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![2-Local degradation of the basement
membrane and interstitial connective tissue
Elaboration of proteases by
– Tumor cells themselves or
– Stromal cells [induced by tumor cells]
Many different families of proteases
– Matrix metalloproteinases (MMPs)
– Cathepsin D &
– Urokinase plasminogen activator](https://image.slidesharecdn.com/invasionmetastasis-csbrp-151030054507-lva1-app6891/85/Invasion-amp-metastasis-csbrp-20-320.jpg)
![3 - Attachment to novel ECM components
• Normal epithelial cells have receptors, such as integrins,
for basement membrane laminin and collagens that are
polarized at their basal surface
– These receptors help to maintain the cells in a resting,
differentiated state
• Loss of adhesion in normal cells leads to induction of
apoptosis [tumor cells are resistant to this form of cell
death]
• The matrix itself is modified in ways that promote
invasion and metastasis
– Eg: cleavage of the basement membrane proteins collagen IV
and laminin by MMP2 or MMP9 generates novel sites that bind
to receptors on tumor cells and stimulate migration](https://image.slidesharecdn.com/invasionmetastasis-csbrp-151030054507-lva1-app6891/85/Invasion-amp-metastasis-csbrp-23-320.jpg)
Uploaded byPrasad CSBR
Invasion & metastasis csbrp
This document discusses the process of invasion and metastasis in malignant tumors. It is divided into two phases: 1) Invasion of the extracellular matrix (ECM) and 2) Vascular dissemination, homing of tumor cells, and colonization. Invasion of the ECM initiates the metastatic cascade and is an active, multi-step process involving changes in tumor cell interactions, degradation of the ECM, attachment to novel ECM components, and migration of tumor cells. Genetic changes can bring about metastatic potential in tumors by altering genes that regulate epithelial-to-mesenchymal transition or function as "metastasis oncogenes" or "metastatic suppressors". Common sites of hematogenous metastatic deposits include the
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Invasion & metastasis csbrp
- 1. INVASION & METASTASISINVASION& METASTASIS Dr.CSBR.Prasad, M.D.,
- 2. Invasion and metastasisare biologic hallmarks of malignant tumors • For tumor cells to break loose from a primary mass, enter blood vessels or lymphatics, and produce a secondary growth at a distant site, they must go through a series of step (the metastatic cascade): Divided into two phases: 1. Invasion of the extracellular matrix (ECM) 2. Vascular dissemination, homing of tumor cells, and colonization
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- 9. The metastatic cascadeThemetastatic cascade Sequential steps involved in the hematogenous spread of a tumor
- 10. Invasion of ExtracellularMatrix Two types of ECM: 1. Basement membrane (BM) and 2. Interstitial connective tissue Composition: ECM is made up of collagens, glycoproteins, and proteoglycans 1. A carcinoma must first breach the underlying BM 2. Then traverse the interstitial connective tissue, and 3. Gain access to the circulation by penetrating the vascular BM This process is repeated in reverse when tumor cell emboli extravasate at a distant site
- 11. Invasion of ExtracellularMatrix Invasion of the ECM initiates the metastatic cascade and is an active process that can be resolved into several steps 1. Changes (“loosening up”) of tumor cell- cell interactions 2. Degradation of ECM 3. Attachment to novel ECM components 4. Migration of tumor cells
- 12. Sequence of eventsin the invasion of epithelial basement membranes by tumor cells: Tumor cells detach from each other because of reduced adhesiveness, then secrete proteolytic enzymes, degrading the basement membrane. Binding to proteolytically generated binding sites and tumor cell migration follow
- 13. Invasion of ExtracellularMatrix Invasion of the ECM initiates the metastatic cascade and is an active process that can be resolved into several steps 1. Changes (“loosening up”) of tumor cell- cell interactions 2. Degradation of ECM 3. Attachment to novel ECM components 4. Migration of tumor cells
- 14. 1-Dissociation of cellsfrom one another (“loosening up”) of tumor cell-cell interactions As a result of alterations in intercellular adhesion molecules
- 15. Normal cells arebound together by adhesion molecules • Cell-cell interactions are mediated by the cadherin family of transmembrane glycoproteins • Intracellularly the E-cadherins are connected to β-catenin and the actin cytoskeleton
- 17. Tumors with down-regulated E-cadherinexpression Seen in several epithelial tumors, including adenocarcinomas of the colon and breast • This down-regulation reduces the ability of cells to adhere to each other and facilitates their detachment from the primary tumor • The normal function of E-cadherin is dependent on its linkage to catenins • In some tumors E-cadherin is normal, but its expression is reduced because of mutations in the gene for α catenin
- 19. Invasion of ExtracellularMatrix Invasion of the ECM initiates the metastatic cascade and is an active process that can be resolved into several steps 1. Changes (“loosening up”) of tumor cell- cell interactions 2. Degradation of ECM 3. Attachment to novel ECM components 4. Migration of tumor cells
