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INVASION & METASTASISINVASION & METASTASIS
Dr.CSBR.Prasad, M.D.,
Sri Devaraj Urs Medical College
Kolar-563101
Karnataka
BCC – locally invasive
Melanoma -
metastasizing
Invasion and metastasis are biologicInvasion and metastasis are biologic
hallmarks of malignant tumorshallmarks of maligna...
Metastasis
In situ carcinoma
Microinvasive
Vascular invasion
Vascular invasion
Metastatic deposit in brain
The metastatic cascadeThe metastatic cascade
Sequential steps involved in
the hematogenous spread
of a tumor
Invasion of Extracellular Matrix
Two types of ECM:
1. Basement membrane (BM) and
2. Interstitial connective tissue
Composi...
Invasion of Extracellular Matrix
Invasion of the ECM initiates the metastatic
cascade:
1. Changes (“loosening up”) of tumo...
Sequence of events in the invasion of
epithelial basement membranes by
tumor cells:
Tumor cells detach from each other bec...
Invasion of Extracellular Matrix
Invasion of the ECM initiates the metastatic
cascade and is an active process that
can be...
1-Dissociation of cells from one another
(“loosening up”) of tumor cell-cell interactions
As a result of alterations in in...
Normal cells are bound together
by adhesion molecules
• Cell-cell interactions are mediated by the
cadherin family of tran...
Tumors with down-regulated
E-cadherin expression
Seen in several epithelial tumors, including
adenocarcinomas of the colon...
Invasion of Extracellular Matrix
Invasion of the ECM initiates the metastatic
cascade and is an active process that
can be...
2-Local degradation of the basement
membrane and interstitial connective tissue
Elaboration of proteases by
– Tumor cells ...
MMPs
Tumors either elaborate large quantities of MMPs or they
may reduce the concentrations of MMP-inhibitors
They regulat...
Invasion of Extracellular Matrix
Invasion of the ECM initiates the metastatic
cascade and is an active process that
can be...
3 - Attachment to novel ECM components
• Normal epithelial cells have receptors, such as integrins,
for basement membrane ...
Invasion of Extracellular Matrix
Invasion of the ECM initiates the metastatic
cascade and is an active process that
can be...
4 – Migration of tumor cells - Locomotion
• Tumor cells propel themselves through the degraded basement
membranes and zone...
Ameboid migration
• In this type of migration the cell squeezes
through spaces in the matrix instead of
cutting its way th...
Molecular Genetics of
Metastasis Development
Malignant tumors have varied
metastatic potential
Cancer with Low metastatic potential
– Basal cell carcinoma
Cancer with ...
Several THEORIES have been proposed to
explain how the metastatic phenotype arises?
1. The clonal evolution model
– As mut...
Mechanisms of metastasisMechanisms of metastasis
development within adevelopment within a
primary tumor:primary tumor:
A n...
Are there genes whose principal or sole
contribution to tumorigenesis is to control
metastasis?
• Genes that function as “...
Metastasis oncogenes
• Genes: SNAIL and TWIST
• Their primary function: is to promote epithelial-
to-mesenchymal transitio...
Modes of Spread
• Seeding the body cavities
– The cavity most often involved is peritoneal cavity
(Krukenberg tumor, pseud...
Lymphatic Spread
• Epithelial tumors
(Carcinoma) spread by
lymphatics
• LN in natural route of
lymphatic drainage
(Eg: Bre...
Hematogenous Spread
• Mesenchymal
tumors (Sarcoma)
• Predominantly veins
(RCC, HCC)
• Lung, Liver &
Vertebra
Common sites of metastatic
deposits (hematogenous spread)
• Liver
• Bones
• CNS
• Lung
Some tumors prefer certain sites
• Adrenals prefered by Bronchogenic.ca
(Lung carcinoma)
• Bone metasizing tumors:
– BK.Pa...
Rare sites for mets
• Skeletal muscle
• Spleen
• Pancreas
Other mechanisms of spread
• Direct extension
• Surgical or procedural transplantation
(iatrogenic)
Unusual modes of spread
• Carcinomas arising close to vertebral
column spread via paravertebral venous
plexus giving rise ...
E N D
Invasion &; metastasis csbrp
Invasion &; metastasis csbrp
Invasion &; metastasis csbrp
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Invasion &; metastasis csbrp

