Three main pathways
Through the lymphatics
Via blood; hematogenous
By seeding surface of body cavities
Passage through basement membranes
Tumor cells produce receptor proteins, enzymes, and autocrine factors to
facilitate attachment to, degradation of basement membrane components and
migration away from site of origin
Type IV collagenase damages type IV collagen → degradation
Primary tumor → metastatic clone evolves → proliferation of the clone and invasion of
vessel → transport by circulation → embolization → invasion → new tumor formation at
the site of metastasis
Tumor-cell invasion and migration: Diversity and escape mechanisms
Cancer cells possess a broad spectrum of migration and invasion mechanisms. These
include both individual and collective cell-migration strategies.
Cancer therapeutics that are designed to target adhesion receptors or proteases have
not proven to be effective in slowing tumor progression in clinical trials – this might be
due to the fact that cancer cells can modify their migration mechanisms in response to
Learning more about the cellular and molecular basis of these different
migration/invasion programs will help us to understand how cancer cells disseminate
and lead to new treatment strategies.
Individual or collective tumor-cell migration strategies are determined by different
From individual to collective movements, increased control of cell-ECM
interaction is provided by integrins and matrix-degrading proteases. Cell-cell
adhesion through cadherins and other adhesion receptors, as well as cell-cell
communication, via gap junctions, are specific characteristics of collective cell
Migration strategy Tumor type
Mesenchymal (single cell) Fibrosarcoma
Mesenchymal (chains) Glioblastoma
Cluster/cohorts Epithelial cancer
Multicellular strands/sheets Epithelial cancer
Tumors secrete angiogenic factors that increase the vascularization and nutrition of an
invading tumor. Those angiogenic factors are similar to those producing during normal
Angiogenesis is initiated at post-capillary venules in response to tissue hypoxia
The growing capillary is attracted to an area of higher O2content, ultimately joining with
other capillaries to permit circulation.
This process is regulated by vascular endothelial growth factor (VEGF) whose
production is influenced by the protein hypoxia-inducible factor 1 (HIF-1)
The newly formed blood vessels facilitate the dissemination of tumor cells to distant
The major key signaling pathways involved in angiogenesis are the vascular
endothelial cell factor (VEGF)-VEGF receptor (VEGF-R) pathway; the Notch
receptor pathway; and the Tie (for tyrosine kinase with immunoglobulin-like and
EGF-like domains) receptor-angiopoietin (Ang) pathway
The VEGF-R and Tie receptors have an intracellular tyrosine kinase domain.
Ligand binding to VEGF-R and Tie receptors leads to their dimerization and
subsequent autophosphorylation. The phosphorylated receptor interacts with a
variety of cytoplasmic signaling molecules leading to angiogenesis involving the
proliferation and differentiation of endothelial cells.
Activation of the Notch receptor by ligand (D11/Jagged) binding results in the
release of the Notch intracellular cell domain (NICD) that translocates into the
cell nucleus to regulate gene expression involved in angiogenesis
Rebound effect of tumor-starving therapy
Based on the importance of VEGF and its receptor in tumor angiogenesis,
blocking tumor angiogenesis by suppressing the angiogenic pathways can
provide maximal surviving benefits to cancer patients. The monoclonal antibody to VEGF bevacizumab (Avastin) and receptor tyrosin
kinase inhibitors (RTKIs) sunitinib and sorafenib have been developed.
However, although tumor antiangiogenic targeted drugs inhibit primary tumor
growth, they promote tumor invasion and metastasis.
The mechanism of tumor hypoxia, caused by oxygen deprivation resulting from
blocking tumor angiogenesis, could explain the selective switch of tumor cells
into an invasive and metastatic program. Hypoxia-inducible factor-1 (HIF-1) acts
as a transcription survival factor that activates genes involved in migration,
invasion, and angiogenesis. Hypoxia generated by tumor angiogenesis inhibition
triggers pathways that make tumor cells aggressive and metastatic.
Clinical Significance: Tumor Angiogenesis and Tumor-starving Therapy
All the three signaling pathways, VEGF-R-VEGF, Tie-Ang, and Notch receptor-
D11/Jagged, contribute synergistically to the process of angiogenesis. Antiangiogenic
drugs exert therapeutic effects by blocking certain specific receptors of the VEGF-VEGF-
R pathway, but none can fully block all the components. Thus, angiogenesis signaling
can continue through the other signaling pathways.
Given the belief that blocking blood supply starves tumors and the importance of VEGF
and its receptor and receptor tyrosine kinase inhibitors (RTKIs) in angiogenesis, tumor
antiangiogenic therapeutic approaches have been developed to provide cancer patients
maximal survival time. Therapy with angiogenesis inhibitors reduce tumor growth but
promote invasiveness and metastasis.
Cancer cell hypoxia → hypoxia-inducible factor-1 (HIF-1); a survival transcription
factor → angiogenesis, cell migration → metastasis
Sedative, sleep aid
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