- 20. 2-Local degradation ofthe basement membrane and interstitial connective tissue Elaboration of proteases by – Tumor cells themselves or – Stromal cells [induced by tumor cells] Many different families of proteases – Matrix metalloproteinases (MMPs) – Cathepsin D & – Urokinase plasminogen activator
- 21. MMPs Tumors either elaboratelarge quantities of MMPs or they may reduce the concentrations of MMP-inhibitors They regulate tumor invasion by: • Dissolving components of the BM & interstitial matrix • Releasing ECM-sequestered growth factors – Cleavage products of collagen and proteoglycans also have chemotactic, angiogenic, and growth-promoting effects • Eg: MMP9 is a gelatinase that cleaves type IV collagen of the epithelial and vascular basement membrane and also stimulates release of VEGF from ECM-sequestered pools Eg: Benign tumors of the breast, colon, and stomach show little type IV collagenase activity, whereas their malignant counterparts overexpress this enzyme
- 22. Invasion of ExtracellularMatrix Invasion of the ECM initiates the metastatic cascade and is an active process that can be resolved into several steps 1. Changes (“loosening up”) of tumor cell- cell interactions 2. Degradation of ECM 3. Attachment to novel ECM components 4. Migration of tumor cells
- 23. 3 - Attachmentto novel ECM components • Normal epithelial cells have receptors, such as integrins, for basement membrane laminin and collagens that are polarized at their basal surface – These receptors help to maintain the cells in a resting, differentiated state • Loss of adhesion in normal cells leads to induction of apoptosis [tumor cells are resistant to this form of cell death] • The matrix itself is modified in ways that promote invasion and metastasis – Eg: cleavage of the basement membrane proteins collagen IV and laminin by MMP2 or MMP9 generates novel sites that bind to receptors on tumor cells and stimulate migration
- 24. Invasion of ExtracellularMatrix Invasion of the ECM initiates the metastatic cascade and is an active process that can be resolved into several steps 1. Changes (“loosening up”) of tumor cell- cell interactions 2. Degradation of ECM 3. Attachment to novel ECM components 4. Migration of tumor cells
- 25. 4 – Migrationof tumor cells - Locomotion • Tumor cells propel themselves through the degraded basement membranes and zones of matrix proteolysis • It involves many families of receptors and signaling proteins that eventually impinge on the actin cytoskeleton – Cells must attach to the matrix at the leading edge, detach from the matrix at the trailing edge, and contract the actin cytoskeleton to ratchet forward - Ameboid migration • Such movement are potentiated by tumor cell–derived cytokines – Cleavage products of matrix components (e.g., collagen, laminin) and some growth factors (e.g., IGFs I and II) have chemotactic activity for tumor cells • Stromal cells also produce paracrine effectors of cell motility – HGF–scatter factor, which bind to receptors on tumor cells – HGF–scatter factor is elevated at the advancing edges of the highly invasive brain tumor glioblastoma multiforme
- 26. Ameboid migration • Inthis type of migration the cell squeezes through spaces in the matrix instead of cutting its way through it • This ameboid migration is much quicker • Tumor cells are capable of switching between the two forms of migration, perhaps explaining the disappointing performance of MMP inhibitors in clinical trials
- 27. Molecular Genetics of MetastasisDevelopment
- 28. Malignant tumors havevaried metastatic potential Cancer with Low metastatic potential – Basal cell carcinoma Cancer with high malignant potential – Malignant melanoma •Why this variation? •What genetic changes bring about metastatic potential?
- 29. Several THEORIES havebeen proposed to explain how the metastatic phenotype arises? 1. The clonal evolution model – As mutations accumulate in cancer cells, the tumor become heterogeneous 1. Metastasis is the result of multiple abnormalities that occur in most of the cells in a primary tumor – “Metastasis signature” • It may involve the cancer cells or in the microenvironment 1. Background genetic variation in gene expression contributes to the generation of metastases 2. Tumors derive from rare tumor stem cells, metastases require the spread of the tumor stem cells themselves
- 30. Mechanisms of metastasisMechanismsof metastasis development within adevelopment within a primary tumor:primary tumor: A nonmetastatic primary tumor is shown (light blue) on the left side of all diagrams. Four models are presented: A, Metastasis is caused by rare variant clones that develop in the primary tumor; B, Metastasis is caused by the gene expression pattern of most cells of the primary tumor, referred to as a metastatic signature; C, A combination of A and B, in which metastatic variants appear in a tumor with a metastatic gene signature; D, Metastasis development is greatly influenced by the tumor stroma, which may regulate angiogenesis, local invasiveness, and resistance to immune elimination, allowing cells of the primary tumor, as in C, to become metastatic.
