2. ANGIOGENESIS
• Angiogenesis is the process of new blood vessel development from existing
vessels .
• Even if solid tumor possesses all the genetic aberrations that are required
for malignant transformation , it cannot enlarge beyond 1 to 2 mm in
diameter unless it has the capacity to induce angiogenesis.
• For oxygen , nutrients and proliferating endothelial cells also stimulate
growth of tumor cells ( by IGFs , PDGF )
• Vessels are leaky and dilated
3. • Angiogenesis is controlled by balance between angiogenesis promoters and
inhibitors
• Initiated by angiogenic switch ( by local production of angiogenic factors , loss
of angiogenic inhibitors)
• Sources of these factors are : tumor cells , infiltrating inflammatory cells , tumor
associated stromal cells , ECM
4. FACTORS INFLUENCING PRODUCTION OF PRO
ANGIOGENIC FACTORS
• Relative lack of oxygen due to hypoxia stabilises HIF1 alpha , activates the
transcription of pro angiogenic cytokines VEGF and bFGF , which leads to
angiogenesis
• Driver mutations in certain tumor suppressors and oncogenes favour angiogenesis. Eg
: p53 stimulates expression of anti angiogenic molecules such as thrombospondin 1
and represses pro angiogenic molecules ( like VEGF ) , loss of p53 thus removes cell
check point and leads to angiogenesis
• Gain of function mutations in RAS and MYC upregulate production of VEGF
5. • Proteases , which may be elaborated by tumor cells or by stromal cells influence the local
balance of angiogenic and anti angiogenic factors .
VEGF inhibitors are used to treat number of advanced cancers and prolong clinical course ,
but are not curative
Bevacizumab , a monoclonal antibody that neutralise VEGF activity is used for treating
multiple cancers
6. INVASION AND METASTASIS
• Invasion and Metastasis are the major causes of cancer related morbidity and
mortality.
• Metastasis is defined as the spread of tumors to sites that are physically discontinuous
with primary tumor , an event that unequivocally marks a tumor as a malignancy.
• This occurs through series of steps known as METASTATIC CASCADE.
• It also requires metastatic phenotype which requires complementary genetic and
epigenetic alters that collectively promote metastatic cascade . ( which might require
subclones providing some needed functions )
7.
8. METASTATIC CASCADE
Has 2 steps
1. Invasion of ECM
2. Vascular dissemination, tissue homing and colonization .
9. 1 .INVASION OF EXTRACELLULAR MATRIX
• ECM has basement membrane and interstitial connective tissue made of collagens ,
glycoproteins , proteoglycans
• To metastasize, cells must breach underlying basement membrane, traverse interstitial
connective tissue , gain access to circulation by penetration of vascular basement membrane.
• Invasion of ECM has 4 important steps
1. Loosening up of tumor cell – tumor cell interaction
2. Degradation of ECM
3. Attachment to remodeled ECM components
4. Migration and invasion of tumor cells
10.
11. 1. LOOSENING UP OF TUMOR CELL- TUMOR CELL
INTERACTIONS
• E cadherin mediated adhesion, they hold cells and relay signals
• E cadherin function lost due to mutations ( adenocarcinoma of breast , stomach )
• E cadherin expression is silenced by EMT ( epithelial mesenchymal transition ) eg :
occurs in breast and prostate cancers .
• EMT is controlled by transcription factors SNAIL and TWIST .
• These activities results into development of pro migratory phenotype, essential for
metastasis
12. 2 . DEGRADATION OF ECM
• It is the second step in invasion
• Done by secreting proteolytic enzymes by stromal cells
• Eg : metalloproteinases ( MMPs) , cathepsin D , Urokinase plasminogen
• MMPs also contribute to malignant behaviour of cancers
Eg : MMP 9 , cleaves type 4 collagen , stimulates release of VEGF , also generates
products with chemotactic , angiogenic, growth promoting effects .
13. 3. ATTACHMENT TO REMODELED ECM COMPONENTS
• Tumor cells demonstrate complex changes in the expression of integrins (
transmembrane protein participate in cell to cell and cell to ECM adhesion )
• In Normal cells loss of adhesion causes cell death but free tumor cells are
resistant to this type of death
• Expression of other altered integrin cause cell survival
• Matrix is modified in way that promotes invasion and Metastasis.
14. 4 . MIGRATION AND INVASION OF TUMOR CELLS
• Propelling tumor cells through the degraded basement membranes and zones of
matrix proteolysis
• Cells must attach to matrix at their leading edge , detach at their trailing end , contract
the actin skeleton to ratchet forward
• These movements are stimulated by
1. Tumor derived cytokines
2. Cleavage products of matrix components
3. Stromal derived paracrine factors
15. 2. VASCULAR DISSEMINATION, HOMING, COLONIZATION
• Tumor cells express a anionic substances like poly phosphate which activate factor
XII , leading to fibrin deposition and stabilisation of tumor emboli
• stem cell properties- plasticity , relentless growth
16. FACTORS THAT DETERMINE HOMING AND
COLONIZATION
• Location and vascular drainage of primary tumor ( colon cancer metastase to liver )
• Tropism of particular kinds of tumor cells for specific tissue ( prostate carcinoma
spread to bone ) . Tumor cells may express adhesion molecules whose ligands are
preferentially on the endothelial cells of the target organ .
• Escape from tumor dormancy – ‘seed soil hypothesis ‘- ability of the tumor cell
originating from a particular site to adapt to a foreign environment may be limited to
certain tissue types . ( eg , spleen skeletal muscles are unfavourable
17. Some breast carcinoma which metastases to bone which secrete PTH related
protien ,
• this stimulate osteoblasts to form RANKL ( RANK ligand )
• This RANKL activate osteoclasts which degrade bone matrix and thus release
growth factors ( IGFs and Transforming growth factor beta )
• They act on receptors present on tumor cells and they lead to the growth and
survival of tumor cells
