Biomedical Engineering Reference
In-Depth Information
have been made by seeking after specific surface markers.
97,98
However, it
could be beneficial to use a ''magic shotgun'' that is selective toward more than
just one target to effect a heterogeneous population of cancer cells.
99
The heterogeneity in the environment and cell population results from the
molecular biology of cancer. The differences in cellular phenotype and states of
growth and quiescence are influenced by stochastic variations of protein
concentrations and interactions that lead to dynamics in molecular signaling,
some of which originate from environmental cues.
100
Furthermore, genomic
and epigenetic instability is characteristic of cancer cells.
101
These dynamic and
heterogeneous characteristics play a role in how cancer is able to resist
treatments.
102
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1.3.2.2 Multidrug Resistance
Tumor heterogeneity at the cellular level has a direct effect on multidrug
resistance. Mutations cause diversity in cell characteristics and that diversity
provides an opportunity to select for survival. Essentially, when a heterogen-
eous mixture of cells is treated with a drug, some will be able to resist the
treatment. Furthermore, with treatment in solid tumors, cells at the periphery
of the tumor often die off, leading to a smaller, yet more resistant, tumor mass.
The apparent increase in resistance in the core could be due to conditioning
from limited drug exposure, adaptations to survive in the already harsh
environment, or the cells being more resistant inherently—as is the case with
cancer stem-like cells.
Resistance comes from factors that range from the tumor environment down
to cellular changes and mechanisms involving DNA. As stated before, only
low amounts of drug are able to enter into the core of the tumor. Cancer cells
are more easily able to adopt drug resistance to a low dose. This is apparent
even in cultured cell lines, as drug resistant lines are made by adding low doses
of the drug to the growth medium.
103,104
Furthermore, the core of the tumor is
hypoxic and acidic and the cells have already adapted to survive to these harsh
conditions. Some of these adaptations and cellular mechanisms for resistance
are: detoxification via active efflux pumps, exocytosis, sequestration in acidic
vesicles, DNA repair, compensation in chemical pathways, triggering of
specific oncogenes, and even quiescence—as it is easy for a cancer cell to resist
the effects of doxorubicin or paclitaxel when it is not actively dividing.
105
As seen in Figure 1.5, cancer cells that are able to survive will be prepared to
resist future treatment, repopulate the tumor, and metastasize. If the cancer
relapses, more aggressive cell types have been selected and the prognosis for
the patient is poor.
The source of a cancerous tumor could be mutated stem cells or somatic cells
that have mutated to become stem-like. Initial treatment can lead to a
reduction of the cancer. Complete elimination is avoided with heterogeneous
expression of targeted antigen, or by incomplete distribution, or by innate
cellular resistance. Despite continued treatment, resistant cells will survive and
