3 1 METASTATIC PROCESS

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METASTATIC PROCESS
	
1. CONCEPT
= propagation of tumor cells from 1st neoplasms to distant organs, their adaptation to different microenvironments and, consequently, tumor growth in these new organs.
→ Change of location
→ Barriers to treatment: heterogeneity of cancer cells in the 1st tumor and at the metastatic site
→ Metastatization is not a random phenomenon
IMPORTANT PROPERTIES OF MALIGNANT CELLS
2. invasion
3. dissemination route
4. reach distant places
5. give rise to new tumors (metastases) at these distant sites
*Metastases are the definitive sign of malignancy and a sign of poor prognosis
6. Benign neoplasms do not metastasize
	PLACE METASTASIS
	PRIMARY TUMORS
	Lung
	breast, melanoma, kidney…
	Liver
	breast, lung, stomach, rectum...
	Bone
	prostate, lung, breast, thyroid…
	Brain
	lung, breast, melanoma, kidney.
7. DISSEMINATION PATHWAYS CANCER CELLS
8. LYMPHATIC WAY
→ main route of initial dissemination of carcinomas
→ 1st site of metastases: 1st lymph node in the lymphatic drainage pathway of the tumor = sentinel lymph node.
9. 1st lymph node metastases from lung cancer = pulmonary hilar lymph nodes
10. 1st lymph node metastases from cancer of the upper outer quadrant of the breast = axillary lymph nodes.
→ involvement of the nearest lymph node chain, other lymph nodes located immediately ahead can be affected
→ lymph nodes with metastases = increased and confluent volume (bulky masses)
→ palpated qnd in superficial chains; qnd imaging exams in deep chains
11. Not every lymph node enlargement close to a cancer means metastasis: tumor antigens are taken to the lymph nodes and induce lymphoid hyperplasia = increase in organ V.
12. BLOOD WAY
→ tumors of tributary organs of the portal system metastasize initially to the liver
→ as they receive all the blood from the vena cava system, the lungs are a frequent site of metastasis
→ common in brain and bones
→ cancers close to the spine (eg thyroid), malignant cells may gain the paravertebral venous plexus and give rise to metastases in the vertebrae
13. OTHER COPIES
14. channels, ducts, natural cavities
15. e.g. pleura and peritoneum → serous metastasis and adjacent organs
16. Clinical aspects
The main manifestation patterns are:
17. the primitive tumor is identified and surgically removed, without identifying metastases, which appear months later;
18. the primitive tumor is diagnosed and there are already metastases;
19. the primitive tumor is identified and excised, not identifying metastases, which appear years later (dormant metastases);
20. metastasis is identified before the primary tumor;
21. metastases are identified, but the primitive tumor is not found;
22. the primitive tumor is already identified with metastases and, after surgical removal, the metastases regress (rare cases of renal cell carcinoma and choriocarcinoma);
23. micrometastases, which are only detectable microscopically in resected sentinel lymph nodes before or during tumor removal.
	
THEORIES
	
SEED AND SOIL THEORY:Tumor cells need organs that offer the necessary conditions for their survival and proliferation.
MECHANICAL THEORY:Tumor cells are retained without specificity in the 1st organ they encounter in the circulation.
→ CURRENTLY:the two theories complement each other
	
GENES
	· Genes for metastasis. Metastasis suppressor genes
→ favors the appearance of metastases and explains why within the same tumor there are clones with different metastatic potential
→ Suppression of other genes favors metastases, being called metastasis suppressor genes (Ex: 2E1a → suppresses the metastasizing action of malignant cells transformed by the RAS oncogene.)
· CP =expression of 55 genes favoring and 480 genes suppressing metastasis = complexity in the difference between a tumor cell without and with metastasis.
→ genes promoting metastasis: H-RAS; MTA-1 and 2 → and prevent p53
→ Micro-RNAs (miRNA) can act as metastasis suppressors (eg in breast carcinoma).
→ The lack of expression of cadherin genes favors metastases, as their reduction or absence facilitates the displacement of cancer cells.
	
