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Metastasis
Mechanisms of
Invasion and Metastasis
A-D, Schematic illustration of the sequence of events
in the invasion of epithelial basement membranes
by tumor cells. Tumor cells detach from each other
because of reduced adhesiveness, and cells then
attach to the basement membrane via the laminin
receptors and secrete proteolytic enzymes,
including type IV collagenase and plasminogen
activator. Degradation of the basement membrane
and tumor cell migration follow.
Stromal microenvironment and
carcinogenesis
Carcinoma associated fibroblasts
(prostate cancer )
The metastatic cascade.
Schematic illustration
of the sequential steps
involved in the
hematogenous spread of
a tumor
Mechanisms of metastasis development within a primary
tumor. A nonmetastatic primary tumor is shown (light
blue) on the left side of all diagrams. Four models are
presented: A, Metastasis is caused by rare variant clones
that develop in the primary tumor; B, Metastasis is
caused by the gene expression pattern of most cells of
the primary tumor, referred to as a metastatic signature;
C, A combination of A and B, in which metastatic
variants appear in a tumor with a metastatic gene
signature; D, Metastasis development is greatly
influenced by the tumor stroma, which may regulate
angiogenesis, local invasiveness and resistance to
immune elimination, allowing cells of the primary
tumor, as in C, to become metastatic.
Alteration
TIMPs
TIMPs
Matrix metalloproteinase regulation. Four
mechanisms are shown: (1) regulation of
synthesis by growth factors or cytokines, (2)
inhibition of synthesis by corticosteroids or
TGF-β, (3) regulation of the activation of the
secreted but inactive precursors, and (4)
blockage of the enzymes by specific tissue
inhibitors of metalloproteinase (TIMPs).
(Modified from Matrisian LM: Metalloproteinases and their
inhibitors in matrix remodeling. Trends Genet 6:122,
1990, with permission from Elsevier Science.)
Cancer Stem Cells
(Tumor Initiating Cells T-IC's)
Predisposition to
Cancer
Geographic
And
Racial Factors
Environmental
and
Cultural Influences
Chronic Inflammation and Cancer
• Production of cytokines and reactive oxygen
species (ROS)
• Increase in pool of tissue
stem cells
The Fire Within
Biology of tumor growth
Biology of tumor growth. The left panel depicts
minimal estimates of tumor cell doublings that
precede the formation of a clinically detectable
tumor mass. It is evident that by the time a solid
tumor is detected, it has already completed a major
portion of its life cycle as measured by cell doublings.
The right panel illustrates clonal evolution of tumors
and generation of tumor cell heterogeneity. New
subclones arise from the descendants of the original
transformed cell, and with progressive growth the
tumor mass becomes enriched for those variants that
are more adept at evading host defenses and are
likely to be more aggressive.
(Adapted from Tannock IF: Biology of tumor growth. Hosp Pract
18:81, 1983.)