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(TNF)-related apoptosis-inducing ligand) it is common for some cells in a clonal
population to die while others survive − a striking divergence in cell fate. Among
cells that die, the time between TRAIL exposure and caspase activation is highly
variable. Imaging of sister cells expressing reporters of caspase activation and mito-
chondrial outer membrane permeabilization after exposure to TRAIL has shown that
naturally occurring differences in the levels or states of proteins regulating receptor-
mediated apoptosis are the primary causes of cell-to-cell variability in the timing and
probability of death in human cell lines (Spencer et al. 2009 ). Protein state is trans-
mitted from mother to daughter, giving rise to transient heritability in fate, but pro-
tein synthesis promotes rapid divergence so that sister cells soon become no more
similar to each other than pairs of cells chosen at random. These results have impli-
cations for understanding ‘fractional killing’ of tumor cells after exposure to chemo-
therapy and indicate that the genetic identity of a tumor cell is an incomplete predictor
for how it will respond to certain treatments. These fi ndings also offer an alternative
to the cancer stem cell hypothesis, which states that certain cancers survive standard
treatments because a population of tumor-specifi c stem cells evades chemotherapy
or radiation. This study, however, offers an alternative explanation, i.e. that certain
cells produce quantities of proteins purely through chance, which fundamentally
alter the cell’s response to treatment. This new insight will make it possible to design
anticancer treatments that are more effective than those currently available.
Proteomic Analysis of Tumor Biopsies to Predict
Response to Treatment
Protein analysis of malignant tissue and the discovery of protein signatures have
been used for assessing the stage of disease as well as their correlation with patient
survival. Protein profi les have been obtained from human gliomas of various grades
through direct analysis of tissue samples using matrix-assisted laser desorption ion-
ization mass spectrometry (MALDI-MS). Statistical algorithms applied to the MS
profi les from tissue sections can identify protein patterns that correlate with tumor
histology and patient survival. Protein patterns serve as an independent indicator of
patient survival. This molecular approach to monitoring gliomas can provide clini-
cally relevant information on tumor malignancy and is suitable for high-throughput
clinical screening.
Real-Time Apoptosis Monitoring
There is need for real-time monitoring of apoptosis because of the serious problems
that result from not knowing if and when anticancer therapy starts to work. For the
patient, receiving a therapy that is not effective means unnecessary suffering, both
from the tumor continuing to grow and any side effects that accompany the
10 Personalized Therapy of Cancer