EVENTS
EVENTS
EVENTS
	depends on numerous interactions between malignant cells and normal tissue components.
1. Detachment of cells from the original tumor mass:lose cell-cell adhesion
2. Displacement of these cells through the extracellular matrix (ECM)
3. Invasion of lymphatic or blood vessels
4. Survival of cells in the circulation
5. Adhesion to the vascular endothelium in the organ where the cells will settle
6. Exit of vessels in this organ → diapedesis
7. Survival and proliferation in the invaded organ
8. Induction of vessels for the blood supply of the new colony
Cancer cells acquire the properties of implanting themselves at a distance at an early stage of tumor development = cells leave the primitive tumor very early, settle in distant locations and undergo distinct genetic and epigenetic alterations in different secondary sites, until they originate subclones capable of to form new tumor lesions. By this logic, metastases originate from cells with a genetic profile different from that of the original tumor.
1st: Invasion of the Extracellular Matrix
The structural organization and function of normal tissues are largely determined by the interaction between cells and the ECM.Tissues are organized into compartments separated from each other by two types of ECM: basement membrane and interstitial connective tissue.
· Tumor cells interact with the ECM at different stages of the metastatic cascade.
· A carcinoma must first break through the underlying basement membrane → then pass through the interstitial connective tissue, and → ultimately gain access to the circulation by penetrating the vascular basement membrane.
This process is repeated in reverse when an embolus of tumor cells leaks from a distant site.
ECM INVASION initiates the metastatic cascade and is an active process that can be separated into several steps:
1. “Relaxation” of tumor cell-tumor cell interactions.
2. ECM degradation.
3. Connection to new MEC components.
4. Migration and invasion of tumor cells
🡨 Figure:Sequence of events in the invasion of epithelial basement membranes by tumor cells.
Tumor cells separate from each other due to reduced adhesiveness and attract inflammatory cells. Proteases secreted by tumor cells and inflammatory cells degrade the basement membrane. Next, tumor cell binding at the proteolytically generated binding sites and tumor cell migration take place.
1. ACELL DISSOCIATIONfrom each other are often the result of changes in intercellular adhesion molecules and are the FIRST STEP in the invasion process. Normal epithelial cells are tightly adhered to each other and to the ECM through various adhesion molecules.
· Cell-cell interactions are mediated by the family of transmembrane glycoproteins called cadherin.
· E-cadherins mediate homotypic adhesions of epithelial cells, thereby serving to hold epithelial cells together and to transmit signals between cells. In several epithelial tumors, including colon, stomach, and breast adenocarcinomas, E-cadherin function is lost.
· It is assumed that thisdownregulation reduces the ability of cells to adhere to each other and facilitates their detachment from the primary tumor and consequent advancement towards surrounding tissues!!!
0. Adegradation of basement membrane and interstitial connective tissueit is the SECOND STEP of the invasion. Tumor cells can do this bysecrete proteolytic enzymes, or induce stromal cells (eg, fibroblasts and inflammatory cells)to elaborate proteases.
· Many different protease families, such as the metalloproteinases (MMP), cathepsin D and urokinase plasminogen activator, have been linked to invasion by tumor cells. MMPs regulate tumor invasion by remodeling insoluble basement membrane and interstitial matrix components, but also by releasing sequestered growth factors into the ECM.
0. THE THIRDSTEP in the invasion involveschanges in the binding of tumor cells to ECM proteins.
· Normal epithelial cells have receptors, such as integrins, for basement membrane laminin and collagen that are polarized on the basal surface. These receptors → maintain cells in a differentiated quiescent state.
· Loss of adhesion in normal cells leads to the induction of apoptosis, whereas tumor cells are resistant to this form of cell death.Furthermore, the matrix itself becomes modified in a way that promotes invasion and metastasis: the cleavage of basement membrane proteins, collagen IV and laminin, by MMP2 AND MMP9, generates new sites that bind to receptors on tumor cells and stimulate migration.
0. Alocomotionis the last / FOURTH STAGE of invasion:thrust of tumor cells through degraded basement membrane and zones of matrix proteolysis.
· Migration is a multi-step process. Cells must attach to the matrix at the leading end, detach from the matrix at the trailing end, and contract the actin cytoskeleton to proceed.
· These movements are stimulated and directed by cytokines derived from tumor cells (autocrine mobility factors).
