1) Cancer metastasis is a multi-step process involving invasion of surrounding tissue, transportation through the bloodstream, and formation of tumors in distant organs. 2) Key steps include degradation of the extracellular matrix, entry and survival in the circulation, arrest and extravasation at distant sites, and induction of angiogenesis to establish blood supply for growing tumors. 3) Factors such as matrix metalloproteinases, integrins, and angiogenic growth factors regulate these steps by promoting degradation of barriers, cell adhesion, and new blood vessel formation to enable metastatic tumors to grow.

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