Page 69 - 20dynamics of cancer

54 CHAPTER 3

include fibroblasts, immune cells, and blood-vessel cells, together form-
ing the stroma (Mueller and Fusenig 2004). Signaling between tumor
and stromal cells regulates many aspects of tissue growth and differen-
tiation. Progressive changes in tumor cells lead to secretion of various
stromal-modifying signals, often disrupting tissue homeostasis in a way
that mimics wound healing with enhanced angiogenesis, inflammatory
response, and activation of nearby cells to secrete additional growth
factors (Mueller and Fusenig 2004; Hu et al. 2005; Rubin 2005; Smalley
et al. 2005).
The extracellular matrix provides another barrier to tumor expansion
(Hotary et al. 2003; Yamada 2003). A network of protein and proteo-
glycan fibers forms a three-dimensional supporting mesh through most
solid tissues. That matrix helps to keep spatial order among the cells
and to limit uncontrolled expansion of a cellular clone. Developing tu-
mors and their nearby stroma frequently secrete proteases that break
down the extracellular matrix, disrupting tissue organization and pro-
viding an opportunity for clonal expansion of tumor cells (van Kempen
et al. 2003).

INVASIVENESS AND NEGLECT OF DEATH SIGNALS

Some tumors invade nearby tissues or migrate to distant sites. In
epithelial progression, tumor cells begin to move by breaking through
the basement membrane (Liotta and Kohn 2001). That membrane walls
off the epithelial layer from neighboring tissues. Tumor cells break the
basement membrane by secreting proteases and changing their cell ad-
hesion properties.
Distant migration requires transport through the blood or lymph sys-
tems. Most cells die during migration because they require the specific
signals of their native tissue to avoid triggering their apoptotic response.
To migrate successfully, cells must evolve to ignore this default death
response (Fidler 2003; Douma et al. 2004).
Few migrating cells survive and grow in foreign tissue. But tumors
send many colonists, and a few may succeed. To survive and grow in
foreign tissue, the colonists must avoid defenses that normally kill for-
eign cells, avoid repressive anti-growth signals, and acquire resources.
Migrating tumor cells often have high mutation rates or rapid genomic