· Cleavage products of matrix components (collagen, laminin) and some growth factors (IGF I and II) have chemotactic activity for tumor cells.
· Proteolytic cleavage releases growth factors bound to matrix molecules. Stromal cells also produce paracrine effectors of cell motility – hepatocyte growth factor/dispersion factor (elevated in the advancing end of the highly invasive brain tumor glioblastoma).
PRE-METASTATIC NICHE
· precedes the release of blood cells into the circulation
· its formation defines the location of the metastasis
· formation induced by growth factors and cytokines produced in the tumor
· Substances arrive from the primitive tumor that induce the modification of the ECM to facilitate the colonization of tumor cells
The concept of the premetastatic niche suggests that a primary tumor modulates the microenvironment of the secondary site before the arrival of most metastatic cells.
VASCULAR DISSEMINATION
· once the cells make their way into the ECM they find the basement membrane on which the epithelium of the vessels rests
cell in the matrix → encounters the basement membrane of the vessel -- > degrades the MB of the V → relaxes the vessel epithelium → enters the bloodstream
· macrophages push aside endothelial cells and allow malignant cells to enter
· after entering the CS some events occur:
a. mechanical shear stress
b. apoptosis by loss of adhesion
c. immune defense action
= makes the cell more vulnerable and makes the process of dissemination more difficult
· main metastatic mechanism
· cells move to the vessels by the action of chemokines produced by endothelial cells (CCL19 and CCL21) that act on the CCR 7 receptors of malignant cells
· Angiogenesis: tumor cells stimulate the formation of new blood vessels within their microenvironment
· Neovascularization generated by neoplastic cells is tortuous, prone to leaks and in a state of continuous reconfiguration
IN CIRCULATION
· tumor cell - tumor cell aggregation = small intravascular masses
· tumor cell aggregation - blood cells (mainly platelets) = aggregates that increase the survival of malignant cells and favor their implantation
MAY ACTIVATE COAGULATION FACTORS, FORMING EMBOLS
emboli = abnormal, insoluble element transported by blood/lymph responsible for obstruction
CIRCULATION SURVIVAL:
· Malignant cells in the circulation do not necessarily indicate the formation of metastases
· Most cancer cells in the circulation are destroyed by shear forces from the bloodstream, innate and adaptive immune responses, apoptosis, and mechanical shock to the vessel wall.
· Survival is greater when they form aggregates with each other and with platelets, lymphocytes and fibrin
ADHESION TO THE ENDOTHELIUM
· adhesion to the endotheliumin the presence of adhesion molecules to the endothelium of the organ
*preparation in the primitive tumor (cell already comes out with an address)
· tumor cells secrete proteases that compromise epithelial adhesion and degrade the basement membrane and matrix, settling in the target organ
CD44 = adhesion molecule present on T lymphocytes and many solid tumors
Adhesion of CD44 to HA induces upregulation of integrins that strengthen stem cell adhesion.
tumors that do not express CD44 bind to T lymphocytes that carry out this function of taking the cells and implanting them in the matrix
tumors that express → have the process facilitated
SECONDARY IMPLEMENTATION SITE
what makes metastases go to places X?
1. first bed available for the tumor
ex: gastrointestinal tumor → liver metastasis (drainage through the portal system leading to the liver)
lung cancer (supplied by pulmonary arteries that drain into the heart and supply the brain)
0. target organ ligands
· expressed substances that bind to tumor cell receptors
ex: lung and adrenal
· CXCR 4 and 6: are expressed in many tumors and are related to tumor progression
· In prostate carcinoma: expression of CXCR4 and 6 facilitates colonization in bones, where agonists of these receptors are produced in large quantities
0. Chemokines in target organs
· attract tumor cells
0. kind of fabric
· in some tissues metastases do not develop due to specific characteristics
ex: skeletal muscle and spleen (they are very vascularized, but they do not develop)
DESPITE THAT
prostate cancer
→ very slow metastatic progression
IN SHORT
1. tumor cell loses adhesion
2. it degrades the basement membrane
3. degrades the MEC
4. meets the basement membrane of the vessel
5. loosens the endothelium of the vessel
6. enters the bloodstream
7. adhere to platelets, T cells, or aggregate together (may form emboli)
· favoring implantation of a distant endothelium
0. loosen adhesion of distant endothelium
1. degrade the basement membrane
2. degrade the ECM
(products generate chemotactic, angiogenic and tumor growth effect = success with metastasis)
0. implant in the distant endothelium