- 31. Are there geneswhose principal or sole contribution to tumorigenesis is to control metastasis? • genes that function as “metastasis oncogenes” or “metastatic suppressors” are rare • At least a dozen genes lost in metastatic lesions have been confirmed to function as “metastasis suppressors” • Their molecular functions are varied and not yet completely clear; however, most appear to affect various signaling pathways • Recent work has suggested that two miRNAs, mir335 and mir126, suppress the metastasis of breast cancer, while a second set (mir10b) promotes metastasis
- 32. Metastasis oncogenes • Genes:SNAIL and TWIST • Their primary function: is to promote epithelial- to-mesenchymal transition (EMT) In EMT: • Some epithelial markers like E-cadherin is down regulated and certain mesenchymal markers (e.g., vimentin and smooth muscle actin) are up- regulated – This favors the development of a promigratory phenotype that is essential for metastasis
- 33. Modes of Spread •Seeding the body cavities – The cavity most often involved is peritoneal cavity (Krukenberg tumor, pseudomyxoma peritonei) • Lymphatic spread – Most carcinomas – Deposits will be in the regional or distant nodes • Hematogenous (through blood stream) – most sarcomas and some carcinomas
- 34. Lymphatic Spread • Epithelialtumors (Carcinoma) spread by lymphatics • LN in natural route of lymphatic drainage (Eg: Breast – upper outer quadrant – axilla) • Effective barrier at least for some time
- 35. Hematogenous Spread • Mesenchymal tumors(Sarcoma) • Predominantly veins (RCC, HCC) • Lung, Liver & Vertebra
- 36. Common sites ofmetastatic deposits (hematogenous spread) • Liver • Bones • CNS • Lung
- 37. Some tumors prefercertain sites • Adrenals prefered by Br.carcinoma (Lung) • Bone metasizing tumors: – BK.Patil • Liver & bone by Neuroblastoma
- 38. Rare sites formets • Skeletal muscle • Spleen • Pancreas
- 39. Other mechanisms ofspread • Direct extension • Surgical or procedural transplantation (iatrogenic)
- 40. Unusual modes ofspread • Carcinomas arising close to vertebral column spread via paravertebral venous plexus giving rise to early bone metastasis • Renal cell carcinoma grows inside renal vein in a snake like fashion • Carcinoma lung gives rise to metastatic deposit in adrenals very frequently
- 41.
Editor's Notes
- #10 FIGURE 7-36 The metastatic cascade. Sequential steps involved in the hematogenous spread of a tumor.
- #13 FIGURE 7-37 A–D, Sequence of events in the invasion of epithelial basement membranes by tumor cells. Tumor cells detach from each other because of reduced adhesiveness, then secrete proteolytic enzymes, degrading the basement membrane. Binding to proteolytically generated binding sites and tumor cell migration follow.
- #14 Now we are going to deal with the first step: Changes (“loosening up”) of tumor cell-cell interactions.
- #15 Dissociation of cells from one another is often the result of alterations in intercellular adhesion molecules. Normal cells are neatly glued to each other and their surroundings by a variety of adhesion molecules.[111] Cell-cell interactions are mediated by the cadherin family of transmembrane glycoproteins. E-cadherins mediate homotypic adhesions in epithelial tissue, thus serving to keep the epithelial cells together and to relay signals between the cells; intracellularly the E-cadherins are connected to β-catenin and the actin cytoskeleton. In several epithelial tumors, including adenocarcinomas of the colon and breast, there is a down-regulation of E-cadherin expression. Presumably, this down-regulation reduces the ability of cells to adhere to each other and facilitates their detachment from the primary tumor and their advance into the surrounding tissues. E-cadherins are linked to the cytoskeleton by the catenins, proteins that lie under the plasma membrane (see Fig. 7-33 ). The normal function of E-cadherin is dependent on its linkage to catenins. In some tumors E-cadherin is normal, but its expression is reduced because of mutations in the gene for α catenin.
- #16 Normal cells are neatly glued to each other and their surroundings by a variety of adhesion molecules.[111] Cell-cell interactions are mediated by the cadherin family of transmembrane glycoproteins. E-cadherins mediate homotypic adhesions in epithelial tissue, thus serving to keep the epithelial cells together and to relay signals between the cells; intracellularly the E-cadherins are connected to β-catenin and the actin cytoskeleton.
- #17 This image is shown to highlight the cell to cell interaction by cadherin, beta-catenin and cytoskeleton.
