Biomedical Engineering Reference
In-Depth Information
mortality by 2% (2) per year, and progress in therapy has achieved cures for a
significant number of patients.
In the last two decades, the success of the reductionist program of research
has yielded unprecedented advances in our understanding of the basic mecha-
nisms of cancer formation at the molecular and cell biological levels (3). This
new knowledge enables us to begin to treat the more complex aspects of tumor
formation at the next level of organizational complexity in mammals: the tissue
level. Understanding the process of cancer formation and progression at the tis-
sue level is relevant because many of the medical and biological characteristics
of cancer depend on the organ or site where the tumor arises, in other words, the
tissue the cancer comes from.
The order necessary for normal tissue function results from the stability,
within homeostatic boundaries, of a complex network of interacting molecules
that control intra- and intercellular regulatory circuits. The structural and func-
tional integrity of the tissues is ensured by a compartmental organization (4).
Each compartment of differentiated cells is maintained by a set of stem cells
that, through asymmetrical division, ensure self-renewal and generate a prolif-
erative population that expands exponentially. For a normal tissue, we can de-
scribe the interactions of cells using concepts and terms not too distant from
those used in community ecology. The integrity of the tissue is guaranteed by
the cooperation of its individual units, formed by the clonal cell population de-
rived from a stem cell in charge of maintaining each unit. The entire tissue sys-
tem functions under a continuous and stable turnover only disturbed by
interaction with the environment and the process of aging. In the absence of
external disturbances, each cell is programmed to play out a developmental pro-
gram. In each tissue compartment the changes in form and function of the cells
follow a transformational mode. Each individual of the ensemble follows a pre-
determined trajectory of change, and the proportions of each constitutive ele-
ment of the ensemble remain constant. Mutations occur infrequently in stem
cells responsible for maintaining the integrity of tissue compartments, and they
are unlikely to be transmitted to the progeny, because normal cells are capable
of repairing genetic damage resulting from errors during DNA replication. In
addition, many mutations will result in deleterious effects and cause premature
cell death by apoptosis. Thus under normal conditions, given the lack of genetic
variation, selection is a weak force molding the populations that constitute a
mature adult tissue. Competition among somatic cells is avoided, but clonal
patches will increase in size when a neighboring clone fails and disappears.
In contrast, both tumor formation and tumor progression (the increase in
biological malignancy with time) can be envisioned as microevolutionary proc-
esses during which change occurs in a variational mode (see also preceding
chapter 6.1 by Pienta). Cancer is a genetic disease affecting somatic cells, and
the emergence of a tumor requires accumulation of several mutations in a single
cell. Mutations in oncogenes and tumor suppressor genes, including lack of
