ruffling. lamellae, and pseudopodia. Factors that are thought to play a role in cancer cell motility include autocrine motility factor. autotaxin, scatter factor (also known as hepatocyte growth factor). TGF-alpha. EGF. and insulin-like growth factors
Serine. cysteine. and aspartic proteinases and matrix metallopro reinases (MMPs) have all been implicated in cancer invasion.Urokinase and tissue plasminogen activators (uPA and tPA) are serine proteases that convert plasminogen into plasmin. Plasmin. in retum, can degrade several ECM components, including fibrin. fibronectin. laminin. and proteoglycans. Plasmin also may activate several MMPs. such as MMP-I. MMP-3. and MMP-9 uPA has been more closely correlated with tissue invasion and metastasis than tPA. Plasminogen activate- inhibitors (PAI-l and PAI-2) are produced in tissues and counteract the activity of plasminogen activators.
MMPs comprise a family of metal-dependent endopeptidases that includes more than 21 types. Upon ectivation, MMPs degrade a variety of ECM components, Although MMPs are often referred to by their common names. which reflect the ECM component they have specificity for a sequential numbering system has been adopted for standardization MMPs are up regulated in almost every type of cancer some of the MMPs are expressed by cancer cells while others are expressed by the tumour stromal cells it is exert it is
effects by cleaving not only structural components of the
ECM but also growth factor-binding proteins, growth factor precursors. cell adhesion molecules, and other proteinases. The activity of MMPs is regulated by their endogenous inhibitors. including alpha2-macroglobulin. membrane-bound inhibitors RECK (reversion inducing cysteine-rich protein with kazal domains). and tissue inhibitors of MMPs (TIMP-I. -2.- 3. and -4) . thus regulation of MMPs occurs at three levels: alterations of gene expression. activation of latent zymogens, and inhibition by endogenous inhibitors. Alterations of all three levels of control have been associated with tumor progression
tags:cancer,invasion
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