Cancer metastasis

1. Cancer Metastasis
Mohammed Fathy Bayomy, MSc, MD
Lecturer
Clinical Oncology & Nuclear Medicine
Faculty of Medicine
Zagazig University

2. Basic Histological Structure
 Stroma or extracellular matrix (ECM) consists of 3 main components:
1) Fibrous proteins: collagens (type I-IX), elastins
2) Adhesion glycocoproteins: (laminin, fibronectin, thrombospondin,
tenasin)
(3) Proteoglycans (glycosaminoglycans & hyaluronic acid)
 Epithelial & endothelial cells are separated from extracellular matrix
(ECM) by basement membrane, which is composed of network of type
IV collagen rich in laminin adhesive molecules
 Cell adhesive molecules or receptors: present on surface of epithelial
cells and help to adhere & cells to each other (E-Cadherins), to vascular
endothelium (integrin VLA-4 & glycoprotein CD44), & to extracellular
matrix (laminin & fibronectin)

3. Steps of Metastasis
1) Invasion of extracellular matrix (ECM)
 Down-regulation of expression of intercellular adhesive molecules
(ICAM) & dissociation of tumor cells from each other
 Actual local invasion involves three main steps, 1) attachment to
ECM (2) matrix degradation by proteolytic enzymes, (3) cell motility
 Attachment is accomplished by binding of laminin & fibronectin cell
surface receptors with their corresponding adhesion glycoproteins in
ECM
 Three classes of proteases have been identified which cooperate in the
degradation of ECM: (1) matrix metalloproteinases MMP (e.g.
Collagenases) (2) cysteine proteases (e.g. cathepsin-D) (3) serine
proteinases (e.g. plasminogen activator)

4.  Increased expression of these enzymes correlates with clinical
aggressiveness of tumor. Conversely, carcinoma in situ cells lack
enzyme collagenase type IV, hence penetration of basement
membrane can not be accomplished
 Tumor cell motility, or migration, is mediated through two
mechanisms: (1) autocrine effect of cell motility factors (e.g. beta 15
thymosin), and/or (2) cleavage products of matrix components which
have chemotactic properties, as well as, growth promoting &
angiogenic properties

5. 2) Vascular Dissemination & Homing
 Tumor cells in circulation protect themselves from hostile
environment (both mechanical and immunologic) by aggregating in
clumps in association with platelets
 Tumor arrest & extravasation at specific metastatic sites (organ
tropism) is commonly (90%) accomplished by binding of specific cell
surface adhesive molecules to endothelium (e.g. integrins such as
VLA-4 or glycoproteins as CD44), but rarely (10%) it is determined
by hemodynamic vascular factors (embolism)
 Organ tropism may also be related to production of growth promoting
or growth inhibiting factors at metastatatic site (favorable or
unfavorable soil)

6. 3) Angiogenesis & Establishment of Metastases
 Tumor cells mass can not grow beyond 2 mm in diameter unless tumor
induces new blood supply (angiogenesis). This critical size represents
maximal distance of diffusion of oxygen & nutrients
 Avascular micrometastases, arising from non-angiogenic primary tumor
subclone may remain for years in "dormant state" with stationary size
due balance between cell production & cell apoptosis, until mutation
(e.g. p53) stimulates angiogenesis, with subsequent active tumor growth
 There are reciprocal interactions, in paracrine fashion, between
tumor cells, extracellular matrix (ECM), & endothelial cells (EC)
 In cooperative manner: tumor cells may either directly produce
angiogenic factors, or stimulate fibrocytes & macrophages to induce
them

7.  ECM may act as a reservoir for angiogenic stimulators or
inhibitors: angiogenic factor b-FGF is sequestrated or stored in ECM, &
is released by action of proteases produced by tumor
 Relation between tumor cell & EC is symbiotic one: tumor cells
produce angiogenic factors to EC, which pay back by producing
polypeptide growth factors to tumor (e.g. ILGF, PDGF, GM-CSF, and
IL-1)
 Angiogenesis & tumor growth, is result of balance between
stimulators & inhibitors of this vascular phenomenon

8.  Angiogenic factors:
1) Vascular endothelial growth factor (VEGF)
2) Basic fibroblast growth factor (b-FGF)
3) Thymidine phosphorylase (TP) = platelet- derived EC growth
factor
 Hypoxia of tumors is associated with survival advantage. Hypoxia may
induce not only VEGF but also EC receptors involved in angiogenesis.
This reaction is mediated by hypoxia- inducible factor (HIF-1) &
hypoxia-regulated genes (e.g. VEGF gene and LDHA gene).
 Inhibitors of angiogenesis (antiangioenic factors):
1) Thrombospondin-1 (TSP-1) expressed by activation of wild p53
2) angiostatin, derived from proteolytic cleavage of plasminogen
3) endostatin, derived from proteolytic cleavage of collagen