3 The Cellular Microenvironment

and Metastases
Erinn B. Rankin, Janine Erler, and Amato J. Giaccia

SUMMARY O F K E Y
Metastases are responsible for more
than 90% of all cancer-related
deaths.
Gene mutations, the tumor
microenvironment, and host cells
drive the metastatic spread of tumor
cells.
Metastasis can be subdivided into
four steps: invasion, intravasation,
survival in circulation, and
extravasation.
Colonization of metastatic that can recapitulate the tumor from
tumor cells requires the ability to
P O I N T S
proliferate in a foreign tissue and
stimulate angiogenesis.
The formation of a premetastatic
niche is essential for the growth potential.
of extravasating metastatic tumor
cells.
Organ specificity of tumor
metastases is determined both by
blood flow and tissue-specific
factors.
Primary tumors possess stem cells
a single cell, and a subset of these
cancer stem cells may inherently
possess altered gene expression
changes with increased metastatic
Antimetastatic therapy will likely
require the targeted inhibition of
many pathways that control
proliferation, invasion, and
angiogenesis.

INTRODUCTION
Tumor metastasis is a highly inefficient process. It has been estimated
that less than 0.01% of tumor cells that enter the circulation develop
into metastases. Despite this inefficiency, metastases are responsible
for more than 90% of all cancer-related deaths. Metastasis selects for
highly aggressive tumor cells that acquire a number of cellular traits
that allow them to disseminate from their tissue of origin and estab-
lish tumor growth at distant sites. Recent studies have characterized
the molecular and phenotypic makeup of metastatic tumor cells.
Additionally, it is now appreciated that cellular and molecular con-
stituents of the tumor microenvironment also greatly affect metastatic
tumor progression. In this chapter, we will describe the cellular and
molecular traits driving tumor metastasis and discuss how the tumor
microenvironment influences this process. Most importantly, we will
discuss how this knowledge is translated into current and future
cancer therapies.
MECHANISMS OF METASTASIS
Hematogenous Metastasis
Most tumors metastasize through the bloodstream. Metastatic dis-
semination through the vasculature involves a series of distinct cel-
lular adaptations, including invasion and migration from the primary
tumor; intravasation into the vasculature; arrest and extravasation
from the vasculature into the distant organ; and proliferation and
survival into the new tissue microenvironment (Fig. 3-1). The acqui-
sition of these biological traits by tumor cells involves the coordina-
tion of both cellular intrinsic and extrinsic signals.
Invasion
Changes in Cell Adhesion
The first step of metastasis is invasion. Cells must undergo changes
in their cell-cell and cell-matrix adhesion interactions to dissociate
themselves from the tumor.1 Acquisition of an invasive phenotype
requires changes in expression of genes that control cell-cell adhesion,
as well as proteolytic degradation of the extracellular matrix (ECM).2
Cell-cell adhesions are mediated primarily by E-cadherin proteins
expressed at junctions between cells.3 Cadherins bind cells through
protein-protein interactions at their extracellular domains, whereas
their intracellular domains signal to catenins and the actin cytoskel-
eton. Changes in E-cadherin expression allow cells to detach from
their neighbors and begin their migratory route toward the circula-
tory or lymphatic system to seek out new terrain. Reduced expression
of E-cadherin is often observed in aggressive cancers through epigen-
etic silencing, proteosomal degradation, proteolytic cleavage, or
mutation. In fact, inactivating mutations of E-cadherin have been
shown to predispose patients to gastric cancer, implicating E-cadherin
as a tumor suppressor gene.1
Loss of E-cadherin is highly associated with epithelial to mesen-
chymal transition (EMT), a program that is essential for numerous
developmental processes. 3 The acquisition of the invasive phenotype
has many similarities to EMT, including loss of cell-cell adhesion
mediated by E-cadherin repression and an increase in cell mobility.
During EMT, a switch occurs from E-cadherin (an epithelial cell
marker) to N-cadherin expression (a mesenchymal cell marker),
which promotes cell-matrix adhesion instead of cell-cell adhesion.3
Several signal transduction pathways, such as the Ras-MAPK and
WNT pathways, have been shown to regulate EMT (Fig. 3-2). In

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