Biomedical Engineering Reference
In-Depth Information
Chapter 8
Invasion Fronts
8.1 Biological Introduction
Solid tumors are thought to arise from small nodes of cells (which are typically
somatic stem cells, as recently suggest in [240]) that have undergone genetic
mutations and/or epigenetic alterations. They are able to escape from DNA
repair mechanisms and to cause abnormal growth regulatory mechanisms [7,
297], surviving and evolving even under extreme conditions, e.g., hypoxia and
acidosis [155]. Such primary malignant colonies go through a relatively simple,
avascular stage of growth, with nutrient and growth factor supply by diffusion
from the local microenvironment [7, 275, 401]. However, a further search of
available quantities of critical substrates results in a subsequent aggressive
phase, with the invasion of the surrounding tissue [7, 47]. In particular, as
reproduced in Figure 8.1, a part of the malignant mass remains densely packed,
while a number of isolated cells detach and begin to invade the neighboring
spaces. These individuals are less adhesive, highly mobile and metabolically
active, due to the fact that they experience a high level of chemical factors,
and are able to secrete an enhanced quantity of matrix degrading enzymes
(MDEs) [193, 379]. In particular, the production of proteolytic enzymes, such
as matrix metalloproteinases (MMPs), is essential during the invasive phase:
the dissolution of the ECM provides in fact both a space into which aggressive
cells can move and a gradient which can be used by the cells themselves
to direct their movement (i.e., haptotaxis); see [74, 286, 379]. The scattered
individuals, evading destruction by the immune system, may subsequently
enter the host bloodstream or lymphatics, extravasate at a distant site, and
establish secondary colonies with devastating consequences for the wellbeing
of the patient, as the likelihood of success of therapeutic interventions strongly
decreases [162, 324].
The invasiveness of a primary cancer mass can be therefore a quantifi-
able function of the altered biophysical characteristic of malignant cells, such
as their enhanced motility and metabolism and the downregulation in their
cell{cell adhesion, as well as of their aggressive interactions with the local
microenvironment, such as the enhanced consumption of available nutrients
and degradation of ECM proteins. A deep understanding of the regulatory
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