- #18 In several epithelial tumors, including adenocarcinomas of the colon and breast, there is a down-regulation of E-cadherin expression. Presumably, this down-regulation reduces the ability of cells to adhere to each other and facilitates their detachment from the primary tumor and their advance into the surrounding tissues. E-cadherins are linked to the cytoskeleton by the catenins, proteins that lie under the plasma membrane (see Fig. 7-33 ). The normal function of E-cadherin is dependent on its linkage to catenins. In some tumors E-cadherin is normal, but its expression is reduced because of mutations in the gene for α catenin.
- #20 Next step in invasion of ECM is degradation of ECM.
- #21 The second step in invasion is local degradation of the basement membrane and interstitial connective tissue. Tumor cells may either secrete proteolytic enzymes themselves or induce stromal cells (e.g., fibroblasts and inflammatory cells) to elaborate proteases. Many different families of proteases, such as matrix metalloproteinases (MMPs), cathepsin D, and urokinase plasminogen activator, have been implicated in tumor cell invasion. MMPs regulate tumor invasion not only by remodeling insoluble components of the basement membrane and interstitial matrix but also by releasing ECM-sequestered growth factors. Indeed, cleavage products of collagen and proteoglycans also have chemotactic, angiogenic, and growth-promoting effects.[112] For example, MMP9 is a gelatinase that cleaves type IV collagen of the epithelial and vascular basement membrane and also stimulates release of VEGF from ECM-sequestered pools. Benign tumors of the breast, colon, and stomach show little type IV collagenase activity, whereas their malignant counterparts overexpress this enzyme. Concurrently, the concentrations of metalloproteinase inhibitors are reduced so that the balance is tilted greatly toward tissue degradation. Indeed, overexpression of MMPs and other proteases has been reported for many tumors. However, recent in vivo imaging experiments have shown that tumor cells can adopt a second mode of invasion, termed ameboid migration.[113] In this type of migration the cell squeezes through spaces in the matrix instead of cutting its way through it. This ameboid migration is much quicker, and tumor cells seem to be able to use collagen fibers as high-speed railways in their travels. Tumor cells, in vitro at least, seem to be able to switch between the two forms of migration, perhaps explaining the disappointing performance of MMP inhibitors in clinical trials.
- #23 Now we will move on to the next mechanism: Attachment to novel ECM components
- #25 Now we will move on to the final mechanism: Migration of tumor cells
- #26 HGF=hepatocytes growth factor Locomotion is the final step of invasion, propelling tumor cells through the degraded basement membranes and zones of matrix proteolysis. Migration is a complex, multistep process that involves many families of receptors and signaling proteins that eventually impinge on the actin cytoskeleton. Cells must attach to the matrix at the leading edge, detach from the matrix at the trailing edge, and contract the actin cytoskeleton to ratchet forward. Such movement seems to be potentiated and directed by tumor cell–derived cytokines, such as autocrine motility factors. In addition, cleavage products of matrix components (e.g., collagen, laminin) and some growth factors (e.g., IGFs I and II) have chemotactic activity for tumor cells. Furthermore, proteolytic cleavage liberates growth factors bound to matrix molecules. Stromal cells also produce paracrine effectors of cell motility, such as hepatocyte growth factor–scatter factor, which bind to receptors on tumor cells. Concentrations of hepatocyte growth factor–scatter factor are elevated at the advancing edges of the highly invasive brain tumor glioblastoma multiforme, supporting their role in motility. It has become clear in recent years that the ECM and stromal cells surrounding tumor cells do not merely represent a static barrier for tumor cells to traverse but instead represent a varied environment in which reciprocal signaling between tumor cells and stromal cells may either promote or prevent tumorigenesis and/or tumor progression.[24] Stromal cells that interact with tumors include innate and adaptive immune cells (discussed later), as well as fibroblasts. A variety of studies have demonstrated that tumor-associated fibroblasts exhibit altered expression of genes that encode ECM molecules, proteases, protease inhibitors, and various growth factors. Thus, tumor cells live in a complex and ever-changing milieu composed of ECM, growth factors, fibroblasts, and immune cells, with significant cross-talk among all the components. The most successful tumors may be those that can co-opt and adapt this environment to their own nefarious ends.
- #31 FIGURE 7-38 Mechanisms of metastasis development within a primary tumor. A nonmetastatic primary tumor is shown (light blue) on the left side of all diagrams. Four models are presented: A, Metastasis is caused by rare variant clones that develop in the primary tumor; B, Metastasis is caused by the gene expression pattern of most cells of the primary tumor, referred to as a metastatic signature; C, A combination of A and B, in which metastatic variants appear in a tumor with a metastatic gene signature; D, Metastasis development is greatly influenced by the tumor stroma, which may regulate angiogenesis, local invasiveness, and resistance to immune elimination, allowing cells of the primary tumor, as in C, to become metastatic.