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Invasion &; metastasis csbrp

  1. 1. INVASION & METASTASISINVASION & METASTASIS Dr.CSBR.Prasad, M.D., Sri Devaraj Urs Medical College Kolar-563101 Karnataka
  2. 2. BCC – locally invasive Melanoma - metastasizing
  3. 3. Invasion and metastasis are biologicInvasion and metastasis are biologic hallmarks of malignant tumorshallmarks 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 • For this, they must go through a series of steps (the metastatic cascade) The metastatic cascade is divided into two phases: 1. Invasion of the extracellular matrix (ECM) 2. Vascular dissemination, homing of tumor cells, and colonization
  4. 4. Metastasis
  5. 5. In situ carcinoma
  6. 6. Microinvasive
  7. 7. Vascular invasion
  8. 8. Vascular invasion
  9. 9. Metastatic deposit in brain
  10. 10. The metastatic cascadeThe metastatic cascade Sequential steps involved in the hematogenous spread of a tumor
  11. 11. Invasion of Extracellular Matrix 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
  12. 12. Invasion of Extracellular Matrix Invasion of the ECM initiates the metastatic cascade: 1. Changes (“loosening up”) of tumor cell- cell interactions 2. Degradation of ECM 3. Attachment to novel ECM components 4. Migration of tumor cells
  13. 13. 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
  14. 14. Invasion of Extracellular Matrix 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
  15. 15. 1-Dissociation of cells from one another (“loosening up”) of tumor cell-cell interactions As a result of alterations in intercellular adhesion molecules
  16. 16. Normal cells are bound 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. 17. Tumors with down-regulated E-cadherin expression 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
  18. 18. Invasion of Extracellular Matrix 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
  19. 19. 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
  20. 20. MMPs Tumors either elaborate large 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
  21. 21. Invasion of Extracellular Matrix 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
  22. 22. 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
  23. 23. Invasion of Extracellular Matrix 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
  24. 24. 4 – Migration of 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
  25. 25. Ameboid migration • 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 • Tumor cells are capable of switching between the two forms of migration, perhaps explaining the disappointing performance of MMP inhibitors in clinical trials
  26. 26. Molecular Genetics of Metastasis Development
  27. 27. Malignant tumors have varied 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?
  28. 28. Several THEORIES have been 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
  29. 29. Mechanisms of metastasisMechanisms of 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.
  30. 30. Are there genes whose 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
  31. 31. 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
  32. 32. 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
  33. 33. Lymphatic Spread • Epithelial tumors (Carcinoma) spread by lymphatics • LN in natural route of lymphatic drainage (Eg: Breast – upper outer quadrant – axilla) • Effective barrier at least for some time
  34. 34. Hematogenous Spread • Mesenchymal tumors (Sarcoma) • Predominantly veins (RCC, HCC) • Lung, Liver & Vertebra
  35. 35. Common sites of metastatic deposits (hematogenous spread) • Liver • Bones • CNS • Lung
  36. 36. Some tumors prefer certain sites • Adrenals prefered by Bronchogenic.ca (Lung carcinoma) • Bone metasizing tumors: – BK.Patil • Liver & bone by Neuroblastoma
  37. 37. Rare sites for mets • Skeletal muscle • Spleen • Pancreas
  38. 38. Other mechanisms of spread • Direct extension • Surgical or procedural transplantation (iatrogenic)
  39. 39. Unusual modes of spread • 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 of lung gives rise to metastatic deposit in adrenals very frequently
  40. 40. E N D

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